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**VMAC Meeting**

**January 31, 2005**

Facilitated by Dr. Arthur Craigmill, Chair

**Welcome/Background**

Dr. Stephen Sundlof 3

**Legal Framework**

Jennifer Gresock, Esq. 12

**FDA/CVM Adverse Event Reporting**

Dr. Margarita Brown 16

**ProHeart 6 ADEs/CVM**

Dr. Lynn Post 28

Dr. Margarita Brown 34

**ProHeart 6 ADEs/FDAH**

Dr. Rami Cobb 53

Dr. Larry Glickman 60

Dr. David Hustead 74

**Clarification of VMAC Questions**

Dr. Dan McChesney 96

**Open Public Hearing**

Aleta Sindelar, RN 128

**Committee Deliberations**

Dr. Arthur Craigmill 180

**Question One** 240

**Question Two** 259

**Meeting Adjourned**

Dr. Stephen Sundlof 279

KEYNOTE: "\-\--" denotes inaudible in the transcript.

"\*" denotes word was phonetically spelled.

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(8:10 a.m.)

**[Welcome/Background]{.underline}**

**Dr. Stephen Sundlof**

DR. SUNDLOF: Good morning, everyone, and welcome to the Veterinary
Medicine Advisory Committee. Today we are going to be discussing
ProHeart 6 and we have a full house here, and so it is very good to see
all these people here. Before we go ahead and start, Aleta Sindelar has
a few housekeeping issues to go over with you. So I am going to hand
over the microphone to Aleta.

MS. SINDELAR: Okay. Thank you. First, there is a conflict of interest
statement for the Advisory Committee to be read which covers the \-- any
perceptions or documentation of possible conflicts of interest. The
following announcement addresses the issue of interest with regard to
this meeting and is made part of the public record to preclude even the
appearance of a conflict of interest at this meeting on January 31^st^,
2005. Federal conflict of interest laws preclude the participation of
committee members and consultants in Advisory Committee meetings if they
have a conflict of interest unless a waiver from exclusion is granted by
the agency. The Associate Commissioner for External Relations FDA has
appointed Dr. Charles Bennett, Dr. John Glisson, Dr. Samuel Groseclose,
Dr. Michael Luster, Dr. C. Thomas Nelson, Dr. Michael Peterson, Dr. Gatz
Riddell, and Dr. Lauren Trepanier as temporary voting members for this
meeting.

Based on the submitted agenda for this meeting and a review of all
financial interests reported by the committee participants, it has been
determined that all interests in the firms regulated by the Center for
Veterinary Medicine which have been reported by the participants present
no potential for a conflict of interest at this meeting with the
following exceptions. Dr. John Glisson discloses consulting with the
sponsor; magnitude is less than 10,001. Dr. Katrina L. Mealey discloses
consulting with the competing firm; magnitude is less than \$10,001. She
discloses a grant with a competing firm; magnitude is less than 300,000.
Dr. Mealey discloses one speaking interest with a competing firm;
magnitude is less than \$5,001. And a speaking interest with a competing
firm under negotiation; magnitude is less than \$5,001. Dr. Mark G.
Papich discloses two consulting interests, both with competing firms and
both interest are less than 2,000 \-- excuse me, \$10,001 each. Dr.
Papich discloses two grants. Both are with a competing firm; both are
less than 100,000 each. Dr. Richard Sams discloses one consulting
interest with a sponsor under negotiation; magnitude is less than
\$10,001. Dr. Sams discloses one contract with the sponsor under
negotiation; magnitude is less than 100,000. He will be granted a
limited waiver and will not vote. In accordance with 18 USC 208(B)(3) a
waiver has been granted to Dr. John Glisson, Dr. Katrina L. Mealey, and
Dr. Mark G Papich. Under the terms of the waiver, Drs. Glisson, Mealey,
and Papich will be permitted to participate fully in discussions and
deliberations to accept the safety of the drug product voluntarily
recalled and make recommendations with regard to the agency's risk
management strategy. Dr. Richard A. Sams will be permitted to fully
participate in discussions to address the safety of the drug product
voluntarily recalled and make recommendations, but will not vote.

In the event that the discussions involve specific interests, products,
or firms not on the agenda for which FDA's participants have a financial
interest, the participants are aware of the need to exclude themselves
from such involvement, and their exclusion will be noted for the public
record. With respect to all other meeting participants, we ask in the
interest of fairness that they address any current or previous financial
involvement with any firm whose products they wish to comment on.

Two housekeeping notes. I would like to make sure everyone knows that
the parking is free, but there is a pass code that you will need to
punch in. If you are in the garage, please press the pound key and 1204.
That is 1204. If you are not in the garage, please do not press the
pound key. Number two, we have a very busy schedule ahead of us. We
would appreciate if everyone sticks to their time limit. Thank you very
much. Steve, thank you.

DR. SUNDLOF: Thank you, Aleta. Okay. We will begin with a series of
presentations. Let me just go first of all and introduce the people who
are sitting at the front. I am Steve Sundlof. Sitting right to my left
is Jenny Gresock. She is with the Office of Chief Counsel of the Food
and Drug Administration. Margarita Brown is the veterinary medical
officer who reviews the adverse drug event reports that we are going to
be talking about extensively today, and Dr. Lynn Post who is the
Director of the Center \-- I'm sorry, the Office of \-- the Division of
Surveillance. It is tough living in a bureaucracy.

(Laughter.)

DR. SUNDLOF: And the Office of Surveillance is the office that conducts
post-market approval studies like the ones we are going to be talking
about today. So those are the folks in the front panel here.

(Slide.)

The purpose of today's meeting is to review the safety of ProHeart 6,
which is a heartworm preventive drug approved for use in dogs. The
sponsor, Fort Dodge, has voluntarily recalled ProHeart 6 from the market
at the urging of the Center for Veterinary Medicine because of reports
from veterinarians, pet owners and others filed through the Center's
adverse drug experience reporting system. They raised questions about
the product safety. So in a few minutes you will be hearing a
description of the ADE system, and so let me just define ADE right now.
That is adverse drug event or adverse drug experience. We are going to
primarily refer to them as adverse drug events today. So ADE is adverse
drug events, and we will be discussing those extensive as they pertain
to ProHeart 6 today and to some other similar heartworm preventive
products.

(Slide.)

I want to introduce the members of the panel here today, the Advisory
Committee meeting, and so let me go through the list and tell you a
little bit about these folks. Our chairman is Dr. Arthur Craigmill. He
is an expert in veterinary toxicology and represents that discipline on
the VMAC in addition to his role as chairman, and we welcome you, Art,
as the new chair. Also today with us is Susanne Aref, but I don't see
her here, so maybe she didn't make it. Susanne Aref is our expert in
biostatistics at Virginia Polytechnic Institute and State University.
Dr. Corrie Brown is with us today. She is an expert in pathology with
the University of Georgia. She made it up from the south, but apparently
Skip Jack didn't. So Sherman Skip Jack, he is our expert in minor use in
minor species. Maybe he will be able to get here later today. I don't
know. Representing the consumers is Greg Jaffe, and Greg is with the
Center for Science and Public Interest. Dr. John McGlone, there's John,
is an animal science expert and does represent animal science as a
discipline on the VMAC. Dr. Katrina Mealey is an expert in companion
animal medicine and represents that discipline. She is from Washington
State University. Lisa Nolan is an expert in veterinary microbiology
with Iowa State University. Mark Papich is an expert in pharmacology
with North Carolina State University, and Dr. Richard Sams is an expert
in chemistry with the Ohio State University.

In addition to the regular members we also have some consultants with us
today because of the nature of the subject. Really we are going to be
going through a number of various disciplines. So we have with us today
Charles Bennett who is an expert in pharmaco-epidemiology with the
Feinberg School of Medicine and with the Midwest Center for Health
Service Policy Research. Dr. John Glisson is an expert in Avian Medicine
with the University of Georgia, and I think like Dr. Jack was unable to
get out of the Atlanta. Dr. Tom Nelson is a heartworm expert and
President of the American Heartworm Association \-- or, I'm sorry,
American Heartworm Society and with the Animal Medical Center in
Anniston, Alabama. Dr. Michael Peterson is an expert in zoonotic and
infectious disease epidemiology with the Office of the Assistant
Secretary of Defense. Dr. Gatz Riddell is an expert in food animals,
food animal medicine, with Auburn University, and Dr. Lauren Trepanier
is an expert in dramatic differences in drug metabolism with the
University of Wisconsin. So that concludes the list of experts who will
be helping us with this, with the decisions that we will be making
today. Oops. Should have done that sooner.

(Slide.)

Just to talk a little bit about CVM's mission, and this is taken
directly from our mission statement. It is part of our mission
statement. Not the whole thing, but it says \"We foster public and
animal health by approving safe and effective products for animals and
by enforcing other applicable provisions of the Federal Food, Drug, and
Cosmetic Act and other authorities.\" So a lot of the things that we
will be talking about today tie directly back to this mission. Not only
our mission to protect animal health, but also how we enforce those
responsibilities through the various legal channels.

(Slide.)

Our responsibility to determine a drug safety does not end after the
drug is approved. We have an extensive pre-market review process that is
intended to try and pick up any abnormalities or adverse events prior to
the approval, and we deal with those in the pre-approval stage. But we
can't always pick up all of them, as folks are well aware, and as a
result there are some \-- there are adverse events that occur after the
approval that were not anticipated during the pre-approval stage. So we
have an extensive post-approval surveillance system to try and pick up
these unintended events. In this case we received several adverse events
regarding this particular product, ProHeart 6, and so we will be
discussing our reasons for taking the positions that we have during the
rest of the day.

(Slide.)

Okay. The information we collect through our adverse drug event system
is carefully and thoroughly analyzed. We use an established review
process for ADEs that provides standards and gives an ordered and
structured system that can be used to analyze information and make
unbiased decisions about product safety. The system CVM uses to analyze
these adverse drug events is much the same as that that is used in our
human counterpart, the Center for Drug Evaluation and Research; and in
just a little while we will provide you with a description of how that
system works, how the causality grading system is set up, et cetera.

(Slide.)

Due to our concerns from the ADE reviews, we approached Fort Dodge
Animal Health and at first asked for label changes, which Fort Dodge
changed. So there were label changes. Generally we asked the company to
change the label if there are adverse events that were not originally
listed but that appeared on post-market evaluation. Oftentimes that
yields a reduction in the number of adverse drug events and has a
substantive effect in improving the safety. In this case, however, even
after the label changes went into effect we did not see a subsequent
reduction in the number of adverse drug events. So after studying this
very thoroughly the Center took the position that in light of the fact
that the adverse events were not decreasing we asked the company to
voluntarily recall the product, which they did.

(Slide.)

So the reasons for this VMAC meeting is in the spirit of openness and
transparency. We want to present our case in a public forum, which is
this Veterinary Medicine Advisory Committee meeting. This is an
important product obviously to veterinarians and to the company. We
think that it deserves a very thorough discussion, and we want to be
sure that all the information gets thoroughly reviewed not only by CVM,
but by independent specialists on the Veterinary Medicine Advisory
Committee so we can get their opinions and benefit from their
experience. This is a fairly common use of an advisory committee, and
this is one of the reasons that we have these advisory committees, to
bring in as much outside expert opinion into the decisions that CVM
makes as possible.

(Slide.)

So in conclusion, CVM has the ultimate responsibility for determining
the safety of animal drugs. The amount of information that we can get
about products through adverse event reports is often broad and can be
complex and affected by confounding factors. We appreciate the advice
and insight of the members of the VMAC and we hope you will help us to
be sure that we are making the right decisions. With that, I will close
my remarks and turn the podium over to Jenny Gresock.

**[Legal Framework]{.underline}**

**Jennifer Gresock, Esquire**

MS. GRESOCK: Thank you, Dr. Sundlof. My goal today is to provide a brief
look at the legal background against which CVM operates.

(Slide.)

The Center for Veterinary Medicine has the regulatory responsibility for
insuring the safety of marketed animal drug products through an approval
process. Drug approval depends on a showing of effectiveness, but also
of safety, and today our focus is on safety. Section 512 of the Act
details the requirements for new animal drug approval.

(Slide.)

When submitting an application for a new animal drug product the
applicant must show that the product is both safe and effective for its
intended use. For drugs used in food animals an evaluation of a drug's
safety includes focusing for instance on human food safety. For
companion animals target animal safety is the primary concern.

(Slide.)

Under the Act, an applicant must submit as part of the new animal drug
application full reports of investigations which have been made to show
whether or not a drug is safe and effective for use. With regard to
safety, an application may be refused if it doesn't contain these full
reports and adequate tests by all methods reasonably applicable to show
whether the drug can be safely used as suggested in the labeling
proposed by the applicant.

(Slide.)

Note that the attention to labeling is a key part of the process of
approving new animal drugs. The labeling for an approved animal drug
product should indicate how to use the product in a safe and effective
manner. The safe use of a drug may for instance require caution
statements that alert the users of the product to particular species in
which the drug should not be used, or the labeling may note particular
effects that a veterinarian or pet owner should be aware of when using
the product. In short, the labeling of an approved animal drug product
must provide adequate directions for use or it is misbranded under the
Act, and that means that FDA can take legal action against it. The
labeling is extremely important.

(Slide.)

After a drug has been approved, CVM monitors the safety and
effectiveness of the drug as it is used more widely. The law requires
drug sponsors to establish and maintain records and to make reports to
FDA of data relating to experience or other date and information
received or otherwise obtained by the sponsor. Specifically the
regulations require drug sponsors to report adverse drug experiences.

(Slide.)

What is an adverse drug experience? Note that it is any adverse event,
whether or not considered drug related and regardless of whether or not
the drug was used in a manner consistent with its labeling. This
includes both ineffectiveness reports as well as events related to
safety of the product. The regulations have special reporting
requirements for adverse drug experiences that are both serious and
unexpected.

(Slide.)

What is a serious adverse drug experience then? This slide highlights
the types of experience that are categorized as serious. Note that they
include those that are fatal or life threatening, but also those that
require professional intervention.

(Slide.)

What then is an unexpected adverse drug experience? The key here is that
an unexpected adverse drug experience is not listed on the current
labeling for the drug or an unexpected adverse event may be much more
severe or specific than a related event that is listed on the labeling.

(Slide.)

I have highlighted serious unexpected adverse events because those are
the ones that must be reported by sponsors within 15 working days of
receiving a report from a consumer or veterinarian.

(Slide.)

Other adverse drug experiences, those that do not qualify as serious and
unexpected, must be reported in periodic drug experience reports. These
are submitted every six months for the first two years after approval
and then yearly thereafter. Note that consumers have no legal obligation
to report adverse drug experiences. Only the drug sponsor has such an
obligation.

(Slide.)

What happens when a drug product raises safety concerns? FDA has a
number of different things that it can do. In some cases, FDA can
request a recall under the regulations. Alternatively, the firm may
initiate a recall also under the regulations. Short of that, FDA would
first try to do smaller steps. For instance, working with the sponsor on
labeling and/or manufacturing changes. Fort Dodge for instance has
worked closely with CVM on several labeling changes intended to make the
drug safe for use. If none of these things work, FDA may issue an order
withdrawing the approval of the product. Such an order would be issued
based on certain findings by the Secretary. Such a finding may be that
experience or scientific data show that the drug is unsafe for use under
the conditions of use upon which the application was approved. That
would be one of the possible grounds. Or such a finding might be that
new evidence not contained in the application or not available to the
Secretary until after the application was approved evaluated together
with evidence available when it was approved show the drug is not shown
to be safe for use under the conditions for which it was approved. These
findings would follow notice to the sponsor and an opportunity for a
hearing. This is the legal framework within which CVM operates.

**[FDA/CVM Adverse Event Reporting]{.underline}**

**Dr. Margarita Brown**

DR. BROWN: Good morning, everybody. I am pleased to have the opportunity
to share with you our adverse drug event procedure here at FDA Center
for Veterinary Medicine. I'm one of the four veterinarians initially
recruited by CVM for the sole purpose of reviewing these adverse drug
events and entering them into our database. We now have seven
veterinarians working at this job part time. The rest of the week six of
these seven practice veterinary medicine here in Maryland and in
Virginia.

(Slide.)

As you can see, we all have strong clinical backgrounds, which is really
critical in understanding and evaluating these reports. Every one of us
knows what it is like to be the person responsible for prescribing and
administering any of these medications, and we also know the many
differentials that must be considered when things start to go wrong.

(Slide.)

Our job is to review and evaluate the drug events that are sent to our
office from the drug sponsors as well as from veterinarians and pet
owners. We do this because there are inherent limitations in the
pre-approval process, and those can't guarantee then the absolute safety
and effectiveness of the approved veterinary drugs.

(Slide.)

Now recognizing that we represent the clinical approaches of at least
five different veterinary schools, it is very important that we have a
way of making our review process objective. We use the Modified Kramer
System. It's a good tool for promoting the consistent application of the
same set of standards, regardless of personal opinion. We don't just
grab a causality association out of the air. We have to get there the
same way each time. There are six axes or criteria that are used. The
first is previous experience. What is already known about this drug and
its possible reactions? The second is an alternative etiologic
candidate. That is, is there something else that could be contributing
or causing this event? The third is timing. Is this a consistent timing
to happen with this type of reaction in this type of patient? The fourth
is, is there evidence of an overdose? The fifth is dechallenge, which is
what happens when the drug is removed from the system; and the sixth is
rechallenge, what happens when the drug is reintroduced.

(Slide.)

When we apply the algorithm to these events in the adverse reports we
add up the scores to arrive at a causality assessment score. Here are
the interpretations of the ranges. Remotely drug related are those with
the negative numbers, -1 to -6. Those that are possibly drug related are
0 to +2. Probably drug related are +3 to +5, and definitely drug related
+6 to +7. For those of you who are familiar with our website where we
post monthly the results of the causality assessment scores for our
different drug events, you will know that the only scores and the only
signs that show up on that website are those that are in the positive
range. That is zero and higher. None of those with negative numbers are
included in that analysis.

(Slide.)

Now when we get an adverse drug event we start by pulling up the label
for that drug. We look at the species and the dose labeled for its use.
We look at the labeled adverse events that are known to occur. We look
at our database to see if similar reactions have been reported. We look
at safety studies in the Freedom of Information Summary to see what kind
of leeway has be documented before adverse events are precipitated at
higher doses. We look at the pharmacodynamics to understand how the drug
is processed in the body and when adverse events might be expected to
occur. We can also refer to published articles in textbooks and
journals. What we don't do is just think, \"Well, you know, it seems
like that could happen,\" and go on the strength of our personal
instincts. We have to use factual information.

Now if this is a newly-marketed drug we might not have a lot of
information to work with as far as previous reactions are concerned. In
that kind of instance we put our heads together, we discuss the
information we do have, and we do our best to standardize the issues
such as timing for labeled reactions. For reactions that are not
labeled, the best we can do is to see if they show up at a time when the
drug is at peak levels in the body.

(Slide.)

Okay. Let's take a look at a sample adverse drug event and apply the
Modified Kramer Algorithm to it. So consider that we have a
four-year-old mixed breed neutered dog. He comes into his veterinarian
for his wellness care. He is good health on physical exam. He has a
negative heartworm test. He is given his ProHeart 6 injection at the
labeled dose, seems to be fine, but four days later he starts vomiting.
So first I need to find out if the adverse event, vomiting, could be an
expected reaction.

(Slide.)

So let's look at ProHeart 6\'s label. The labeled adverse events when it
was first approved were vomiting, diarrhea, listlessness, weight loss,
seizures, injection site reaction such as itching or swelling, and
fever. Okay. This complaint is for vomiting, and it is on the label.

(Slide.)

So I can clearly give this a plus one in the first axis of the
algorithm, that for previous experience. It is generally recognized to
occur in this species at this dose. It's on the label.

(Slide.)

Well, how about the second axis for alternative etiologic candidate? Is
there absolutely nothing else that could cause this reaction? Might we
expect this sort of reaction to occur spontaneously in this type of
patient? Are any other drugs being given concurrently that can cause the
same reaction? Is there a preexisting condition? You will notice that we
need very firm evidence here to say that there is really no other
candidate other than the administration of the drug. Often the strongest
score we can give here is a zero. It might occur spontaneously or there
might be an alternative candidate, but not a good one.

(Slide.)

We give it enough data to rule out the possibility of a contributing
factor. For example with vomiting. Well, have there been changes in the
diet? Has this animal been thoroughly checked for parasites? Is there a
history of vomiting in the past? Have blood values been checked and
found normal?

(Slide.)

Now sometimes there has been a good physical exam, and excellent medical
history and work-up are provided. In serious instances if we don't have
that information we might call the sponsor or the reporting veterinarian
for follow-up information. If we get that kind of complete information
we might be able to score a +2 on that second axis. There is no good
reason other than administration of the drug for the reaction to have
occurred.

(Slide.)

But here in the real world I would like to represent a typical report
and say we have no known dietary changes. We have one negative stool
sample for parasites. There is no blood work. We can't really say for
sure that something else is going on or isn't going on. We have to put a
zero at that second position.

(Slide.)

The third component of the algorithm is timing. Now we know from the
pre-approval studies that PH 6 blood levels peak at seven to 14 days
after injection. So the complaint is one of vomiting that started eight
days after injection. I'm clearly able to give this a +1 at the third
line for timing. It is consistent and expected.

(Slide.)

Now let's look at overdose. The way this is worded if I want to put a +1
in the position for overdose I need to know that this reaction is
expected to occur in the species at this elevated dose. We will say we
have safety studies showing that the drug was safely administered at
three times and five times the regular dose. If there was a slightly
highly dose given, but it is within that three-times to five-times
range, then we cannot score anything stronger than a zero at this point
in the algorithm. We are required to say that technically it was an
overdose because it was higher than the approved label dose, but we do
not score it as an overdose.

And let me add that we don't often score overdose for ProHeart 6 because
it is given by medical professionals, either veterinarians or veterinary
health technicians. It is not like you have the situation where the
husband comes home early, he gives the dog its pill, then he rushes off
to take the kids to their soccer game and say an hour later the wife
gets home. Oh, she dutifully remembers to give their dog their heartworm
pill, and the dog has wound up with a double dose right in that instant.
Or sometimes some of these medications are so delicious that the dogs
will go ahead and gobble up a whole bottle full of them all by
themselves. We don't usually see that happen with an injectable.

(Slide.)

Dechallenges is part of the algorithm, another one that doesn't really
apply to ProHeart 6 because it refers to what happens when the drug is
stopped, when it is removed from the system, or when its levels are
reduced by decreasing the dose. With a six-month injectable, the drug
stays in the animal's body for all that time. So it's difficult to say
that when the vomiting stops in three weeks it is because the drug is no
longer there. It is not like stopping a pill and seeing the vomiting
stop in a few days. We can really only give this a zero in the
dechallenge axis. Dechallenge is difficult, inappropriate, or impossible
to assess.

(Slide.)

Rechallenge refers to what happens when the drug

is given again. This again usually gets a zero in the ProHeart 6
reports. Well, there could be some instances where neither the owner nor
the veterinarian suspects that the vomiting was caused by the injection
until the same thing happens when the drug is given six months later.
But unless that kind of follow-up information is given, the score here
usually remains a zero for no rechallenge attempted. Again, compare this
to seeing the vomiting occur several hours after every time a pill is
given.

(Slide.)

So when we add up the scores assigned for this report of vomiting, which
is on the label and happens during the time of peak concentration in the
body, the strongest score we can give adds up to a +2, possibly drug
related. I think you can see that usually this scoring system gives the
benefit of the doubt to the drug. Now let's take a look at what happens
with an event that is not on the label but starts showing up in the
post-approval marketing, a complaint like anaphylaxis.

(Slide.)

Characterized by such things as sudden profuse vomiting and diarrhea,
swollen head or face, hives, pale mucus membranes, or collapse.

(Slide.)

In many complaints as in this example, ProHeart 6 was given along with
routine vaccinations. So here you have a three-year-old small-breed dog.
Again she comes in for her wellness visit to her veterinarian and is in
good health on her physical exam. She has a negative heartworm test. She
gets her ProHeart 6 injection at the label dose along with her annual
distemper vaccination, and two hours later she breaks out in hives, her
face swells up, and she collapses.

(Slide.)

Now because this reaction was not on the original label or in the
Freedom of Information studies, we could only give it a zero in that
first position for previous experience. How about an alternative
candidate? Vaccinations are certainly known causes of anaphylactoid
reactions. So we have to give a -1 score at that second axis to
accommodate for the vaccination. In the third axis, timing, this was
very closely associated with the injections and well within the time
frame for this type of reaction. So a +1 can be assigned there. The
regular dose was given, so this dose stays zero at overdose. Dechallenge
and rechallenge not applicable in these reports, zero for each of those.
So adding up the overall score we get a zero. That is possibly drug
related.

(Slide.)

Now in some reports vaccines were not given at the same time, and
neither was anything else such as a penicillin injection or a cortisone
injection. We would put a zero then at that second position for
alternative etiologic candidate, bringing up the total score to a +1,
still possibly drug related. Such a large number of these types of
reactions were reported that the label was changed in June of 2002 to
include anaphylactoid reactions as adverse events. So we can now put a
+1 at that first position for previous experience. Some of these dogs
were closely observed after their injections, and we were thus able to
put a +2 in that second position for no alternative etiologic candidate
if the dog were kept inside and observed after the injection and insect
exposure was unlikely. We did not have a circumstances where a dog had
an anaphylactoid reaction and then was given a second dose of ProHeart
6. Again, overdose, dechallenge and rechallenge remain at zero. So a +4,
probably drug related, is the highest score that could be assigned to
many of these ProHeart 6 reports, and that demanded very complete
reporting. No other medications administered, a patient closely
monitored after administration to reach that score.

Now of course in many other circumstances you don't have a dog that is
closely monitored after these injections. Many people, they would just
take their dog home and let him outside in the yard, and in that kind of
circumstance in that second axis for alternative candidate we have to
leave it at a zero. So for those again the highest score we could reach
would be a +2, possibly drug related.

(Slide.)

So this level of information could rarely be provided for other
complaints of illness, even if labeled and expected, such as the example
of the vomiting dog I gave previously, and in addition we must keep in
mind that these three components of the Modified Kramer Algorithm do not
really apply to ProHeart 6. That is overdose since it is given by a
health professional, dechallenge because the drug remains in the body,
rechallenge because the drug is rarely given again if a reaction was
recognized after the first administration. So most of these complaints
can only be scored as possibly drug related, even if they are expected
events that begin while ProHeart 6 is exerting its peak effect in the
body. I hope this review of our scoring system will serve as a basis for
understanding the rest of today's presentations. Thank you.

MS. SINDELAR: We are going to proceed with the agenda since we are
moving along so well with Dr. Post.

**[ProHeart 6 ADEs/CVM]{.underline}**

**Dr. Lynn Post**

DR. POST: Good morning. I am going to give an overview of the ProHeart 6
adverse drug events.

(Slide.)

The evaluation of adverse drug events falls under observational studies.
In general, the advantages of observational studies are a larger and
more diverse population and under actual conditions of use. The
population at risk has differences in diet, genetics, breed, age,
environment, and so on. In a diverse population there are many
confounding factors, such as preexisting disease and concomitant
medications. It is the variation in the population that makes it
difficult to define a control group.

(Slide.)

Reporting rate is defined as the number of adverse drug events, the
numerator, divided by the number of exposed patients, the denominator,
over time. The ADE reporting rate is not an incidence rate for two
reasons. First, ADEs are under-reported by the clinician because of such
things as the adverse drug event may not be connected to the drug, there
may be fear of litigation, just more paperwork, and the clinician wishes
to protect the client's privacy.

(Slide.)

Second, accurate data on the number of exposed patients, the
denominator, is often lacking. It is only a guestimate.

(Slide.)

A reporting rate compared to the background incidents may provide a
signal that there is a problem with a product. This is expected. But
what happens if the reporting rate falls below background? Well, this
does not prove that there is not an increased risk of the adverse drug
event. The signal could still be valid. Furthermore, spontaneous ADE
reports give uncertain numerators due to under-reporting with no
denominator at all. The use of denominators only serves to compound the
uncertainty of the numerator. Therefore, CVM has not used denominators
in this presentation.

(Slide.)

Okay. Now I will go over a little of the pre-approval history. ProHeart
6 was approved in June of 2001. The laboratory studies revealed no
serious adverse drug events in healthy dogs, but this does not prove
that or mean that there will no adverse drug events in the post-approval
period. It only means that no adverse drug events were found in the
pre-approval studies. Clinical field studies revealed several adverse
drug reactions of vomiting, diarrhea, listlessness, weight loss,
injection site pruritus, itching, and increased body temperature. In
clinical field studies ProHeart 6 was used safely in conjunction with a
variety of veterinary products, including vaccines.

(Slide.)

In the clinical field trials there were three deaths which resulted in
the following precaution statement on the label: Use with caution in
sick, debilitated, or underweight animals.

(Slide.)

The ProHeart 6 active ingredient, moxidectin, is also a macrocyclic
lactone. Neurotoxic science for macrocyclic lactones may include
seizures or convulsions. Seizures have been added to the post-approval
safety information on several labels.

(Slide.)

There have been three label changes since product launch in June, 2002.
Anaphylaxis/anaphylactoid reactions, depression, lethargy, urticaria \--
that's hives \-- and head and facial edema were added to the label. In
November of 2002, cardiopulmonary signs associated with the
administration of the product in heartworm-positive dogs. ProHeart 6 was
originally approved as safe in heartworm-positive dogs.

(Slide.)

The third label change was in July of 2003, and a client information
sheet and the phrase \"and rare reports of death\" was added to the
label. Two \"Dear Doctor\" letters were sent out by the sponsor
describing the three label changes, on in June, 2002, and the other in
June, 2003.

(Slide.)

The annual number of initial ProHeart 6 adverse study reports has not
appreciably decreased. I am talking about the column under initial
reports.

(Slide.)

The annual reports are further broken down by initial, follow-up, and
total ADE reports. That initial is in red, follow-up is in black, and
total is in green, and the X axis is calendar year and quarter. The
reporting pattern shows a peak frequency in each of the second quarters
corresponding with heartworm prevention season. Notice that the
frequency has not appreciably decreased since product launch to
September 1^st^, 2004. The manufacturing changes indicated by an arrow
in the third quarter of 2002, and the residual solvents were removed
from the formulation. The minimal residual solvent lots were in use by
the first quarter of 2004, the arrow marked MRS lots. Despite the
manufacturing change, again there has been no appreciable decrease in
frequency as of September 1^st^, 2004.

(Slide.)

Of the nearly 22,000 assessments for all the clinical manifestations,
more than 19,000 of them, of the clinical manifestations, have a
positive causality of possible, probably, and definite. Then 32 reports
were categorized as definitely drug related, and all had causality
assessment scores of +6 for heartworm ineffect. The top row marked
definitely drug related.

(Slide.)

Time of onset refers to the duration between administration of ProHeart
6 and observation of clinical manifestation. All clinical manifestations
had a positive causality assessment represented in this slide.
Approximately one-half of the clinical manifestations were with
concomitants. That is vaccines and drugs. Approximately one-third of the
clinical manifestations were without concomitants, and approximately
one-sixth were of unknown concomitant status. The majority of the
clinical manifestations, over 15,000 of them, occur in zero to 14 days.

(Slide.)

Time of onset coincides with peak serum concentrations of moxidectin
from seven to 14 days.

(Slide.)

Clinical manifestations zero to 14 days.

(Slide.)

Peak serum concentrations of moxidectin seven to 14 days.

(Slide.)

Numbers of dogs with reported ADEs. The website numbers will be larger
because of extra-label use. The ADEs on the website are listed by
species and active ingredient, so a product labeled for a horse could
end up under a dog. As you can see, we get a lot of adverse drug event
reports for heartworm preventatives, including reports of
ineffectiveness. Ineffectiveness seems to involve the entire class of
macrocyclic lactones, and we addressed this concern of ineffectiveness
at the American Heartworm Society Meeting in July of 2004. All of the
products have ineffects for heartworms, but depending on the label
indications one or more of the heartworm preventatives have ineffects
for hookworms, roundworms, whipworms, fleas, ticks, and mites.
Selamectin since it is applied topically also includes a lot of
application site reactions, things like local hair loss. CVM worked with
the sponsor to conduct post-approval studies and implement an
educational program for selamectin ADEs. That would include ineffects.
As a result, ADEs decreased in frequency and severity.

(Slide.)

But when we addressed the frequency of series adverse drug events such
as death, you can see that there are more assessments of death
associated with ProHeart 6 compared to all the monthly heartworm
preventatives combined. Dr. Brown will now outline some of these serious
events in more detail. Thank you very much.

**[ProHeart 6 ADEs/CVM]{.underline}**

**Dr. Margarita Brown**

DR. BROWN: So Dr. Post has just given you an overview of ProHeart 6. Let
me now take you through some of our specific concerns. Let me move this
back up until we get there. You remember that this is a spontaneous
reporting system, meaning that someone has to take the time and effort
to fill out a report. Large numbers of reports in relatively young,
healthy dogs can be what we call a signal that something is going on.
Now if we are talking about reports of side effects that are simply
upsetting or inconvenient we might not be so concerned. I am not going
to waste your time with those. Instead let's take a look at some of the
serious reports that have been submitted for the marketed heartworm
preventatives other than the complaint of ineffectiveness. Now for all
the tables that follow I am including only data for events with the
highest-ranking morbidity and mortality with a causality assessment
score of zero or higher. That is possibly, probably, or definitely drug
related.

(Slide.)

Now I know you were all paying close attention during my earlier
description of the Modified Kramer Algorithm, but just as a quick
reminder, we use these six axes to arrive at the causality assessment
score for each clinical manifestation in the adverse drug event reports
that we receive. There are seven different reviewers, and we apply the
same criteria to all the adverse drug report events sent to us.

(Slide.)

We use these interpretations for each score that is reached, and I am
presenting only information that falls in the category of possibly,
probably, or definitely drug related, and that is a score of zero or
above. I think every pet owner's worst fear is death, so let's look at
that first.

(Slide.)

This table shows you that between the approval of ProHeart 6 in June,
2001, and its voluntary recall in September of 2004, there were more
than twice as many deaths reported among dogs that received ProHeart 6
\-- that is 485

\-- than for all the other heartworm preventatives combined \-- that is
219 \-- even though ProHeart 6 sales represent approximately 24 percent
of the market.

(Slide.)

One of our foremost concerns has been the number of anaphylactoid
reactions associated with the use of ProHeart6, and as you know those
refer to sudden shock events, swelling of the head and face, sudden
profuse vomiting and diarrhea, even death. As you can see, there are
almost 20 times the number of such events associated with ProHeart 6,
1,820, than for all the other heartworm preventatives combined, 97.

(Slide.)

These events are occurring very shortly after administration of ProHeart
6. This shows the distribution of the onset times for these
anaphylactoid reactions. You can see that almost all of them, 80 percent
of them, occur within the first three hours. Remember these are dogs
that came into their veterinarian for preventative care. Most of them
were examined by their veterinarian and judged to be in good health,
good physical condition, before ProHeart 6 was given.

(Slide.)

For these 1,820 episodes of anaphylactoid reactions, there reporting
veterinarians indicated that at the time of ProHeart 6 administration
the health status was good in 1,741 of them, fair in 69, poor in three,
and unknown in seven; 54 of these dogs died.

(Slide.)

Some of these dogs had at least one vaccination given at the same time
as ProHeart 6 injection since they were at the veterinarian for
preventive care, or they might have been given some other drug such as
cortisone or antibiotic. The label clearly states in well-controlled
clinical studies ProHeart 6 was safely used in conjunction with a
variety of veterinary products, including vaccines,

anthelmintics, anti-parasitics, antibiotics, analgesics, steroids,
non-steroidal anti-inflammatory drugs or NSAIDS, anesthetics, and flea
control products. In 1,816 anaphylactoid episodes, dogs did not have any
concomitant drug or vaccine given. In 731 episodes they did have a
concomitant drug or vaccine, and the concomitant status is unknown for
the dogs in those 273 episodes.

(Slide.)

Another category with a lot of reported reactions concerns convulsions
or seizures. These may be fairly minor or occur only once, or they may
be so severe and protracted that the dog requires ongoing medication or
even dies. Convulsions are a known possible side effect with the class
of drugs it is used for, all the monthly heartworm preventatives and
ProHeart 6, and convulsions or seizures are on the label for each of
them. As you can see, each of the marketed heartworm preventatives
except for the ProHeart or moxidectin tablets, which are not extensively
used here in the United States, has more than 100 assessments for
convulsions since the time of the approval until September of 2004. But
ProHeart 6 accounts for more than half or 378 of the 630 for all the
rest of them combined.

(Slide.)

Approximately half of these convulsions occurred within three days after
the administration of ProHeart 6. As you can see, the distribution of
the onset times falls well within the time of rising or peak levels of
ProHeart 6 in the body. That is seven to 14 days.

(Slide.)

For these 378 episodes of the convulsions, the reporting veterinarians
indicated that at the time of ProHeart 6 administration the health
status of the dogs was good in 302 of them, fair in 64, poor in seven,
and unknown in the remaining five; 61 of these dogs died.

(Slide.)

In 87 episodes, dogs did not have concomitant drugs or vaccines, and in
215 episodes they did. The concomitant status for dogs in the 76
episodes is not known.

(Slide.)

Let's look at liver problems next. There are many ways that liver
problems can be manifested or diagnosed, so I have chosen to use the
most specific markers in our database; elevations in an enzyme found in
the blood called SGPT/ALT, and lesions found by pathologists on
examination of biopsies of the liver or in the livers from dogs that
died. Here again you see that the number of SGPT/ALT elevations and
liver lesions reported for ProHeart 6 since in the first three years of
its approval, at 192 and 65, surpass those reported for all the other
marketed heartworm preventatives combined since 1987. That is 145 and
30.

(Slide.)

For the 192 SGPT/ALT elevations the reporting veterinarians indicated
that at the time of Proheart 6 administration the health status of the
dogs was good in 149 of them, fair in 36, poor in six, and unknown in
one; 38 of these dogs died. Among the 65 dogs with liver lesions the
reporting veterinarian said that at the time of administration the
health status of these dogs was good in 50 of those 65, fair in 13, and
unknown in two; 47 of these dogs died.

(Slide.)

Of the dogs with SGPT/ALT elevations, 50 of them did not receive a
concomitant drug or vaccination, 112 of them did, and the concomitant
status for these 30 is unknown. Of the dogs with liver lesions, 13 did
not have concomitant drugs or vaccines and 44 had concomitance. The
concomitant status for eight dogs is not known.

(Slide.)

Onset times for liver problems may be seen in the first three months
after an insult. Here you see an interesting distribution pattern for
these liver enzyme elevations represented in the light green of the bar
charts. There is what may be an acute process after administration with
episodes corresponding to rising or peak serum levels at up to 14 days.
Then you get a second set of what may be more latent reactions at one to
three months after the administration. The onset times for the liver
lesions is more difficult to interpret because of course with these
lesions the onset time is considered to be the time that the lesion is
\-- that the biopsy or the histopath tissues are taken. And so it is
difficult of course to retroactively decide when the actual onset was,
but these are the times that they were determined.

(Slide.)

Another serious concern has been the number of dogs with hematologic or
blood-related problems. Thrombocytopenia or low platelet count and
anemia or red blood cell count were among the most commonly reported
hematologic signs. In dogs low platelet count is frequently caused by
the destruction of platelets by an immune response. Immune-mediated
hemolytic anemia represented here as IMHA is a life-threatening
condition that occurs with an immune response causes the destruction of
red blood cells. Again, the assessments for these two problems in dogs
receiving ProHeart 6 during the first three years of its approval exceed
the assessments for all the other monthly heartworm preventatives
combined for all marketed use. For low platelets there were 124
assessments for ProHeart 6, 86 for the other heartworm preventives. For
hemolytic anemia there were 67 assessments for ProHeart 6 and 51 for all
the other preventives.

(Slide.)

The onset times for low platelets were similar to those for hemolytic
anemia; 43 percent of the low platelets, represented here by the
dark-brown bar graph, occurred between one week and one month following
the ProHeart 6 administration. Approximately one-half of the hemolytic
anemias, represented by the lighter-brown bar graph, occurred between
one week and one month following the ProHeart 6 administration.

(Slide.)

For the 124 episodes of low platelets, the reporting veterinarians
indicated that at the time of ProHeart 6 administration the health
status of the dogs was good in 91, fair in 28, and poor in four. The
health status for the dog in that one episode is not known; 45 of these
124 dogs died. For the 67 dogs with hemolytic anemia, the reporting
veterinarians indicated their health status was good at the time of
administration for 56 of them, fair in 10, and poor in one; 34 of these
67 dogs died.

(Slide.)

Looking at the concomitant status of the dogs with low platelets, in 26
episodes no concomitants were given. In 76 episodes concomitant drugs or
vaccines were given, and the concomitant status for 22 episodes is not
known. Of the dogs with hemolytic anemia, 19 did not have concomitant
drugs or vaccines, 34 did, and the concomitant status for 14 is unknown.

(Slide.)

I have outlined for you several categories of striking debilitating
effects that we have assessed as being possibly associated with the
administration of ProHeart 6 such as anaphylactoid reactions,
convulsions, low platelets, hemolytic anemia, elevation of liver enzymes
and the emergence of liver lesions. They are strongly associated with
ProHeart 6 administration by their timing. These are the effects that
have driven our concerns.

Dr. Post described the regulatory history of ProHeart 6 showing that the
Center for Veterinary Medicine recognized problems and met with the
sponsor about them. Label changes, \"Dear Doctor\" letters, and client
information sheets were established. But despite these efforts, we have
not seen an appreciable decrease in the numbers of reports received or
of serious reactions if you will look at each marketed year from 2001,
2002, 2003, and 2004. The number of deaths possibly or probably related
to ProHeart 6 has increased each year since the product was marketed

(Slide.)

The number of assessments for anaphylactoid reactions has decreased
since the June, 2002 label change, but it still remains relatively high.
The number of assessments for convulsions as we look at each marketed
year is not appreciably different. The assessments for the other
clinical manifestations involving liver changes and low platelets have
increased over time. The assessments for hemolytic anemia appear to be
unchanged over the past year.

(Slide.)

The sponsor of an animal drug product has the responsibility to
demonstrate that the product is safe and effective prior to approval,
but due to the limited size and controlled nature of pre-marketing
studies only the most common adverse drug events are known before a new
animal drug is marketed. The Center for Veterinary Medicine has a
post-marketing system to detect adverse drug events that occur after
marketing and when an animal drug is used in a larger and more diverse
population. If we determine that a marketed animal drug is likely to be
causing serious adverse drug effects, we must take action to prevent
additional harm to the animals receiving the product.

(Slide.)

The frequency of ProHeart 6 adverse events, the severity of these
events, which include death, and the temporal association with the
administration of ProHeart 6 correlating with established serum levels
in dogs that are n good health at the time of administration all raise
serious questions about the safety of this product. In working with Fort
Dodge Animal Health to address the adverse events associated with
ProHeart 6, the Center for Veterinary Medicine has requested three label
revisions. Despite these changes, we have continued to receive a large
number of serious adverse drug events related to ProHeart 6.

(Slide.)

ProHeart 6 is used to prevent disease in healthy dogs. The adverse drug
events associated with ProHeart 6 are particularly striking when
compared to other marketed heartworm preventive products. These other
products have been on the market longer and have fewer reported serious
adverse effects. These are the reasons that led the Center for
Veterinary Medicine to request that Fort Dodge Animal Health stop
marketing this product until we are satisfied that ProHeart 6 can be
safely used in dogs.

Fort Dodge Animal Health will now have the opportunity to present their
information on ProHeart 6. I would like to ask you to keep several
points in mind while listening to their presentation.

(Slide.)

First of all, the toxicology data presented in Fort Dodge's narrative
refers to the oral route of administration. Fort Dodge makes the
statement that the toxicological profile of the oral route is relevant
to the other routes of administration because of limited metabolism and
the long terminal half life. But considering the large numbers of
allergic assessments after injection and the possible association with
immune-mediated diseases such as low platelets and hemolytic anemia seen
in the post-marketing period, this is no longer an assumption that can
be made.

(Slide.)

Fort Dodge's narrative states \"Approximately 18 million doses of
ProHeart 6 have been sold, with more than 12 million doses
administered.\" Fort Dodge calculated reporting rates by taking the
number of reports, divided by an estimate of doses sold to veterinarians
for the same period. Well, this is problematic because only two-thirds
of the doses sold were actually administered, and the doses were not
necessarily administered in the same quarter in which they were sold.
Also, a dose administered is an estimated dose. It is based on the
average number of doses in a vial. Now if one practice sees many small
dogs and another one sees many large dogs, then one will have many more
doses in a vial compared to the other. That might all even out in the
wash, but it is still just a guesstimate.

It is also important to point out that the numbers calculated by Fort
Dodge represent reporting rates, not incidence rates, and that a decline
in reported events over time does not necessarily mean a decline in
incidence. Reporting of adverse events is usually highest when the
product is first marketed and declines over time, sometimes referred to
as the Weber Effect.

(Slide.)

According to the Fort Dodge narrative, there were 1.26 allergy event
reports per 10,000 doses sold. This reporting rate is two-and-a-half
times higher than for Rabvac 3, Fort Dodges rabies vaccine, and 3.1
times higher than for Duramune Max 5L, their distemper-parvo-lepto
combination vaccine. Additionally it is mentioned that only 37 percent
of these allergy event reports had concomitant vaccine, meaning 63
percent did not have any other reason to react.

Of course many of us are not comfortable in the first place with
comparing of biological products such as a vaccine that is supposed to
stimulate the immune system, and that might just be expected to result
in allergic reactions, with a drug that has an entirely different
purpose and mode of action for which we are not expecting allergic
reactions at all. Keep in mind the label clearly states in
well-controlled clinical studies ProHeart 6 was safely used in
conjunction with a variety of veterinary products including vaccines,
anthelmintics, anti-parasitics, antibiotics, analgesics, steroids,
non-steroidal anti-inflammatory drugs, anesthetics and flea control
products.

(Slide.)

According to the Fort Dodge narrative, there were 1.19 non-allergy event
reports per 10,000 doses sold. This reporting rate is four times higher
than for Duramune Max and 3.4 times higher than for Rabvac 3; 42 percent
of these dogs had concomitant vaccines, leaving us with 58 percent that
did not have any other known reason to react.

(Slide.)

Fort Dodge's narrative states \"The adverse event case fatality rate
associated with ProHeart 6 reports is lower than many Fort Dodge Animal
Health harmaceuticals and similar to case fatality rates for the Fort
Dodge Animal Health canine vaccine product lines, including Duramune Max
5/4L. Thus the incidence of death does not appear to be causally related
to ProHeart 6 usage.\" Now this is a difficult connection to make. What
are these other Fort Dodge Animal Health pharmaceuticals, and under what
circumstances are they be used? What is their target population? Are
they injectables? If so, are they anesthetic agents such as Ketaset and
Telazol? Are they non-steroidal anti-inflammatories like Ketofen? Does
this included euthanasia products like Sleepaway? And how do case
fatality rates for Fort Dodge vaccines compare to those for other
manufacturers? That information is simply not available. We just cannot
make this kind of statement.

(Slide.)

On page 49 of their narrative, Fort Dodge explains how it evaluated
adverse event reports by body system, and this is a schematic based on
the narrative. All the events were assigned to the medical association
category of possible as a starting point. Events considered not likely
to be associated with ProHeart 6 were excluded over here as unlikely.
The possible group was further reviewed to distinguish between events
that were potentially or probably related to specific body systems. The
probable group included only those clinical signs that have a reasonable
probability of being related to that body system. Events classified as
allergic were excluded from the probable group. For neurologic,
hematologic and hepatic cases, only those in the probable category were
submitted by Fort Dodge to the highly-esteemed experts for review.

I find this description thoroughly confusing. What is the formalized
process for deciding on the categories of unlikely, possible, potential,
probable? What is the standardized process for determining which reports
go into which categories? What happens with signs like fever or death
that aren't associated with any one body system? This all seems highly
selective and very subjective. Furthermore, only those in this probable
group are included in the calculated reaction rates. It is especially
hard to understand why all the cases considered as allergic defined by
Fort Dodge as those occurring with the first 48 hours of administration
seem to have been excluded from the probable category. Is not the large
number of allergic reactions to say nothing of the possibility of
subsequent lasting after-effects one of our primary concerns?

(Slide.)

Finally we come to analysis from Banfield, the pet hospital. At first
sight you may be impressed by the thought of the wealth of data here for
the mining; more than 700,000 doses of ProHeart 6 administered across
the country, over eight million patient records available for analysis.
But as always, the analysis is really dependent on the study design. One
significant problem is selection bias. Fort Dodge Animal Health compares
the number of events that occur among dogs that receive ProHeart 6 here,
dogs that received an oral heartworm preventive one or an oral heartworm
preventive two, and dogs that received no heartworm preventives at the
time of their office visit. Keep that in mind. Both with and without the
concomitant administration of vaccines.

Now you will notice that there are more than 5.5 million office visits
where dogs received no heartworm preventives. Right away you know that
many of these dogs must actually be on heartworm preventive of some
kind. It just was not dispensed at that visit. Many owners buy six
months supplies or even 12 months at a time. Many owners buy their
supplies online or from catalog companies. Perhaps some of these dogs
received ProHeart 6 a couple of months before their owners decided to go
to Banfield. Also the dogs are not randomly allocated to these different
treatment groups, and there is no evidence that these different groups
of dogs are comparable, particularly with respect to health status. In
fact, there is evidence to the contrary. The adverse event rate was
highest for dogs that did not receive a heartworm preventive or a
vaccine. And might the health status of these dogs be skewed by
participation in the Banfield Wellness Plan? So these are not in fact a
control group, and neither can they be used as a normal baseline for
incidence of background effect.

Now what about just comparing the different heartworm products? ProHeart
6 has a market share of about 24 percent in the United States. Among the
heartworm preventive encounters at Banfield, 63 percent of them involve
ProHeart 6. Consider also that dogs that received heartworm preventive
one and two, the oral forms, may have been in poorer health to begin
with than those that received ProHeart 6. The ProHeart 6 label states
use with caution in sick, debilitated or underweight animals.
Furthermore, in this study Fort Dodge assumed that these oral monthly
heartworm preventives were administered on the same day that they were
dispensed. They concluded that this assumption would result in an
underestimate of adverse events. However the opposite may well be true.
An owner that brings a sick dog into Banfield for treatment may also
purchase a refill of their monthly heartworm medication during that same
encounter.

Information bias or observation bias is defined as a flaw in measuring
exposure or outcome data that results in different quality or accuracy
of information between two comparison groups. It arises from a
systematic difference in the way that exposure or outcome is measured
between compared groups. Well, we have already seen how exposure was
assessed different, injection of one drug versus oral administration

or, excuse me, purchase perhaps, not necessarily administration that
same day of another, versus none dispensed or injected at that
particular visit. Another big limitation of this retrospective study is
the follow-up of cases. Fort Dodge indicates that each encounter was
evaluated for potential adverse events over the following 30 days.
However, Fort Dodge does not state how follow-up was done and whether
follow-up was similar among these different treatment groups.

Now Banfield has a quality assurance team, and I understand they make
follow-up telephone calls after a pet has left their care. But does that
continue for 30 days? What if the pet is fine at the three-day callback,
but has a problem at day 15 and the owner just doesn't report it? We all
know how frustrating it is to think a pet is doing well because the
owner hasn't brought him in, and then we find out, oh, they didn't think
it was something we should be troubled with, or they tried something
suggested by the attendant at the health food store, or they couldn't
afford care at the time, or even that they were so upset with the
treatment they received that they went somewhere else. Often when there
is an after-hours emergency it is the emergency clinic staff that
handles the diagnosis and the referral. Owners may be so upset and angry
they never come back to their primary veterinarian. We may never find
out what happened until we send that annual checkup reminder for the
second or the third time; and of course there may be people who use
Banfield for wellcare like vaccines and heartworm preventive, and use
another veterinarian for more serious issues. Without an established,
consistent method of follow-up for all patients you cannot say a
reaction didn't happen just because the owner didn't come in.

Thank you very much for the attention you have given me today, and I
will ask you to please keep these points in mind as you now turn that
same attention to the representatives from Fort Dodge Animal Health.

MS. SINDELAR: Thank you, Margarita. We are moving along very well. Why
don't we take a break now until 10 a.m. If you all will please reconvene
at 10 a.m. in the room. Thank you.

(Whereupon, a brief break was taken.)

DR. SUNDLOF: Okay. We are missing our chair. Oh, there he is. Okay. We
will reconvene, and you have heard from the Center for Veterinary
Medicine. Now it is my pleasure to have speakers from Fort Dodge Animal
Health present their interpretation of the data. So we will go through
these presentations and then hopefully we will have a little time,
approximately a half-hour before lunch, so that we can start the
discussion. We will ask the Advisory Committee to begin the discussion.
You are free to ask any of the speakers any questions that you want
clarification on, and then after lunch we will begin again. So the first
speaker is Dr. Cobb from Fort Dodge.

**[ProHeart 6 ADEs/FDAH]{.underline}**

**Dr. Rami Cobb**

DR. COBB: Good morning. My name is Rami Cobb. I am Vice President for
Pharmaceutical Research and Development at Fort Dodge Animal Health, and
I would like to thank the panel and I would like to thank the FDA for
the opportunity for us to present the data which support the safety of
ProHeart 6.

(Slide.)

Very quickly, moxidectin is the active ingredient in this product. It is
a macrocyclic lactone and it is widely used in veterinary medicine as an
antiparasitic for horses, dogs, cattle, sheep, swine, and a number of
minor species in more than 70 countries around the world. This compound
is also in co-development with the World Health Organization for control
of river blindness, onchocerciasis, in humans.

(Slide.)

It is an innovative product in that a single dose provides six months of
protection from heartworm disease called by Dirofilaria immitis. In
addition, it treats existing hookworms in treated dogs and it brings a
singular advantage of overcoming the compliance failures that do exist
when monthly products have to be administered to dogs by their owners.

(Slide.)

Reference has been made to the toxicology package which supports
ProHeart 6. This is a very extensive toxicology package because this
product is approved for use in food-producing animals. In addition to
the core tox package, we have recently completely 60 receptor screens
that showed no adverse potential for pharmacologic or toxicologic
effects, and the data from these screens will be submitted to their CVM
for the review as soon as the report is written. In terms of the
relevance of the toxicology studies, we have studies of up to two years
duration in mice and rats and of one year in dogs. There were no target
organs in these studies. There were no histologic or biochemical effects
on any organ system. So when we consider the relevance of these oral
toxicology studies to blood levels obtained from injection of ProHeart
6, we find that the exposure of dogs to moxidectin in these studies was
454-fold higher than would be obtained from being given two doses of
ProHeart 6 over a one-year period. The two-year carcinogenicity studies
showed no increase in tumors.

(Slide.)

In addition to the toxicology, we have conducted a large number of
clinical safety studies. These studies demonstrate that the product, the
formulated product ProHeart 6, has a wide margin of safety. It is safe
to use in breeding animals, both female and male, and it is safe to use
in unique canine populations such as ivermectin-sensitive

breeds of dogs and heartworm-positive dogs. In all of these studies at
the commercial dose rate of ProHeart 6 there was 100 percent efficacy in
controlling heartworm infection, and this occurred not just in
laboratory strains of dogs, but in studies with a large number of breeds
and crossbred dogs. In the US studies alone, a total of 770 dogs were
evaluated, and there were additional studies conducted in international
markets.

(Slide.)

If we look at the factors that limit heartworm control in US dogs, we
find that information can be difficult, but I would reference an
American Heartworm Society survey conducted in 2001 which found that
despite the widespread availability of monthly heartworm preventives
there had not been a change in the infection rate of dogs with heartworm
in the past 10 years. Some 240,000 dogs were reported testing for
heartworm in the United States in 2001. In another survey of dog owners,
one-fifth of the dog owners surveyed had missed giving one or more doses
of a monthly product to their dogs and had stopped giving oral
preventives altogether.

(Slide.)

If we look at our field experience with ProHeart 6, it has been approved
and marketed in many countries where heartworm is endemic. The approval
in the United States was in June, 2001, and I have listed the other
countries where this product is approved and sold. In Australia a
similar product, ProHeart SR 12, was approved in October, 2000. This
product is used in dogs to provide 12 continuous months of protection
against heartworm since the heartworm transmission season there is 12
months long. This product is administered to dogs and is three times the
ProHeart 6 dose.

(Slide.)

Our experience with this product has been that there was rapid and broad
acceptance by dog owners and veterinary professionals of these products.
In the United States the product achieved 24 percent market share and in
Australia 47 percent market share.

(Slide.)

If we look at that evolution we find that ProHeart 6 has shown a steady
increase in acceptance from launch until the time of its removal from
the US market, and similarly in Australia. This is in the face of either
steady or declining usage of the monthly products. Almost half of all
dogs in Australia that received preventives for heartworm are protected
by ProHeart.

(Slide.)

If we look at our adverse event reporting experience recognizing all the
deficiencies that go with passive reporting systems, we find that in
Australia we, too, have sold significant numbers of doses. Something in
excess of 2.2 million doses have been sold in Australia, and I have
listed there for you the adverse event reporting rates split out by
allergy and by death, areas that were classed as significant by the CVM.
The reporting system in Australia is very similar to that in the US. It
relies on voluntary reporting by veterinarians, pet owners and the
public, and mandatory reporting by companies.

(Slide.)

In September, 2004, Fort Dodge announced a voluntary recall of ProHeart
6 based on CVM's expressed concerns about the adverse events. These
data, we obviously notified the regulatory agencies of other countries
where these products are sold, and data were reviewed by the Canadian,
Australian, European, and Japanese regulatory authorities. They reviewed
not only their own country's post-marketing experience. They also
reviewed the US post-marketing experience, and all of these countries
confirmed our authorization to continue marketing the product.

(Slide.)

I would like to introduce the two speakers we will have to present our
case, and I believe that they will certainly address all of the
questions that have been raised by the CVM. Firstly, Dr. Larry Glickman
from Purdue University. I think he is known to many of you through his
publications. He is he professor of epidemiology and head of the section
of clinical epidemiology at Purdue's School of Veterinary Medicine. He
is a veterinarian and a Ph.D. in epidemiology. He is also the recipient
of many awards and honors, and I would like to just highlight several of
those. The Merck Award for Creative in Veterinary Education, the Pfizer
Research Award, the AKC Award for Outstanding Canine Research, and the
Outstanding Alumni Award from the University of Pennsylvania. Dr.
Glickman comes with excellent credentials.

He conducted a landmark epidemiological survey from a large independent
nationwide database, and I want to express my thanks to Banfield, The
Pet Hospital, for making that database available for the study, and it
covers almost seven million encounters of office visits by dogs to
veterinarians. The study evaluated ProHeart 6, two heartworm preventives
and vaccines. The results of the study demonstrate no clinically
significant increase in adverse events following ProHeart 6 treatment,
and that the ProHeart 6 safety profile is similar to that of two monthly
heartworm preventives.

Our second speaker is Dr. David Hustead of Fort Dodge Animal Health. In
addition to working for Fort Dodge, Dr. Hustead is a member of the VICH
Expert Working Group on Pharmacovigilance and is qualified to speak to
this issue.

We did conduct a re-review of our database for adverse event reports
following the September recall. In this we were assisted by independent
experts with expertise in particular areas such as liver, hematology,
and neoplasia. Our conclusions following this review are that the
overall reporting rate for ProHeart 6 is low. The reporting rate is
declining, and we will specifically address that. Most adverse events
appear to be allergic, mild, and self-limiting, that the assignment
causality is confounded by concurrent vaccinations, and there is a very
varied database of non-allergic adverse event reactions with no pattern
that reflect diseases that are commonly seen in dogs.

So thank you. I would like to welcome our first speaker, Dr. Glickman.

**[A Controlled Epidemiological Study: The Safety Profile of ProHeart 6
and Two Monthly Heartworm Preventives in Dogs]{.underline}**

**Dr. Larry Glickman**

DR. GLICKMAN: Thank you, Rami. I would like to take this opportunity to
present to you the results of the controlled epidemiologic study that we
conducted. We call it \"The Safety Profile of ProHeart 6 and Two Monthly
Heartworm Preventives in Dogs.\" Now as Rami says, it used the large
Banfield database and support for development of the database to do this
kind of study has been received from Fort Dodge Animal Health, the
Centers for Disease Control, Center for Infectious Diseases, and the
Food and Drug Administration Center for Veterinary Medicine. This report
will summarize the experience of approximately 900 Banfield
veterinarians nationwide who at the time we did the study had
administered greater than 700,000 doses of ProHeart 6 to dogs. Banfield
practices are \-- emphasize preventive medicine, and they are evidence
based. Many of their dog owners do belong to the

Wellness Program, which then covers examinations, parasite testing twice
a year.

(Slide.)

There are now over 400 Banfield hospitals located in 43 states in the
United States, making them very representative geographically. All these
hospitals follow similar protocols in the diagnosis, prevention, and
treatment of illness. All drugs and vaccines are thoroughly evaluated by
Banfield committees before they are adopted and used.

(Slide.)

Now what are some of the advantages of using a large database like this?
You have heard from previous speakers the disadvantages of just
receiving unfiltered passive reports about adverse events. So what
advantage does using this database bring for post-marketing
surveillance? First of all, Banfield veterinarians serve two percent or
more of the US dog population and is certainly representative with
respect to breed and geography. What is really important to
epidemiologic studies is all their medical records are standardized.
They are computerized, and they are stored electrically in a central
data warehouse. They do routine quality assurance of these records, and
all dogs that died routinely review the case records to try and
determine causality. You heard before that passive reporting lacks good
numerators and good denominators. We think we have both. Good
denominators because there is more complete ascertainment of adverse
events, follow-up calls are made to all clients after each visit, and
since all drugs and vaccines are warranted by the company owners are
more likely to return if a problem arises or they perceive a problem.

(Slide.)

Now we were not selective in how we chose the Banfield dogs to include
in this study. We took all dog encounters or dog visits over a two-year
period from

January 1^st^, 2002, to August 31^st^, '04, when the drug was
voluntarily recalled. Each encounter was evaluated for potential adverse
events over the subsequent 30 days, and I would like to emphasize all
follow-ups were done the same way regardless of what drug or other
treatment the animal may have received. We divided these office visits
or encounters into whether the animal, the dog, had received ProHeart or
not, whether they got one of two monthly heartworm preventives which we
are going to call heartworm one and heartworm two, whether they were
vaccinated or not, or whether they received none of these products. We
then calculated adverse events per 10,000 dog visit or encounters, and
because of this I will explain in a few minutes the follow-ups weren't
necessarily exactly 30 days. For example, when an animal dies. We also
calculated the adverse event rate per 10,000 days at risk.

As has been alluded to previously, there are potentially many
confounding factors when doing adverse event studies. Other drugs to be
given, vaccines to be given. Dogs could have been treated with drugs for
other reasons, for example steroidal anti-inflammatories. We took this
into account in our final analysis by taking all these potential
confounding factors into account.

(Slide.)

Now this first slide actually was shown to you earlier this morning. We
looked at a total of almost seven million encounters over this two-year
period of time. We broke these encounters down into whether the dogs had
received ProHeart or not, heartworm preventive one or not, heartworm
preventive two or not, or no treatment. That included then all dogs seen
at Banfield. Within each of those categories we subdivided them into
whether they had received a vaccine or not, and that is shown on the
website of this slide.

Now I would like to point out some interesting highlights here for you.
You see three sets of numbers under each drug. For example, you see a
large N, which are number of encounters in which that drug was given. So
for ProHeart it would be a total of 735,000-plus. For heartworm
preventive one vaccine, yes/no, heartworm preventive two vaccine,
yes/no, and you also see then the number of animals in the category, the
number of dogs. That's the N. The NA is the number of adverse events,
and the rate which is the second column divided by the first column. So
we are looking at incidence rates. We are not just counting events, and
several things are striking from this.

First of all, if you look at the ProHeart and the heartworm one or the
heartworm two, and they are in yellow there, if you look at the rates
you can see that when animals receive this product, any of these
products without vaccine, the rates are remarkably similar; 89.2 for
ProHeart, 89.1 for heartworm preventive one, and 70 for heartworm
preventive two. Now the rates are higher in the last group, the animals
that received no heartworm treatment, because those are probably sicker
animals coming to the hospital for diagnosis. So for completeness we
include them, but they are not really our primary comparison group. We
are comparing events between the three heartworm preventives.

Within each of the heartworm preventive categories you can see if you
look at vaccine yes and vaccine no there are approximately twice as many
dogs that receive vaccine at the same time they receive ProHeart. Same
for heartworm preventive two, approximately twice as many were
vaccinated as not vaccinated, and the same for heartworm preventive two.
Why is this important? Because we know vaccines are associated with
adverse events themselves, and so you cannot ignore this heavy use of
vaccine at the same time these preventives are given. Otherwise you get
a biased outcome.

(Slide.)

Now this shows the use by Banfield veterinarians over time of ProHeart
6. There are two lines on the graph. The upper are dotted lines. It
shows the number of animals that received ProHeart with vaccine. The
bottom solid line are the number of dogs that had ProHeart without
vaccine, and you can see it is roughly a two-to-one ratio there. You can
also see the seasonal pattern in the use of ProHeart with the peaks
occurring each year during the peak of mosquito activity, usually from
about April or May through September. The third thing is obvious that
over this period of time there was increased use of ProHeart by Banfield
veterinarians.

(Slide.)

I would like to walk you through our initial analysis where we looked at
and calculated adverse event rates for animals receiving each of these
products or divided into these eight groups. These eight groups are
shown on the left. As we said, there are four possibilities \--
ProHeart, heartworm one, heartworm two, or any vaccine \-- and we show
you then in the top row the animals that received none of these, and so
there are no Ys in those boxes. The next one would be animals that
received any vaccine, so it would have a Y under a vaccine, and then
further down you see each of the heartworm preventives, both alone and
with a vaccine. We looked at a variety of potential associated adverse
event types. They are shown across the top: liver disease, neurologic
disease, ocular disease, immune-mediated disease, and allergic
reactions.

First let me focus your attention on ocular disease, for which there was
a very low rate of adverse events. Overall if you look in the any row,
the bottom row, there was only 0.3 per 10,000 ocular events, and so it
was hard to distinguish between drug types. For neurologic disease the
rate was higher overall, 6.1, and the rates were fairly consistent
between the three heartworm preventives. Immune-mediated the same, the
overall rate is 5.1, and the comparisons between the three heartworm
products did not point out any major differences. Allergic reactions are
very interesting, and I will talk to them in a separate slide shortly. I
would like to focus your attention here to liver disease, where if you
look at the top row these are the animals we expected to be the sickest,
and they had the highest adverse event rate per 10,000 at 61.6. If you
look at vaccine alone, which would be the second row, the rate is 35.0.
Then if you look at the three heartworm products going down with or
without vaccine, you can see the rates are fairly similar. But in this
analysis, which was unadjusted for any potential confounders like age or
weight or use of other drugs like steroids, the ProHeart group,
especially with vaccine, has the highest rate at 41.6 per 10,000.

(Slide.)

Now as I said, we also looked at adverse events when calculated per
10,000 days of risk. Why did we do this? Because the way we follow it up
in animals, an animal following a drug administration, for example
ProHeart 6, we looked over the next 30 days to see if they had any
adverse events. If they had for example an adverse liver event we
counted that and then kept looking over the remaining part of the 39
days. However, if they are in the 30-day period an animal had received a
vaccine \-- let's say on day 14 following ProHeart, we would stop the
follow-up with ProHeart at day 14 and then start a new 30-day follow-up
associated with the vaccine. As a result, not all of the follow-up
periods for all the products were exactly the same. In fact, they were
slightly longer for ProHeart 6. Therefore, the importance of adjusting
our rates per 10,000 days at risk, and if you look at this graph then
you can see that the adverse event rate for the oral monthly heartworm
preventives being 1.15 and 0.79 are not too different from what you see
for ProHeart 6 when adjusting for days at risk. Again, the animals that
received none had the highest rate, which we expected.

(Slide.)

Now let's look at some other potential adverse events in the same way.
We have looked at death, cancer, cardiovascular disease and anaphylaxis.
Now the rates for both \-- for anaphylaxis were extremely low, a total
of 0.5 per 10,000, and were not very different between the products. The
cardiovascular disease rate was slightly higher, overall 16.6, but also
not different between the two monthlies and the ProHeart.

There are some striking findings though with respect to what we all
agree is the most serious adverse outcome, which is death. When you look
at the overall death rate, the last row under death and under rate, you
can see that rate is 116.2 per 10,000. Then when you look further up now
and look at the different products, the heartworm products of vaccines,
you see that they are very similar except for one product. Heartworm one
when given without any vaccine, the adverse event rate was the highest
at 22.0 per 10,000.

The cancer rates I am going speak to separately. They also seem not to
be similar between the groups in that the adverse event rates, meaning
cancer, are slightly higher for the ProHeart 6 group both with and
without vaccine, 6.1 and 4.2 per 10,000. We are going to get back to
this and look at it in more detail.

Now I said I was going to get back to the allergic reactions because
we've never had data like this to look at in terms of what products are
associated with what reactions. But we look at the second row down,
which is vaccine, only vaccine, the adverse event rate was 44.3 per
10,000. But if you then look at heartworm two alone, heartworm one
alone, or ProHeart alone, you get 51.8, 14.3, 54.3. Very similar but
slightly higher than what we see for vaccine. So that was for the
products given with vaccine.

When you look at the products give alone, heartworm two alone the rate
is 18.7, heartworm one alone allergic reaction is 14.3, and ProHeart
alone 18.4. Here we can really see the impact of vaccine when given with
a heartworm product. It increased the rate by about two-and-a-half fold,
once again suggesting you cannot ignore administration of concurrent
vaccine with heartworm preventives when you are looking at adverse event
reports.

(Slide.)

Once again to adjust for differences in the length of follow-up, this
shows the relative rates of allergic reactions per 10,000, and you can
see heartworm one, heartworm two, and ProHeart 6 are very comparable
with vaccines clearly having the highest risk of allergic events.

(Slide.)

Now I said I would come back to cancer. We looked at three cancers \--
lymphosarcoma, histiocytoma, and mast cell tumors \-- because these are
very common tumors in dogs, and previously we saw that ProHeart might be
associated with a high risk of cancer. Well, in fact, that increased
risk is only found with mast cell tumor. If you look at the adverse
event rate for heartworm one only it is 0.024, whereas for ProHeart 6 it
is 0.072. So the important point here is the absolute rates are
extremely small, but there is a slight increase with ProHeart 6 when it
comes to mast cell tumor and it is also higher than you see with
vaccine, but again the absolute difference is very small.

(Slide.)

As I said, it is important to adjust the potential confounding factors
like age, like weight, when you are looking at the effects of the three
heartworm preventives, and that is what we did in each of these models.
So the results I am showing you are fully adjusted for everything else
that we looked at, and the ones that I am going to show you are the only
ones that came out statistically significant at P less than 0.05. So in
the adverse event model for liver disease, which this one is, steroids
increase the risk of liver disease by 25 percent. Which is not a
surprising finding knowing what we do about the effect of steroids on
the liver. In this fully-adjusted model now, ProHeart 6 is not
associated with an increased risk of liver adverse events. Matter of
fact, it suggests a decreased risk, and each additional dose of ProHeart
given further decreases the risk by eight percent. Now the reason this
may be a little misleading is because of the bottom entry there. You see
interaction of Proheart 6 and age, and the high significance level
suggests that age is modifying the effect of ProHeart in terms of
adverse events regarding the liver.

(Slide.)

So we plotted out what the age effect is. So on the X axis you see age
in years, Y axis is the risk of liver disease, and you can see there is
a relations. It is a straight line. But in dogs less than four years of
age ProHeart is actually associated with a decreased risk of liver
disease, while with older dogs, older than four, it is associated with
an increased risk. But the overall net effect is no increased risk.

(Slide.)

Now we built a similar model for allergic reactions. We can go over this
quickly because ProHeart, heartworm, and vaccine \-- and this is
heartworm one \-- appear to all increase the risk of allergic reactions
consistent with the previous findings. But vaccine has by far the
greatest effect, increasing risk of allergic events by 151 percent. Now
the two anti-inflammatory classes, non-steroidals and steroidals, also
increased the risk of allergic events, but it was theorized we are
pretty sure this happens because steroids are actually used to treat
allergic events. Once again each additional dose of ProHeart is actually
a decreased risk of liver events. That is important. So the more
ProHeart you give, you would not expect to see an increase in allergic
event, but actually a decrease.

(Slide.)

Now this is the adjusted model looking at the adverse events associated
for cancer. Lymphosarcoma and histiocytoma, there were no relationships
between risk for those cancers and any of the heartworm preventive
products. Steroids still increase the risk of lymphosarcoma, but that is
because it is used to treat lymphosarcoma. Now with mast cell tumor we
did confirm a slightly increased risk associated for ProHeart use,
increased by 27 percent, and a very unexpected finding was an increased
risk of mast cell tumor associated with non-steroidal anti-inflammatory
use, and we need to explore this further.

(Slide.)

Of course death certainly is the most severe reaction, and in this
fully-adjusted model heartworm one, the most commonly used monthly oral,
appeared to increase the risk of death by 23 percent. Whereas ProHeart
actually decreased the risk by 71 percent, and each additional ProHeart
further decreased the risk of death by nine percent.

(Slide.)

So what do we conclude from these analyses? I concluded that the safety
profile of ProHeart is similar to two monthly heartworm preventives, the
two orals, with two exceptions. One, there is an up-to-now biologically
unexplained but very small increased risk of mast cell tumor following
ProHeart 6 administration. Perhaps more important is the 23 percent
increased risk of death following the use of the most common monthly
heartworm preventive. In our study that is heartworm one. The other
thing I think it is important to realize is that the adverse events
probably were underestimated for the monthly heartworm preventative
versus the injectables. Why? Because veterinarians are more likely to
observe an adverse event when they give the product and the animal is
actually in the office, whereas they are less likely to observe adverse
events when the drug is given at home by the owner. Also we know and we
have heard that many owners don't administer the oral medications when
they are supposed to, and yet we are counting adverse events as if they
were given. So again we are going to underestimate the rates with these
products.

(Slide.)

I want to emphasize that these epidemiologic analyses adjusted for
effects of concurrent vaccination and other potential confounding
factors of which we found several, and it is hard to interpret results
of adverse events without adjusting for these. Unlike passive reporting
systems that are unable to calculate incidence rates, we can calculate
incidence rates, and as important we can compare these incidence rates
between the heartworm products. We utilize recorded medical events and
not unfiltered reports from veterinarians or owners. We know there are
biases associated with reports from owners and veterinarians, and
certainly unreporting. We don't have that problem with our database.
This database gave us an opportunity to test causal hypotheses that were
generated through the FDA CVM passive reporting system, and I think this
is the appropriate use of epidemiology, both in human medicine and
veterinary medicine.

(Slide.)

My final conclusion, and I believe this based on the results I showed
you and based on results I have not shown you for lack of time, that the
safety profile of ProHeart 6 in controlled epidemiologic studies was
definitely favorable compared with two monthly heartworm preventatives.
My own conclusion is that there appears to be no scientific rationale
for the continued withdrawal of ProHeart 6 from the marketplace. Thank
you.

**[FDAH Adverse Event Report Re-Analysis]{.underline}**

**Dr. David Hustead**

DR. HUSTEAD: My name is Dave Hustead. I am a Senior Director at Fort
Dodge Animal Health. My areas of responsibility are technical and
regulatory affairs. I am going to present to you today a re-analysis of
ProHeart 6 adverse events.

Before I start my prepared presentation though, I have been asked by the
FDA to offer a subtle correction to Dr. Post's presentation. Dr. Post
did show you a very nice three-line graph with three different colors
for the numbers of adverse drug experience reports received by the CVM.
While the graph he presented was correct, his verbal description of the
legends for the three lines was incorrect. So we would ask that you look
at that graph carefully and interpret it appropriately. The graph does
show that the number of initial adverse drug experience reports are
declining to the CVM.

(Slide.)

At Fort Dodge Animal Health our Professional Services Department is
responsible for adverse event investigations. They are also responsible
for the regulatory compliance associated with those investigations. They
have additional responsibilities in technical support and professional
customer service. We have 28 veterinarians in our Professional Services
Department. They have extensive practical clinical experience prior to
joining industry. In addition, we have three PhDs and seven veterinary
technicians.

(Slide.)

All reports of suspected adverse events are investigated by Fort Dodge
Animal Health staff. To improve the quality of the data that we collect
during those investigations, Fort Dodge Animal Health routinely pays for
diagnostic services, including referrals to specialists. All reports
received, regardless of causality and regardless of scientific
plausibility, are recorded and submitted to the CVM per our regulations
21 CFR Chapter 514.8.

(Slide.)

To add in the analysis of adverse event reports, Fort Dodge places those
reports into four categories. Those categories are injection site
reports, allergy reports, non-allergic systemic reports, and lack of
efficacy reports.

(Slide.)

We conduct medical association assessments based on VICH-approved draft
guidelines. VICH is an international group of regulators and industry
attempting to standardize and harmonize the differing regulations
involved with adverse event reporting. I am proud to be a member of that
group. As recommended by VICH, Fort Dodge Animal Health assesses each
event as a whole. This is in contrast to the CVM practice of assessing
each causality assessment individually and in isolation. We use three
categories of the VICH system: possible, unlikely, and probable. All
events are placed into the possible category. Possible means that the
drug of concern is one of equally plausible explanations.

(Slide.)

If during our investigation we obtain sufficient information to
determine that the event is not likely to be associated with the product
or there are other more plausible explanations, the event is then placed
in the unlikely association category. For an event to be placed in the
association probable category all the following must be met. There must
be a reasonable association in time; the adverse event should be
reasonable given what is known about the pharmacology of the drug and
the toxicology of the drug; and there should be no other equally
plausible explanations.

(Slide.)

Now the CVM has said to you that ProHeart 6 has a very large number of
adverse event reports associated with this use, and that this number of
adverse event reports compares very unfavorably to monthly heartworm
preventatives, and that this then supports a conclusion about the safety
performance of ProHeart 6. Fort Dodge Animal Health believes that to
make valid comparisons between products you must resolve a host of data
inconsistencies, and often these comparisons are difficult if not
impossible. Two primary areas of data inconsistencies are in the
products themselves and then the users' expectations of those products,
and then of the differing adverse event collection systems used to
record adverse events for the different products. Product differences
with ProHeart 6 as compared to monthly preventatives are that most
monthly preventatives are given at home as a treat. There is a common
belief among owners that medications given at home in this manner are
not really drugs. If they are not really drugs then adverse clinical
signs which are seen in the post-administration period may draw no
association from the owner to product administration. If no association
to the product is ever made, then no adverse event report is created.
These products, the monthly preventatives, are rarely given by
veterinarians, and they are rarely given in conjunction with injectable
products. These products have radically different sales, and sales
differences do impact the numbers of adverse event reports which are
received. Finally, the differing companies in this instance have
differing adverse event collection systems. These systems collect,
investigate, quantify, and then submit adverse event reports
differently, and this creates substantial bias within the datasets for
review. Unless these differing issues can be resolved, valid conclusions
and comparisons are difficult if not impossible.

(Slide.)

ProHeart 6 has a substantial over-reporting bias associated with its use
as compared to monthly heartworm preventatives, and these over-reporting
biases become extremely valid if what you want to do is compare the rate
of reporting of one product to another. ProHeart 6 is an innovative,
sustained-released product. It was recently released on the marketplace.
Early in its use veterinarians lacked an effective frame of reference to
make reasonable conclusions about clinical signs they see in the
post-administration period, drawing questions as to whether those
clinical signs are or are not due to the drug which they have just
given. These questions then stimulate calls to our Customer Service
Department because they know there is a wide range of veterinarians
there with expertise to answer their questions. The product is a
sustained-release drug. It is now plausible for a veterinarian to think
that a set of clinical signs they see months post-administration just
might be related to products used, again generating a call to the
company.

Concurrent use with vaccine is common.

Dr. Glickman has shown to you that vaccine use dramatically impacts
adverse event reports. The CVM considers these events where ProHeart 6
and vaccine were used together as ProHeart 6 adverse events with
concomitant vaccine use. It is equally valid to say the event is a
vaccine adverse event with ProHeart 6 concomitant use. ProHeart 6 is
injected by veterinarians. Injected drugs are viewed as powerful
medications by the users and the clients. Veterinarians know exactly
when the product was given because such is documented in the patient's
record. If the animal subsequently has signs, the veterinarian easily
sees in his record when ProHeart 6 was given.

Fort Dodge Animal Health has sent out two \"Dear Doctor\" letters during
the time the product was on the market. These discussed safety issues
associated with the product. It is not unreasonable to think that these
letters have created a bias amongst veterinarians to be concerned about
clinical signs they would see in the post-administration period.
Finally, there have been a large number and widely disseminated news
reports and website postings critical of ProHeart 6. I can assure you if
the veterinarians themselves have not seen these their clients have, and
they have drawn these to the attention of their veterinarian. Clearly
ProHeart 6 is subject to reporting biases that would not apply to
monthly heartworm preventative products.

(Slide.)

Let me give you an example of how this over-reporting bias works. The
practitioner is presented with a dog who has anemia and lethargy. When
presented with a diagnostic dilemma the veterinarian will ask the owner
questions about the dog's medical history. It is my experience based on
decades now of adverse event reporting that veterinarians don't ask
\"When was your dog given his last heartworm preventative?\" If this
question is never asked then the veterinarian never draws an association
to the clinical signs they are observing and the product that was given
in the previous period. If they don't make that connection and adverse
event report is never generated.

ProHeart 6 is very different. The veterinarian knows when ProHeart was
given. He is then very likely to make a temporal association between the
use of the product and the clinical signs being seen. As we have an
effective Technical Services Department, this leads to a telephone call
which basically goes, \"This is what I've seen. What you guys think?\"
At that instant an adverse event report has been created, and that
adverse event report, regardless of what we find in our investigation,
will be submitted to the CVM.

(Slide.)

We believe we need to take a much closer look at the numbers of adverse
event reports that the CVM has presented to you, and especially as how
they compare the monthly heartworm preventatives to ProHeart 6. This is
information that Fort Dodge was able to obtain from the CVM based on the
Freedom of Information request. This is information not freely
available. What I want you to see is to look carefully at the year 2003
and compare it to 2002, and notice for the monthly heartworm
preventatives there is a dramatic increase in reporting between 2002 and
2003. Now Fort Dodge is not going to speculate about why this change
exists. It is not germane to the issue that we have come here to discuss
today, but it is important for you to notice the difference in the
pattern of reporting. It is also important for you to know that we have
reviewed the pattern of reporting prior to 2001, and the low level that
is seen in 2001 and 2002 continues in the previous history of these
products.

Based on this data, Fort Dodge believes that it is inappropriate to sum
the number of adverse event reports for the monthly heartworm
preventatives and to conclude that the low number of adverse event
reports associated with those monthly preventatives somehow supports a
conclusion about the safety of ProHeart 6. It is very much apples and
oranges. We believe that the differences in the numbers of adverse event
reports much more clearly are an effect of the system involved in
reporting those adverse event reports than the biological behavior of
any of the products.

I would now draw your attention to the ProHeart 6 adverse event numbers.
In 2001 we had 677 adverse event reports. This is a relatively low
number compared to 2002, but this is completely explainable as the
launch of ProHeart 6 was in June of 2001, well past when most
veterinarians are administering their annually-based heartworm
preventative programs. So therefore the amount of ProHeart 6 that was
actually used in dogs in 2001 is relatively small. 2002 was the first
year where we had the product on the market for a full heartworm season,
and so we saw a large increase in the amount of product use. This brings
about an increase in adverse event reports, as would be expected. In
2003 you will notice that this number drops, and we believe this is
important and significant as veterinarians grow accustomed to products
the adverse event reports typically do drop.

In addition, we would like to draw your attention to the market share
information provided in the final column. This is Fort Dodge's best
estimate of the relative market shares of these three products, and this
information is obtained from an outside source. If you assume for just a
moment that all three of these products have the exact same biological
behavior, and if you assume for the moment that all three products have
identical adverse event reporting systems, then you would assume that
the number of adverse event reports would follow the ranks that the
products are sold in the marketplace. This is exactly what you see. The
product with the highest market share has the highest number of adverse
event reports. The product with the lowest market share has the lowest
number of adverse event reports, and the product in the middle is in the
middle for the number of adverse event reports.

(Slide.)

This is the same information which I just provided, but it excludes
inefficacy reports. In general when we are using passive surveillance
systems you have two issues that you are interested in. One is safety.
The other is efficacy. If your question is safety then it is more
important to drop out the lack of efficacy reports so you can just look
at those reports which imply a safety concern about the product. I will
not go into detail in looking at this slide because what you need to
know is everything I told you about the previous slide applies to this
slide as well. Therefore, Fort Dodge concludes that the number of
adverse event reports associated with ProHeart 6 in 2003 compares
favorably to other heartworm preventative products, and that any
comparison of adverse event numbers from periods before 2003 is
inaccurate.

(Slide.)

This is the number of adverse event reports that Fort Dodge Animal
Health has received associated with ProHeart 6 from launch to recall by
quarter. There are just a few interesting take-home messages here. You
will see a peak in the second and third quarters of the year 2002. This
is with the same peak that I showed you in adverse event reporting
numbers in the graph that I just showed you. This is certainly to be
expected. You will also notice that there are three peaks in this graph,
each of them associated with the second and third quarter of each year.
This corresponds to increased use of the product in the spring and
summer as would be expected with a heartworm preventative in the United
States. You should also notice that these peaks go down each year with
subsequent use of the product. We believe these decreased are
significant.

(Slide.)

Now we do use reporting rates as an analysis tool. We believe that while
these are not perfect assessments, they do offer some advantages to just
looking at gross reporting numbers. The primary problem with gross
reporting numbers is that they fail to provide any estimate at all of an
incidence rate. We completely agree that reporting rates are not
incidence rates. No one has ever made such a claim. In addition, gross
numbers fail to account for changes in products used, and so reporting
rates are a valuable tool as long as you understand what they are and
you understand their deficiencies. Reporting rates are calculated by
dividing the number of adverse event reports you get by the doses of
product which are sold in that same period of time.

(Slide.)

This is the same data that I showed you in the previous graph looking at
gross numbers of adverse event reports, but corrected for reporting
rate. What you see here again is the peak in 2002. I have addressed
this. The reason for the rise in the numerator number that represents
this peak. But the reason this peak is so high in this analysis is
because the denominator number or the sales number has been artificially
reduced. The reason for that artificial reduction is that as I said
before ProHeart 6 was launched late in 2001. We sold a lot of product in
2001 that didn't get used. That product was then used in 2002. If the
product is used in 2002 but not sold in 2002 then it doesn't get into
the 2002 calculation. In addition, much of the product that we sold in
2001 was short dated. This required veterinarians to return the product
to us in exchange for product with better dating. These exchanges don't
show up in our sales figures. So therefore the large peak here in
incidence rate is an artificial elevation based on increasing numbers of
adverse event report rates, balanced off at actual decreases in sales
when looked at in this analysis method. After the peak, though, that is
seen in 2002, you will notice that the product rapidly falls and
establishes a steady stayed graph, which is what we expect when we look
at incidence rates calculations over time.

The annualized reporting rate of ProHeart 6 in June, 2001, through May,
2002, was 2.45 reports for 10,000 doses sold. For the next calendar
year, June, '02 to June, '03, it's 4.3 per 10,000 doses sold. But
following that period it then reduces to 2.13 for 10,000 doses sold. It
is clear that looking at ProHeart 6 either from a reporting numbers
standpoint or a reporting rate standpoint that following a peak in early
2002 that the reporting for ProHeart 6 is decreasing.

(Slide.)

The CVM has previously presented to you that there are 485 deaths which
are at least possibly related to ProHeart 6 and that this number
compares very unfavorably to the numbers of death which have been
associated with other monthly heartworm preventative products. I have
addressed earlier in my presentation the reasons why these comparisons
are inappropriate. They are inappropriate for total numbers of adverse
event reports as they are inappropriate for the numbers of death. There
are no differences.

There are additional issues, though, with the numbers, with the death
reports that we would like to discuss with you. Fort Dodge was able to
obtain 353 adverse event reports from the CVM from a Freedom of
Information request. We then took a look at those causality assessments
conducted by the CVM and simply graphed them on a chart.

(Slide.)

You will see that five percent of the death reports have been
characterized by the CVM as probably related to ProHeart 6. This
compares to 77 percent of those assessments which are possibly related
to ProHeart 6. There has been some indication this morning that the
Kramer Modified Algorithm is an unbiased and objective way to review
causality assessments. This is not the opinion of the VICH Working
Group. They don't think \-- the do not recommend the Kramer assessment
to be used. In addition, while the Kramer system appears to be unbiased
and objective, we believe \-- I believe that is because it produces a
number, and we as people are always predisposed to treat numbers as an
objective and unbiased assessment of something. But if you look at the
Kramer Algorithm what you see is that each of its components asks an
extremely subjective question subject to all sorts of biases. A question
like \"Were there other reasonable alternative candidates?\" Well,
whether there are other reasonable alternative candidates depends on how
far you look. So these are subjective questions producing an objective
answer.

We would like to point out that the single highest category of
assessments on this graph is the zero causality score. It compromises
\-- or comprises, excuse me, 37 percent of the causality assessments
given. If during the causality assessment conducted by the CVM if just
one of the questions in the causality component scoring had come up with
one less number in it, all of those causality assessments would have
fallen to the other side of that black line, and now suddenly 55 percent
of the adverse event reports are now remotely associated with ProHeart
6.

(Slide.)

So to summarize, the CVM themselves have assessed five percent of these
events as probable \-- these death reports as probably related to
ProHeart 6. The CVM has assessed 77 percent of them to be possibly
related to ProHeart 6. We would ask should all of these greater than
possibly assessed adverse events be treated equally in an analysis of
the safety performance of the product? We would say the answer to that
is no. Also we would ask should market withdrawals be supported on
events whose assessments are possibly related to ProHeart 6.

(Slide.)

Fort Dodge Animal Health believes there are other significant issues
involved with the death assessments which have been performed by the
CVM. From our review of the cases that we have been able to look at
closely, we believe there is a large number of scientifically
implausible cases still within the clinical assessments of possible or
above. These begin with concurrent vaccination. It is my opinion that
when vaccines and ProHeart 6 is given that any assessment to which
product is causality associated with the product is impossible. There
are events in the database where cancers have been reported in patients,
and these cancers have been reported less than six weeks after ProHeart
6 administration. We believe there is no scientific data to support the
speculation that a medically-reasonable product can be given to a
patient and induce clinically-observable cancers in less than six weeks.

I have already discussed with you the reasons for being concerned about
causality assessments of zero. If these events are not removed from the
database, any conclusion about the seriousness of ProHeart 6 based on
the numbers of death reports is an exaggeration.

(Slide.)

Additionally, we have concerns simply about how the causality
assessments were done all by themselves. Fort Dodge Animal Health again
has reviewed a subset of the death events it could get. We reviewed 29.
In one-third of these events we found that the FDA had assessed the
death as possibly related to ProHeart 6. Fort Dodge Animal Health using
the Kramer scoring system as the CVM recommends assessed these events
are remotely related to ProHeart 6.

Let me give you two examples. A dog with a hemorrhagic episode is
presented a few days after administration of ProHeart 6. The dog dies.
An necropsy is conducted. During the analysis of the information
clinically significant levels of rat poison are found in the dog's
liver. All this information is provided to the CVM, but regardless they
score the case as possibly related to ProHeart 6.

Another case, a dog is presented with pain its abdomen four months after
administration of ProHeart 6. The dog dies. A necropsy is conducted. A
hemangiosarcoma is found in the dog's liver. This information is
provided to the CVM. Regardless, this case is assessed as probably
related to ProHeart 5.

MR. : \-\-- five minutes.

DR. HUSTEAD: Yes. Thank you.

(Slide.)

We believe that the numbers of death reports need to be placed in their
proper context. Even if you take the number of adverse \-- of deaths
associated with adverse events which the CVM has stated, which is
approximately 500, you need to compare that rate of dating with the
expected mortality rate in a large number of dogs. If you do the math on
the 500 assessments of the CVM divided by the number of dogs exposed
over time, you will see that approximately 20 dogs per million have been
reported associated with death associated with the use of ProHeart 6.
The obvious question is what is the mortality rate in the canine
population. I wish I knew. We have scoured the literature to try to
determine what the established amount of death and mortality is in dogs,
but we don't know. Various sources give various different information.
We believe that very conservatively we have assessed this to be five
percent. We would point out that a peer-reviewed journal article will
show up in the peer-reviewed press very quickly showing that this rate
is actually eight percent.

If you use five percent as your assessment and divide that by time, you
will find that if you give any medication at all to one million dogs
that approximately 50,000 of those dogs would be expected to die over
the next one year. What we are saying here is that the numbers of death
reports associated with ProHeart 6 when looked at amongst the numbers of
dogs which have been presented, that rate cannot be extracted from the
background of mortality in the dog population.

(Slide.)

Fort Dodge does place its adverse event reports into categories. Two of
those categories are allergic reports and non-allergic systemic reports.
Our allergic category are the largest events that we see, but only
slightly thus so. The signs in this category are typical for what you
would expect in a dog with allergy occurring within 48 hours. The
systemic non-allergy reports involve any body system that is not typical
of an allergy. We would point out that many of the events in this
category overlap into the allergic category, but they are just not
stereotypical enough to be called allergy.

(Slide.)

The rate of adverse reporting with allergy is low at the rate that has
been previously told to you at 1.26 reports per 10,000 doses sold. The
vast majority of 80 percent of these events are self-limiting and the
dog does return to normal. The relative frequency of these allergy
events are decreasing over time with no breed predilection. We have
stated that the rate of these reports is similar. We have never said
that they are identical, and what we have said is that given the
limitations in the systems, trying to measure biologically complicated
systems, these reporting rates are similar to Fort Dodge Animal Health
vaccines.

(Slide.)

Now the CVM has expressed to you a concern about some unknown toxic
mechanism that seems to be involving a wide variety of systemic
responses in the dog. We believe that it is widely recognized that when
an approved medicinal product causes toxicity that this toxicity would
be expected to be seen in a small number of target organs. In contrast,
the wide variety of suspected adverse event syndromes assigned to
ProHeart 6 by the CVM is consistent with these standards.

(Slide.)

Fort Dodge has conducted a complete re-analysis of all of its
non-allergy adverse event reports. To assist us in this analysis we did
obtain the expertise of outside consultants who are extremely well
recognized. We had the neurological cases reviewed by Dr. DeLahunta,
Diplomat of Internal Medicine, specialty in neurology. The hepatic and
hematologic events were reviewed by Dr. Alan Rebar, Diplomat of
Veterinary Pathologists with a specialty in clinical pathology. The
neoplasia cases were reviewed by Dr. Phillip Bergman, Diplomat of
American College of Internal Medicine, specialty in oncology.

(Slide.)

It is the opinion of these independent experts and Fort Dodge Animal
Health that the majority of the adverse events are not causally related
to ProHeart 6 and reflect the normal range of diseases occurring in the
dog population.

(Slide.)

To summarize, Moxidectin-based products are used in a variety of animal
species in over 70 countries around the world. There is an extensive
toxicology study conducted in mice, rats, and dogs to support the
approval of moxidectin for use in food animals, and this food animal
approval is important. The food animal, the regulations to get a food
animal drug approved are much higher than a domestic animal. So
therefore the amount of information we have associated with moxidectin
use in animals is much higher than would be associated with most
domestic animal approvals. I have three more slides.

In a one-year dog toxicology study, the daily dose of moxidectin
resulting in a monthly moxidectin exposure that is 454 times greater
than the doses administered that are recommended with ProHeart 6
resulted in no toxicologically-significant findings.

(Slide.)

The rate of submission of initial adverse drug experience reports to the
CVM has decreased in 2002 and \-- excuse me, 2003 and 2004 as compared
to 2002. ProHeart 6 is subjected to substantial over-reporting bias.
Even with this over-reporting bias and when corrected for market share,
the numbers of adverse events associated with ProHeart 6 is similar to
major competitors.

DR. CRAIGMILL: Dr. Hustead, I am very sorry, but we are out of time. You
have exhausted your hour plus a few minutes and we must move on. If you
could skip to your last slides please very quickly. Most people on the
panel have the handouts and can review them.

DR. HUSTEAD: My last slide is based on this analysis. Fort Dodge Animal
Health concludes that ProHeart 6 is a safe and effective product for
prevention of canine heartworm disease.

DR. SUNDLOF: Okay. We are skipping ahead in our agenda to a
clarification of VMAC questions, and at this time we are going to ask
the VMAC committee members to ask questions of any of the speakers that
have presented today and begin the discussion. I am going to ask Dr. Dan
McChesney who is our Director of the Office of Surveillance and
Compliance in CVM to go over the questions which we will ask for a
committee response to later on this afternoon. Dr. McChesney.

**[Clarification of VMAC Questions]{.underline}**

**Dr. Dan McChesney**

DR. McCHESNEY: Thank you. As you can see up on the slide there, we have
really two questions. The first question we would like to ask the
committee is \"Based on the presentations and information provided, is
ProHeart 6 safe for use in dogs?\" We would like a yes or no answer to
that. We would also like to know, \"If there are remaining safety
concerns with ProHeart 6, what additional avenues of research could be
explored to mitigate and/or prevent the adverse events?\" So we would
believe there should be discussion on that. Thank you, and turn it over
to the committee now.

DR. CRAIGMILL: Thank you very much. With that I would like to open up
for questions from the committee to the people who have made
presentations this morning. Lauren.

DR. TREPANIER: I have a question for Dr. Glickman. I would like better
clarification of the way the Banfield study was done. I'm not really
clear on how the adverse event was defined and what time frame. It says
30 days, but in what time frame were clients called? That seems a little
unclear to me.

DR. GLICKMAN: Okay. As part of normal \-- maybe I will let someone from
Banfield address the question of when are clients called first before
then I will answer your question.

DR. CAMPBELL: I'm Scott Campbell. I'm a veterinarian \-\--.

(Adjusting equipment.)

DR. CAMPBELL: Okay. My name is Scott Campbell. I'm a veterinarian and
CEO of Banfield, and what we do is we call all of our clients three days
after they have been in the hospital. We also cover reactions at no cost
to the clients, and they get a warranty when they leave that says that.
So they all know that, and our clients on average come in about
three-and-a-half times a year. So we see them very, very frequently, and
of our clients about 94 percent come back for all their future care and
service. So whenever we get a reaction we are very confident we get it
reported because we pay for it, and that is one of the reasons we do it,
because we want our patients to get the very best care.

DR. TREPANIER: Are you open for emergencies?

DR. CAMPBELL: Most of our hospitals are open seven days a week and we
refer. We have relationships with emergency clinics, you know, in the
area, and then those clinics of course refer back to us in the morning,
or at least we get the report and any reports are followed up on by
telephone that day.

DR. TREPANIER: But if a patient was seen in an emergency clinic that
wasn't associated with Banfield you wouldn't necessarily know about it?

DR. CAMPBELL: I suppose it's possible, but emergency clinics generally
\-- you know, we have a relationship with a clinic that we refer to, and
we give the clients the number of that emergency clinic when we are not
closed. Those clinics, you know, prepare a report for us the next day.

DR. GLICKMAN: I will answer the second part then. I believe it was how
do we define adverse events? Is that the second part? What we did is we
looked at the list of adverse events that had been reported on the
website from FDA CVM and reports that Fort Dodge has received. Then we
classified them into neurologic disease, liver disease, et cetera.
Mostly it is by system and also allergic reactions and anaphylaxis. Then
we go to experts in the field and say what would constitute a legitimate
or accurate diagnosis, and we go into the database then from Banfield
and pull out all the codes. The consist primarily of two types,
clinically diagnosed abnormalities, like hepatitis, and then laboratory
abnormalities. In the case of liver disease it would consist of three
enzymes and bilirubin, and so we look for abnormalities in laboratory
values, clinical diagnosis, and in different combinations of the two.

MS. : A slide is up there is you want to.

DR. GLICKMAN: Okay. There's a slide. This is actually \-- it was too
busy to show, but it's a detailed breakdown for each class of adverse
event, what went into defining an animal with that event.

DR. TREPANIER: So how does the diagnosis get coded? So let's say an
animal is seen and then a week later calls and speaks to a veterinarian
and the animal is vomiting. Does that get coded as a diagnosis in the
record, or is it only a diagnosis if it gets coded associated with a
visit?

DR. GLICKMAN: No, it can get coded either way. It gets into the medical
record either as a code if there is a corresponding code in the Banfield
database or as medical notes, which are also computerized and are
searched. So we can do it either way, but it does get into the record
when it is reported back to the Banfield clinic.

DR. MEALEY: Thank you. Going back to \-- this is for you again, Dr.
Glickman.

DR. GLICKMAN: Good.

DR. MEALEY: You had a slide up there and the slides in here, I didn't
think I was getting old, but I couldn't see the print in here. So I am
going back to the original that you guys sent us. For anaphylaxis, you
know, you broke down allergic reactions and things like that, but for
anaphylaxis you didn't further break down the rates of ProHeart, you
know, with vaccine, and heartworm one with and without vaccine. And I
think if I remember right, your conclusion was that the rate was low for
anaphylaxis?

DR. GLICKMAN: Yes. The rates as we showed, overall rate, was 0.5 per
10,000 for anaphylaxis, and the rates then within the different
categories, the highest one was actually 1.7, which would have been
heartworm preventive two with the vaccine. The rest were somewhat lower
for the other products without vaccine.

DR. MEALEY: But if you look at the heartworm preventives alone \-- tell
me if I am looking at this correctly. ProHeart by itself was more than
twice \-- had more than twice the rate of anaphylaxis than any of the
other heartworm preventives, is that correct?

DR. GLICKMAN: That's correct. The 0.7 versus roughly 0.2, and when we
looked at those \-- and I didn't show you all the models we developed.
When we looked at the risk factors or the associated factors for
anaphylaxis they do not come out. None of the heartworm preventive
products come out in the multivariant models. That is why there was no
multivariant model to show with significant findings, and because the
rates are so low those models are more unstable than would be the models
for let's say liver events, which are more common. But we didn't find
any significant risk effects for any of the heartworm products for
anaphylaxis.

DR. MEALEY: Okay. Thank you.

DR. McGLONE: Dr. Glickman, you are very popular today. I was struck by
the difference in the rate of death of dogs in the FDA data and in your
model, and also in the raw data it appeared that there were \-- it was a
higher rate of death among dogs vaccinated and treated with the product
in question. But in your multivariant model near the end of your
presentation, the risk for death was actually decreased. So I am
wondering what was in that multivariant model that accounted for the
differences that when they weren't in the model.

DR. GLICKMAN: Right. I don't remember specifically for that model, but
we did further analysis of every model. We put all potential
interactions into the model, all potential two-way interactions, and the
variable that seemed to have the greatest impact on most of these models
in terms of changing the appearance from the initial analysis to the
adjusted was age of the animal. For example, we know that liver disease
and death are highly correlated with age. The older the animal, the more
likely they are to experience this. So in answer in general, age
appeared to be the largest confounding factor. That is why I would
almost rather rely rather on the absolute rates, the adjusted models, to
come up with the true independent impact of these products.

DR. McGLONE: Right. Were any of the variables in model correlated with
heartworm use, and were they also included?

DR. GLICKMAN: Yes. All the variant models \--

DR. McGLONE: Heartworm medication.

DR. GLICKMAN: Yeah. I mean frequency of use or what product is used. We
tried to look at the factors that could be either associated with the
use or the product or the adverse events we were looking at and put them
in the model, and not discriminate and actually put them in all models.
There are a lot of relationships between the variables in the models
like age and weight obviously and those things, and you can't anticipate
all of them. It's nice we have the luxury with such a large data set to
be able to put all the potential confounders in the model and still come
up with stable estimates, and that's what we've done.

DR. McGLONE: But doesn't including correlated variables remove the
effect of the correlated variable? In other words, if the product is
given more to older dogs than younger dogs for example, and then age is
in the model, then doesn't the age effect sort of seem to account for
the effect that might also be the product?

DR. GLICKMAN: It is a little more \-- that is true, but it's a little
more complicated because for age to be a confounder in one of these
looking for associations it would have to be both associated with the
use of the product, but also associated with the outcome that you are
looking at.

DR. McGLONE: Well, age would be a \--.

DR. GLICKMAN: And age is, yeah. It's just the most obvious one. But then
of course age and weight are highly correlated in these databases.

DR. McGLONE: Thank you.

DR. LUSTER: I had a couple of clarifications, one for Dr. Brown and one
for Dr. Glickman. On the FDA data, does the anaphylactic responses that
are measured, are the reported? Maybe I missed the data, but I saw that
you look at concomitants with all disease, but is there concomitant
vaccination data particularly with anaphylaxis that you have available?
And secondly, do you have any data that would suggest that ProHeart 6 is
used when anaphylaxis is observed which seems to be very high incidence
that there is \-- that that occurs after the first use or after multiple
uses?

DR. CRAIGMILL: Dr. Luster, is that a question for Dr. Brown?

DR. LUSTER: Dr. Brown, yeah.

DR. BROWN: I'm not sure that I heard the first part of the question. I'm
sorry. If you \--

DR. LUSTER: Okay. The first question was whether the data from the ADEs
indicated that there was concomitant, specifically concomitant
vaccination with the anaphylactic responses.

DR. BROWN: Yes. We have for the anaphylactic reactions that
approximately half or a little less than half of them also had
concomitant vaccinations with drugs.

DR. LUSTER: Okay. You mentioned that with the whole, all the
pathologies. Is that specifically for vaccination for anaphylaxis as
well?

DR. BROWN: It would not necessarily be only vaccinations. It could be
some other injection or tablet at the same time.

DR. LUSTER: So you don't have that information then. Do you have
information on the incidence of anaphylaxis \-- not the incidence, but
when anaphylaxis occurs whether it is after the initial first time the
drug is used or after multiple uses with ProHeart?

DR. BROWN: There are instances were a dog might not react with the first
injection of ProHeart 6, but subsequently have a reaction after say the
second or the third. It seems that those reactions tend to be more
involving say the liver signs or sometimes possibly the hemolytic
anemias. In other words, there wouldn't necessarily be a full-blown
anaphylactoid reaction, but could include some of those other signs as
well. Typically if there were an anaphylactoid reaction the first time
you wouldn't get a subsequent injection, but there are dogs that have
had two or three, or some of them more than that, injections of ProHeart
6 and we are not seeing the reactions until say the fourth injection.

DR. CRAIGMILL: Essentially your ADEs do distinguish that?

DR. BROWN: Yes, they do. We do write that down in reports and take a
look at that.

DR. CRAIGMILL: And one quick question for Dr. Glickman. I was a little
confused on how does diagnosis differentiate between anaphylaxis,
allergy, and immune-medicated specifically?

DR. GLICKMAN: I think I'll pass that question on to Dr. \-\-- perhaps or
Will.

DR. NOVAK: So could you repeat the question?

DR. CRAIGMILL: What are the specific differences in the diagnosis
between immune-mediated, allergy, and anaphylaxis?

DR. NOVAK: As far as the database system we would look for both anything
that is clinical signs as well as any laboratory findings that are
tracked. And so as far as what Dr. Glickman's work did on analyzing all
of that, he was \-- my understanding is that he was searching through
the database for anything that was in the medical notes as well as any
laboratory findings as well as any clinical signs that were associated.
Is that correct, Larry?

DR. GLICKMAN: Yes. We really only used medical notes as backup. So it
was not part of our original search. But codes are up here. The actual
codes that were used to describe each of those. Now if you are asking
how does the clinician distinguish when they write down auto-immune
hemolytic anemia, that would be based on Banfield diagnostic protocols.
They do have protocols that they shared with me for an auto-immune
hemolytic anemia.

DR. CRAIGMILL: I am still a little confused, because I mean an immune
hemolytic anemia would be relatively straightforward diagnosis, but
allergy, I am not sure what that might \-- how that was specifically
addressed.

DR. GLICKMAN: Okay. That is a good question. I said we used medical
notes as a backup. So for example when there was a diagnosis of allergic
event vaccine associate or allergic event drug associated, we took a
sample, a very large subsample of the medical notes to go in and
characterize what they are calling the allergic events, and it parallels
what you see in the veterinary textbook as a description of allergy.
Facial swelling, pruritus, urticaria, and vomiting were the major ones.

DR. NELSON: A different avenue I want to approach here. In the paper
that we got from Fort Dodge there are talking about the
heartworm-positive dogs in trials, and on page 26 there were two safety
studies that are quoted and one of these \-- well, first of all, are
these experimentally-infected animals or naturally-infected animals?

DR. COBB: There were two types of studies conducted, one in which
heartworm-positive dogs were determined by circulating microfilaria.
There was a second study that was conducted at the request of the Center
that involved implanting adult heartworms into the dog so that the
actual age of the adult heartworm was known and when the infection was
established was known. So there were two types of studies done.

DR. NELSON: So one experimental and one naturally infected?

DR. COBB: Right.

DR. NELSON: Okay. The other thing, on page 22 when you were testing for
efficacy against three- and four-month-old heartworms there is talk
about now effective it is. There weren't any reactions noted during that
time period on the three-month and four-month-old heartworms.

DR. COBB: I would ask Dr. Rock to comment on that one.

DR. ROCK: My name is David Rock. I am Director of New Product
Development for Fort Dodge Animal Health, and could I just hear the
question one more time as far as the three- and four-month infection
retroactive studies?

DR. NELSON: Right. On page 22 of your report there is talk about the
efficacy against three- and four-month-old heartworms post-infection.

DR. ROCK: Correct.

DR. NELSON: The question is was there any reactions noted when this was
\-- when the drug was given to these dogs? It talks about efficacy but
nothing about any reactions.

DR. ROCK: Okay. There were no adverse reactions to the dogs. There was
no adulticidal activity of the drug in those experiments. You will see
that these worms were classified as abnormal but still alive. So the
rate of kill again as an adulticide was not very fast and did not cause
an adverse reaction, no.

DR. NELSON: Next one. When you were testing the product, because \-- you
know, partly the heartworm label was added later about, you know, if
adverse effects were seen in heartworm-positive dogs. And just from, you
know, kind of doing some review, you know, Veterinarians VIN, we see
some Veterinarians Report no cases, and some veterinarians report
multiple cases. Has anybody tested or seen what happens to this product,
you know, just for example theoretically, if a technician drew it up
with the 18 or 20 gauge but then try to force it through a 22 gauge
needle? Do the microspheres break up? Would it cause an increased dosage
of moxidectin release, or has that even been looked at?

DR. COBB: What we do see, the product is designed to go through a 21
gauge needle or larger. What can happen if you use a finer gauge needle
is that sometimes you may get a blockage in the needle and the product
is difficult to force through. That is the only information I can
provide you. It is impossible to push them through very, very fine
needles because they are particles that are suspended in the carrier.

DR. NELSON: Now if the product sits like where you have from the time it
is mixed up there is, what, a 30-day? If it sits for two months is the
moxidectin released in the vehicle?

DR. COBB: We have tested this quite extensively after three months
post-reconstitution, and moxidectin is not significantly acceleratedly
released upon storage. The vehicle is specifically designed to maintain
suspension of the microspheres and it does not draw out the moxidectin
selectively. So we do recommend that the product is used only with the
appropriate vehicle. It should not be resuspended in saline for example
where the microspheres could settle fairly quickly.

DR. NELSON: One other thing I noticed in reviewing the 36 cases that
were given to us by the CVM, about 22 of those 36 cases there was no
heartworm status provided, whether they were negative, positive. Any
previous heartworm preventative, one particular dog had had one
injection, two years later had another injection, but no mention of what
was given in between or any preventive history.

DR. HUSTEAD: That is a reflection of the data that you can get from
veterinarians. You can ask the questions and you get the answers that
you get. We recognize the deficiency in the information.

DR. CRAIGMILL: Dr. Nelson, we can continue this after lunch. I am
informed that we must break now. Ms. Sindelar has some information
before we do so. We will reconvene at 12:30.

MS. SINDELAR: All right. Thank you very much. There is a restaurant
downstairs. There are also local restaurants in the area which you can
walk to, and if the members and consultants will stay for just a minute
so that we can all have lunch together, and we will reconvene here at
12:30. Thank you.

(Whereupon, a luncheon recess was taken at

11:30 a.m.)

[A F T E R N O O N S E S S I O N]{.underline}

(12:30 p.m.)

MS. SINDELAR: Thank you, everyone. Please take your seats and we will
restart the meeting. Because we have so many questions still to the
panel members we would like to continue for the next 30 minutes, from
12:30 until 1:00, entertaining questions to those who have presented
today. At 1:00 we will begin with the open public hearing as originally
planned. So, Art, you can take it from here. Thank you.

DR. CRAIGMILL: With that I would like to open up questions again for
both representatives from CVM and from Fort Dodge. Panel members? Yes,
Corrie, Dr. Brown.

DR. C. BROWN: I have a question for Dr. Cobb and Dr. Brown. We heard a
lot of numbers this morning about the numbers of animals that were
affected by various clinical syndromes and the numbers that died.
However I didn't see much in the way of pathologic reports. What is the
correlation for instance of 378 dogs with convulsions, 61 died. How many
of those was a necropsy performed, and what were the histopathologic
findings? I see that there is sort of \-- I haven't quite seen a
biological correlation between adverse events and death.

DR. BROWN: Let me address that, a portion of that for you. I can't give
you any exact consistent type of necropsy finding because necropsies
aren't always done. For the necropsies that were done, the reports would
vary very much. For example, sometimes you might have encephalomylacia
with hemorrhage in the brain. You might have hemorrhage or lesions in
other organs in the body with the comment consistent with anaphylaxis.
With some of them the lesions might be consistent with severe protracted
seizures. It depended very much on the type of death that occurred.

DR. C. BROWN: So in how many of these 485 deaths do we have necropsy
data?

DR. BROWN: I can't say exactly. I would say probably in a third or less.

DR. C. BROWN: Well, a third would be a lot to look at, and that would be
very helpful, and we have 192 \-- 257 dogs with liver problems; 85 died.
Did those 85 die due to liver problems? It is not clear from the report
and Dr. Cobb from the Fort Dodge information, all I saw was that there
were 15 livers examined histologically. Is that the sum total of what
was looked at from your perspective?

DR. COBB: I would like to answer that question in a little bit more
detail by asking Dr. Rebar to comment. He did the expert evaluation of
all the liver reports that we believed could possibly be related to
ProHeart 6, and they did include liver reports that did have either
pathology or clinical pathology liver enzyme, and I would ask Dr. Rebar
if he would describe what he did.

DR. REBAR: So I will focus specifically on the hepatic adverse event
reports.

DR. C. BROWN: Yes. You know, Dr. Rebar, I have read the report so I know
about all the \-- you know, the liver enzymes. I want to know about the
anatomic pathology.

DR. REBAR: Well, in that case I might defer to Keith Harris who actually
did the pathology.

(Laughter.)

DR. HARRIS: Thanks. Thanks, Dr. Brown. That is a good question and we
did only look at 15 cases, and those were selected based on the cases
that we actually felt confident \-- were graded as confident that were
added cases. We were looking at ones that we were trying to look for a
pattern to see if we had a common \-- morphologic changes that would
suggest a common mechanism for any toxicity we might see. So we selected
the more severe cases to look at. You know, it has been brought up
before there is not a lot of full post-mortem cases. They weren't done
in a systematic way. Some are more thorough than others, but that is the
reason we chose this subset.

DR. C. BROWN: Okay. So 485 cases. If you think there are necropsy
results on a third, well, that's what, 150? And of that looking at it in
this context in a controlled systematic way, there were a total of 15
livers examined?

DR. HARRIS: That is all we examined that we could identify clear-cut
cases with liver signs.

DR. C. BROWN: And CVM didn't consult with any other pathologist to look
at this series of cases?

DR. BROWN: The liver lesions that we are looking at are not necessarily
of course the same ones that Fort Dodge has looked at, and the pathology
reports would have come in from across the country. The reason for
pathology, the types of lesions found in histopath are not any one
specific type of lesion. They are not all hepaticellular necrosis for
example. Some of them could have been that. Some of them could have been
consistent with allergic type reactions or hemolytic anemia. It depended
very \-- we don't have any one consistent type of lesion across the
board.

DR. REBAR: Dr. Brown, if I could make one comment that may expands a
little bit what Dr. Harris was saying. I actually examined the case
studies from about 251 animals, and of those there were 15 that had
histopathology of the liver. I think that those were the cadre of 15
that were actually examined by Dr. Harris.

DR. C. BROWN: So no one looked at the pathology reports with an idea in
mind about what moxidectin might cause pathologically?

DR. COBB: We examined all the histopathology reports that were available
to us, and they numbered 15. We did ask for them to be looked at by Dr.
Harris. In addition, we did identify a number in excess of 200 reports
that had diagnoses that were either liver or were hematologic; and for
those, although they did not necessarily have histopath reports, they
may have had clinical reports, they may have had autopsy reports, and
those we referred to Dr. Rebar since he has expertise both on hematology
and on liver. So, yes, we made a very extensive effort to evaluate in
excess of 250 of those cases that met the case definition of possibly
related. Thank you.

DR. CRAIGMILL: Other members of the panel? Yes, please go ahead.

DR. GROSECLOSE: Question for either Dr. Post or Dr. Brown. What is the
FDA policy on follow-ups once you receive a report?

DR. BROWN: It is usual for the drug company, the sponsor, to perform
follow-ups on adverse events and send them in subsequently to the
initial report if there is any further information to be gathered. If we
are able to and we feel that we really need to have further information,
we might inquire back to the sponsor if further information is
available, and if not could they please find out if it is and if so
submit it to us. Sometimes we might call the veterinarian for
clarification.

DR. GROSECLOSE: You mentioned that your report mentioned that 99 percent
of most adverse events are reported from the sponsor. In this particular
case, what was the proportion of adverse events that were reported from
the sponsor versus from the general public or veterinarians directly,
and did that change over time?

DR. BROWN: I think that with ProHeart 6 as with all the other drugs
really the large, the vast majority, are the ones that are submitted by
the sponsor. We will have reports also submitted directly from the
public, and as you might expect those numbers of reports increase
significantly after increased publicity. But we have not included any of
the reports coming in from the public since the voluntary recall.

DR. GROSECLOSE: Among the seven veterinarians who review the adverse
events, have you ever \-- do you do a single classification, or do you
have numerous observers classify the cases to see whether different
observers would classify them similarly?

DR. BROWN: Usually it is one person doing each report. But if someone is
having trouble really trying to understand the information in the
medical record or if there are a lot of factors to be considered we
might say, \"Hey, could you take a look at this report and run it
through the algorithm and see what you come up with?\"

DR. GROSECLOSE: Okay. Thank you. Dr. Glickman, could you talk a little
bit about the risk window that you talked about, and for example if a
dog is treated with heartworm preventive there was the three-day
follow-up. But when you looked at that dog's experience over time and
following the treatment, how long was the typical follow-up to capture
any adverse events that might have occurred? And also any treatment, for
example the steroids, and how did that enter into your multivariant
analysis?

DR. GLICKMAN: Okay. I think there are a couple of questions there. With
respect to the callbacks, that was not part of any of our research. That
was a normal part of Banfield practice. The information captured from
those callbacks gets into the medical record. We go only with what was
in the medical record. Our follow-ups were intended to be 30 days for
each exposure, whether it was ProHeart or one of the monthlies. Our
intent was to follow those animals for 30 days to see what happened in
that 30 day window. The only time we cut it short, we would have
terminated of course if the animal died, or if during the 30-day window
for example an animal that had previously gotten ProHeart and we were
following then received a vaccine we would stop the 30-day window with
ProHeart at the time of the vaccine and then start a new 30-day period
for the vaccine and so on. So it turns out that of course not every
animal was followed for 30 days unless they fall in for ProHeart, but
the average length of time is 29.2 days. So it is pretty close, and for
heartworm one, which is the major product oral, it was 27.2 days. So we
are pretty close at 30.

Now you can arbitrarily say 60 days or 90 days. Of course you can get
more and more being cut off when you go that far, and it is pretty
standard in human vaccine and drug studies to use the 30-day window. Why
I am not quite sure. What we do know though from the 30-day window is
that the first three days will capture about 90 percent of the allergic
reactions. Day seven to about 21 will capture most of the
immune-mediated like hemolytic anemia and ITP, and then the other events
it is hard to tell. They are scattered throughout the window. So that
was our approach. I agree with it could have been 60 days. I certainly
wouldn't want it to be less than 30 days for most of these events.

DR. GROSECLOSE: So any steroids that would have been administered within
a 30-day period would have showed up in the model as well, and they may
not have been administered at the time of the ProHeart administration.

DR. GLICKMAN: That is correct, and we felt it important to look
especially at steroids because of course we have very little
quantifiable information about what they do, and for the non-steroidals
that is also true as it was up until a little while ago in human
medicine. So we felt we had to improve. While we could have picked other
classes of drug, you know, where do you stop? So we decided to at least
with drugs use the steroidals and the non-steroidals, especially knowing
about the effect of the steroidals on the risk of liver disease.

DR. GROSECLOSE: While I am hogging the mic, one question about did you
look at the group of dogs that during this time period received only one
ProHeart administration versus those who received two or more to see
what the model might have looked like in that?

DR. GLICKMAN: Yes. Every time we found a significant relationship
between ProHeart and an adverse event we followed up with a days at risk
analysis, but we also followed up with a dose response analysis. So we
went back in the record to see whether this was the first, second,
third, fourth, fifth time. The most we had was five, but given every six
months and we did it for two-and-a-half years, that is all we would
expect. So when possible we looked for a dose response relationship. Now
a little bit of caution. I mean, it is possible that an animal had gone
previously to another vet, a non-Banfield veterinarian, and received
ProHeart. We would have not known about that. But, yes, we always look
for a dose response relationship and did not find it.

DR. GROSECLOSE: Thank you.

DR. PAPICH: Dr. Brown, when you were talking about the elevations in
liver enzymes, are the elevations that are assessed by comparing one
measurement to another? Or were these simply liver enzymes that were
above normal as a single measurement.

DR. BROWN: These would have been liver enzymes that were above normal as
reported by the individual veterinarian according to their laboratories
that they used.

DR. PAPICH: So is it possible then that these could have been liver
enzymes above normal that the animal had prior to any drug
administration?

DR. BROWN: That's always possible. Now sometimes of course we were
fortunate and there it was based on blood work drawn before, and in
those circumstances then of course we could assign a higher score.

DR. PAPICH: Relating to the liver enzymes, Dr. Glickman, when you talked
about in your evaluation liver disease, are you talking about elevations
in liver enzymes or is this documented liver disease in those animals?

DR. GLICKMAN: A comment about liver enzymes first. We had the benefit
that Banfield submits virtually all of their laboratory work to one
laboratory nationwide, and that is Antech. So that built in some sort of
degree of consistency on the results for liver enzymes. We collaborated
with Al Rebar to tell us what the conservative cutoff levels are for
each enzyme, and in fact originally I just took what was in the Banfield
databases as being normal or abnormal. When Dr. Rebar looked at that he
says, \"No, I'd rather be more conservative and more specific.\" So he
set the enzyme levels. Then what we did was we looked at either any
abnormal laboratory value of the enzymes, any clinical diagnosis of
liver disease or combinations of those \-- meaning having both a
clinical and a laboratory finding or either one of those. We looked at
it all different ways, and it really didn't change any of the
relationships. So we went with what I showed you was primarily a liver
disease diagnosis plus a laboratory abnormality.

DR. PAPICH: I would like to ask a couple of questions about the
pharmacokinetics of the drug. In this slow-release preparation in the
graphs that were shown to us today it shows a peak of about seven to 10
days in the picture that we saw. It is in the handouts that we have. It
shows a nice average plasma concentration. For anyone at Fort Dodge that
is familiar with the kinetics, I don't know who that would be, if they
could answer this. The picture that we have seen representing average
concentrations, just how variable are those concentrations? Like what is
reality in other words when we talk about a peak of seven to 10 days? Is
that highly variable or is that consistent? Can somebody comment about
that?

DR. COBB: There is individual dog-to-dog variability, and we did run
pharmacokinetic studies in laboratory beagles which generally gave more
uniform results than in the crossbred dogs that we looked at. The window
of peak blood levels appears to range from about five days to 12 days in
individual dogs. We do not see gross, huge variabilities or peaks at 30
days or later. It generally is a pretty indicative value to say that the
product peaks between seven and 10 days.

DR. PAPICH: Relating again to the nature of the formulation, could
somebody from Fort Dodge fill us in a little bit about the nature of the
formulation? I'm not sure that everybody around the table understands
the \-- just what makes this formulation slow release versus something
else so that we can better understand how this drug is released over
such a long period.

DR. COBB: I would be very pleased to answer that, Dr. Papich. It's in
two parts. One relates to the inherent characteristics of the molecule.
Moxidectin is a very highly

\-\-- molecule with a very long half life in dogs, approximately eight
days. So it particularly does lend itself to a sustained release
formulation. It also has a very large volume of distribution regardless
of whether it is applied topically or orally or by injection. So it
penetrates into the fatty tissues of the body. It makes it very suitable
for sustained release. We put this molecule into a microsphere that is
based on glyceryl tristearate.

So when the product is presented to the veterinarian it comes in two
vials. One vial has the microspheres, glyceryl tristearate containing 10
percent moxidectin. The micropheres are manufactured to very, very
strict size criteria so that the surface area is very uniform and the
release of moxidectin from these microspheres occurs in a very uniform
manner. The second bottle contains the diluent, and the diluent is
formulated to a very specific viscosity to maintain the microspheres in
suspension after the product is reconstituted. Because in order to get a
uniform dose it is very important that the microspheres remain uniformly
distributed through that vehicle. So that is just a thumbnail sketch of
what the product is and why it does work in the way that it does work.

DR. PAPICH: Are there studies that you have done in dogs where either
the diluent and/or the material in he microsphere minus the moxidectin
has been injected into dogs?

DR. COBB: We have indeed. In our investigations of allergic events we
ran a great many tests looking both at complete product and looking at
every component within the product including the preservatives that are
used because they are not \-\--. We were not able to consistently
demonstrate allergic reactions in dogs to any of the components or the
finished product. We could on occasion by intradermal skin allergy
testing see a wheel or a flare with either moxidectin or the moxidectin
microsphere, but that was not repeatable and not consistent. We did try
to reinduce allergic infection \-- reactions in dogs that had reacted to
ProHeart.

We were not successful in doing that with either the complete product or
with any of the components, and through the University of Wisconsin we
ran a large-scale study where more than 7,000 dogs were treated with

ProHeart 6. They concurrently received vaccines, either five antigen,
seven antigen, or nine antigen parenteral vaccines. They also received
kennel cough vaccines, some of which were intranasal and some were
parenteral. What we were trying to do was to identify reactive dogs so
that we could look at investigating the problem further.

With these 7,000 dogs we were able to identify one dog that showed
facial swelling on treatment with ProHeart. We have subsequently
retreated that dog twice with ProHeart and have been unable to reproduce
any clinical manifestations at all. So it does appear to be
idiosyncratic.

DR. PAPICH: Thank you.

DR. RIDDELL: I have got a couple of questions relative to reporting for
Dr. Brown, and also a question for Dr. Hustead. Dr. Brown, relative to
the suggestion that there is under-reporting, when I looked through the
FDA packet all the reference are human. So my questions are what general
comments do you have supporting the under-reporting phenomenon, two,
specific to ProHeart 6, and the third, what would be your response to
Dr. Hustead's comment that there may actually be over-reporting of
ProHeart 6?

DR. BROWN: I think that when we are talking about the reports that come
in we have to consider that they come in from the same kinds of people,
that is veterinarians and from owners, and they come in from all across
the country and they come into the drug companies who then submit them
to us. As far as comparing under-reporting in veterinary medicine with
under-reporting in human medicine, I don't know that I could make that
kind of comparison. I do know that we are far more limited in veterinary
medicine as far as being able to have patient information available and
to look prospectively particularly at any kinds of reaction to
reporting.

With ProHeart6 as far as claiming that that might be over-reported, I
think that if you are looking to a relation to media interest and public
interest such as the websites for example, those really started to kick
in early in the spring of last year. But as you can see from our slides
that we've shown you before, we already had a great many reports coming
in before any public interest was stimulated.

DR. RIDDELL: Thank you. Dr. Hustead, the Modified Kramer System may
actually have been a benefit for ProHeart 6 because the dechallenge and
rechallenge really wouldn't be totaled into the score. But you say with
your familiarity with VICH that they don't recommend that system. Does
the system that VICH recommends have some added objectivity to it as far
as grading adverse events?

DR. HUSTEAD: Let me try to address both your questions about
under-reporting and about VICH and the Modified Kramer System. I don't
think there is any question that adverse events in general are
under-reported. I would think every expert in the world would say that
as a general rule of thumb all adverse events are under-reported. The
point that I was trying to make is that if you are going to compare two
products that you have to look at the relative issues between those two
products and determine if the same level of under-reporting exists. It
was my point that in a comparison that the reporting biases are
different with the two products. So I hope that was clear.

Versus the Modified Kramer System, I think you can argue the advantages
and disadvantages of the Kramer System for a couple of days, as you can
with the VICH system for a couple of days; and we have done so, haven't
we, on VICH? Numerous times. There is no objective information that
would say which system is better or not. At the end of the day, it was
VICH's interpretation that both systems are subjective, and that with
the Kramer System you get a number and that makes people have some
confidence that that's objective. But at the end of the day all you are
doing is asking an educated person \"Do you think timing is positively
or negatively correlated with the event? Do you think the pharmacology
and toxicology of the event are positively or negatively associated with
the event? Do you think there are alternative explanations positive or
negative associated with the event?\" And then you make an assessment at
the bottom.

DR. RIDDELL: Thank you.

**[Open Public Hearing]{.underline}**

**Aleta Sindelar**

DR. CRAIGMILL: Thanks very much keep those questions. We will be coming
back. At this time we are gong to move to the public comment section of
the program. You are not off the hot seats yet, folks. Lots more to
come. Ms. Sindelar will lead this discussion, but before we begin with
the public hearing I am going to read this statement into the record
about the open public hearing.

\"Both the Food and Drug Administration, FDA, and the public believe in
a transparent process for information gathering and decision making. To
insure such transparency at the open pubic hearing session of the
Advisory Committee meeting FDA believes that it is important to
understand the context of an individual's presentation. For this reason,
FDA encourages you, the open public hearing speaker, at the beginning of
your written or oral statement to advise the committee of any financial
relationship that you may have with any company or any group that is
likely to be impacted by the topic of this meeting. For example, the
financial information may include the company's or a group's payment of
your travel, lodging, or other expenses in connection with your
attendance at the meeting. Likewise, FDA encourages you at the beginning
of your statement to advise the Committee if you do not have any such
financial relationships. If you choose not to address this issue of
financial relationships at the beginning of your statement, it will not
preclude you from speaking.\" Ms. Sindelar.

MS. SINDELAR: Thank you very much. To begin the open public hearing
let's begin with Tom Stafford. Please remain standing at the mic for
your entire presentation, and you have five minutes.

MR. STAFFORD: Well, anyway, I have no financial reason to be here. I'm
financially poor. I drove myself from Texas and spent the night in my
van. My daughter wrote you all something. I wrote about three or four
different speeches, and after reading hers the night before I left I
threw mine away. She was five years old when we got Bear. At his death
she was 13. I have a son 17 and a wife.

She starts out, \"To the makers of ProHeart 6, to my knowledge my dad
and I took our dog, Bear, and our two other dogs, Angel and Mickey, to
the vet as we did every year to get a checkup. As my dad waited for the
vet to call us in he noticed that they had come out with a new shot, a
six-month heartworm shot. So he decided to look into it, asked the vet
about it. Everybody thought it was okay, even though Bear had had 15
seizures just three months prior. Three of our other dogs got the same
shot on the date of May 9^th^, 2002. Not two days after that my
nine-pound Pekinese had a seizure.\"

At that point I really thought my kids were overreacting or just looking
at the dog seeing our other dog having seizures just \-- I didn't
believe it to be quite honest until after everything else happened.
Anyway, back.

\"Poor Bear had his first reported seizure on 11/13 of '01, not long
after my dad stayed up all night with Bear watching over him and taking
care of him because in the night total Bear had 15 seizures. I woke up
the next day to my mom taking me to school, and I come out of my room
and saw that Bear was having another seizure. I was very horrified. I
was sad, scared, confused all at once. It hurt me to see him, and I went
to school so disturbed I could hardly focus.

\"Over a period of time Bear had three more shots of this ProHeart 6 and
a lot more seizures, and my family and I helped him through them all. It
was really heartbreaking. On the day of September 14, 2004, five months
after his last shot, my dad and I had helped him through a little
seizure before we left. We put him in a wire cage, kennel-type, very
large. We put a blanket in there to comfort him in case he started
banging around like he normally does. We went to load some furniture
that we had bought. We loaded it, came back home.\"

She got the keys from me and unlocked the door to the house. \"I went
inside and looked at Bear. I said after I walked by him putting my stuff
down I thought at first my best friend of eight years, long, loving
years, was just sleeping. Then I bent down to pet him in his cage
calling his name trying to wake him up. After a little while of trying
to wake him up I finally realized my best friend in the whole wide world
was dead. The look on his face, his teeth were bared, his eyes were wide
open. I broke out in tears. Just ran outside hysterical trying to get it
out that Bear was dead. My dad realized what happened, ran inside, a
couple of seconds later came out crying. I'll never forget that look in
his eyes. I don't think I could ever forget seeing it. That is one of
the things. I found him, Bear, myself. I was the one. I'll never love
another dog like I loved him and there'll never be another dog like him.
He was the sweetest dog you'd ever meet, a 90-pound solid black German
Shepherd. He knew when you were upset, and he would always come in my
room and whine and sit right down by me, comfort me. He was the best dog
ever. Because of the makers of ProHeart 6 I will never see him again.\"

MS. SINDELAR: Tom, thank you very much for your testimony. Our second
speaker is Dr. Scott Campbell.

DR. CAMPBELL: Okay. Thank you very much for giving us the opportunity to
speak. My colleagues and I are here today. We are the purchasers of many
pharmaceuticals and from many of the folks here in the room, and our
practice is a general practice, and so we buy a lot of stuff. Fort Dodge
has picked up our hotel bills for being \-- as one of the things \-- as
the only thing for being here.

A couple of things I want to tell about our practice in the next slide.
I guess the next slide.

(Slide.)

Our practice is an evidence-based practice. We make all of our decisions
based on evidence, and we are continually trying to find new evidence
every day. Pets are certainly a part of the family unit for our
three-and-a-half million clients, and so that is the standard that we
hold ourselves to. Really providing those pets the same care that we
want for ourselves. We do that in a lot of different ways, and if we had
more time I could go into those. But it is a very high standard that we
hold ourselves to.

Products that are on our formulary, our criteria, you know, are many,
but certainly the top ones are it has to be safe. That's a go/no-go for
us. We believe every product on our formulary is safe, and we'll take it
off the formulary immediately if we believe that it's not.

The second thing is, you know, does the patient receive it? You know, is
it in a formulation where the client, you know, is actually going to
give the medication; and then it has to be effective, and the
effectiveness is a combination of how good is the chemical or the
molecule as well as is the client going to give it.

We can, you know, certainly show anybody that we have the same case mix
as most traditional practices. As I said, 1,016 veterinarians and 443
hospitals.

DR. NOVAK: Next slide.

(Slide.)

I'm Dr. Will Novak. I'm the chief medical officer for Banfield, and one
of my responsibilities is managing our surveillance system. This was
mentioned earlier. We have a quality assurance team which is about a
dozen people that are tracking a number of different things on quality
client service, medical records to making sure that the documentation is
accurate, and then our surveillance system. So we are tracking the
incidence of disease, and we compare that to rate of reactions that may
be seen with vaccines, with antibiotics, with any of the drugs. And we
are constantly using this to do a national risk assessment on each
component of the products that we're using. Next slide.

(Slide.)

So we track medication reaction rate and it is on a national reporting
system, and so this is not a passive system. It is an active system.
Anytime that there is a report of any problems from a client or it is
noted during the healthcare visit that is automatically put into our
reporting and tracking system. So that is required as a practice
standard. So as such we are constantly reviewing that data, running
statistical analysis against it, and the analysis that we have done has
shown that whenever we compare our medical record details back to our
reporting system we find that there is a very, very high,
statistically-significant correlation. So as such we got a lot of
confidence in the information that we've got. Next slide.

(Slide.)

We do approximately 2.7 million doses of vaccine annually, and that rate
is going up every year. So one of the things that we believe is that we
do have a really good understanding of how preventative care works based
on the science of large numbers. All of our vaccines are warranted,
including the vaccine reactions as was mentioned earlier today. So that
is another reason that we have good information on having really
excellent follow-up care when it comes to any patients having problems.
Overall reaction rates on our reporting system for anaphylaxis is 1.8
per 10,000 doses, and that is not purchased or delivered. That is what
was actually given to the patient. So this is one of the few cases where
we have got data that really says what did the patient get, what was the
reaction rates that we are seeing. We also have a peer-review process
that anytime that there is a adverse event we do a full medical case
review with a group of boarded specialists, and we go through all the
different components or do follow-up laboratory work as needed to make
certain that we know what is going on with that case. Next slide.

(Slide.)

So I will turn it over to Dr. Lewis.

DR. LEWIS: I'm Hugh Lewis, and I'm a veterinarian and in charge of new
knowledge business called Data Savant. This slide is a simple one that
just shows the acceptance over a period of a few years of moxidectin in
our hospitals. At the time it was taken from the market, about 90
percent of the pets that we were seeing were being given the six-month
treatment. Next.

(Slide.)

This is our incidence of adverse reactions using our internal system,
and when we became aware of the concern that the FDA had about adverse
effects we immediately reviewed our database. This is just some of the
combinations of vaccines and other treatments just to put it into
perspective, and you can see from just ProHeart 6 alone next to the end
there we had 109 dogs that received only that and 4.4 cases per 10,000
adverse effects. The adverse effects are delineated on the bottom
right-hand corner, and 0.8 per 10,000 of anaphylactic reactions. So this
is very much within the range both qualitatively and quantitatively that
we see with vaccines, and for us this puts a great deal of perspective
on the product and it seemed to be as safe as vaccines.

MS. SINDELAR: Thank you very much, gentlemen.

DR. : Last slide? There is one more.

DR. CRAIGMILL: I am afraid the time has expired, sir.

MS. SINDELAR: Thank you. Our next speaker is Lauren Simpson.

MS. SIMPSON: Hi. My name is Lauren Simpson. I have no financial gain
with any organization or any group. I would like to thank everybody for
allowing me to speak today. Let me clarify I am not any kind of
scientist, vet, or in any medical field. But as a \-\-- I have started
collecting information regarding this drug, especially after my Pug had
a reaction to ProHeart 6 back in April of '03. Very minor compared to
what you guys see and hear about today. She was only getting this
injection because the vet was conveniently out of her normal
preventative. Later I found out it was suggested that vets carry only
one preventative so as not to confuse the consumer with choices.

I stand before you today, though, not just as an individual, but for
thousands of caregivers that feel their companion is part of their
family and not just a dog. When they were told this product was safe,
\"There's no reactions. It's better than monthlies,\" they thought they
were doing the right thing for their dog. Then to watch them suffer and
possibly die spending hundreds, thousands of dollars trying to save
them, all the time being told by their professionals, \"No, it cannot
possibly be ProHeart 6 because that is safe,\" or being the reaction is
too soon or too late, or that this type of reaction \"Has never been
reported to us before.\" The guilt we have all felt because we not only
okay'd this drug, we paid for it and blamed ourselves for not
researching it.

I recommended \"Rainbow Bridge\" more times than I could ever think
possible, but I've been told recently we have a ProHeart 6 bridge now.
But we are here to discuss the safety of ProHeart 6 with our pets.
Safety seems to have been sidelined for our pets either for the almighty
dollar or something bigger. There are two parts of ProHeart 6 to
consider, moxidectin and also the delivery system. Microspheres are new
in the vet world. They are also new in the human world where they are
being used for females with uterine fibroids. They are described as
little golf balls that emit moxidectin. They are supposedly fragile.
Directions say shake to mix, but then once it has been stored you only
roll it gently. I can't help but wonder what happens to these
microspheres after an injection if the dog is roughhousing or playing
and that injection site gets hit. Remember, we are talking everyday
dogs, not dogs kept in a cage.

Moxidectin is used in horses, cattle, sheep, and many other animals. It
has been tested on fish, tortoises, humans. It's administered by gels,
porons, orally, injections, and time-released injections. In 2000,

ProHeart 12, also known as SR 12, was approved in Australia as a
one-year preventative, just nine months before the approval here in the
United States. Australia may not have the adverse reaction reporting
system as we do here, but they do have one, although little known to the
public, and they do have reports that have already been evaluated as
probable and possibly related.

The manufacturer has stated repeatedly in the last three to four years
that ProHeart 6 is not effective against adult worms, that it is not
effective for microfilaria clearance, but that circulating microfilaria
may decrease. Yet in 2000 the World Health Organization say the single
treatment produces slow death of adult worms in dogs. Not effective for
microfilaria clearance, but on page 30 of the document you have before
you they admit microfilaria counts were reduced to almost zero three
weeks after treatment. I have no doubt that the manufacturer presented
testing that was required by the FDA CVM at that time, yet I wonder was
it ever taken into consideration that being innovative maybe more
testing should have been done.

Alabama did testing for heartworm-positive dogs; 20 dogs were in the
test, 10 were in control, 10 dogs received ProHeart 6, but only at three
times the regular dose, and they were sacrificed only after 28 days.
Texas did testing for repeated doses. The tests lasted three years
according to FOI summary, but look deeper and apparently only four dogs
received a regular dose of ProHeart 6 every six months for three years.
Extensive testing.

In field trials, FOI summary in the document before you it states 200
dogs received regular doses of ProHeart 6 for a year and that three
died. Then a press release to Chicago and Boston CVS in February of '03
they stated that 330 started this trial, receiving ProHeart 6, and only
280 finished. That is a difference of 50 dogs. In document they present
to you on page 27 it states that in an 18-month study 12 dogs died or
were euthanized, and apparently after the manufacturer's review their
deaths could not be attributed to ProHeart 6. I wonder what it was
attributed to? Old age? Heart failure? Liver failure? Kidney problems?
Or maybe while crossing a street they had a seizure and were hit by a
car.

We all know what the label states, so I won't repeat it here. Give to
healthy dogs. Use with caution on sick dogs. How much caution can you
use with a six-month time-released formula with no antidote except not
to use it? According to charts I found suggested ages to start geriatric
screening can be as early as four years of age for a larger breed. Were
there any warnings for this?

MS. SINDELAR: Thank you, Lauren. But please remain standing because our
next speaker, Ingrid Zorge, who registered \--

MS. SIMPSON: Ingrid Zorge is not here today.

MS. SINDELAR: Correct, and she requested that Lauren Simpson please read
her submission. Thank you.

MS. SIMPSON: She wrote it. She sent it to me. She wanted me to introduce
you to Tigger and to Mac. Her name is Ingrid Zorge and she is a legally
blind Canadian citizen, and she would like to offer apologies for not
being personally present to give her statement. But the priority had to
be taken care of, her dying dog which passed away yesterday.

\"I would like to state that all the information in this statement are
my personal opinions only and conversations I recall to the best of my
knowledge. On

May 27^th^, 2004, I made a decision that would forever change my life. I
agree to allow my vet to give a ProHeart 6 injection to all three of my
dogs. One of those dogs was my lifeline, my seeing eye dog named Tigger,
a 10-year-old Golden Retriever. I had raised Tigger from a sickly
six-week-old puppy into a happy, healthy, and extremely intelligent
friend who later was privately trained to become my sight. During the
course of his duties as a service dog Tigger saved my life twice in
traffic. I cannot begin to explain the bond that we shared or the depth
of my feelings for this extraordinary animal who is my best friend.

\"Within a few hours of receiving ProHeart 6 Tigger developed diarrhea,
vomiting. He became lethargic, depressed, weak, lost his appetite. At
times he would collapse on the floor too weak to stand. These symptoms
continued, and after three weeks of supportive vet care an ultrasound
revealed tumors on his spleen. His spleen was removed and during the
surgery it was discovered that he had many more on his liver and his
abdominal cavity was full of blood. Tigger did not improve from the
surgery, and after about a week he died a painful, horrible death,
vomiting blood, suffering through his back legs.

\"He diagnosis was hemangiosarcoma, a canine cancer. This cancer did not
develop nor did it end by normal standards. He was healthy, happy, and
energetic prior to this injection. This cancer is usually diagnosed by
ultrasound only after the dog has shown signs of weakness and collapse.
Several studies suggest the average time until diagnosis is eight weeks.
Usually the spleen is removed, the dog makes a positive recovery, and
the average life expectancy is three months.

\"My second dog to receive ProHeart 6 on the same day was Mac, my
seven-year-old Rotty. Mac also vomited several hours after receiving the
shot, but he appeared to return to normal in a day or two. In July and
August, about six to eight weeks after the shot, Mac began vomiting,
lethargic, had a fever. His symptoms increased. In November, '04, he had
an ultrasound which showed tumors on his spleen and liver. Diagnosis,
same as Tigger. Again, Mac was happy, healthy, very energetic prior to
receiving the ProHeart 6 shot. Yesterday, January 30, Mac collapsed
again and began vomiting. I was forced to make the painful decision to
have him put down by our vet. This beautiful, courageous animal fought
for his life to the very last minutes, struggling to rise even though he
was heavily sedated. I will carry this disturbing image for a long time.

\"Three days ago, January 28^th^, my third dog who had received
ProHeart6 on the same day collapsed, vomited, many pools of blood and
bloody diarrhea. Rain is a one-year-old Border Collie mix and has had
intermittent vomiting and diarrhea for the past six months. We are
waiting for the test results now.

\"There are approximately 1,000 diseases that can affect dogs. The
mathematical probability of all three dogs developing the same cancer
within this time period would be about one in 160 million. Think about
it. Three breeds of dogs, three different ages, three different diets,
only one common denominator. Do I believe that ProHeart 6 is safe for my
dogs? Absolutely not.

\"Drug companies are powerful entities. I am sure we would all agree to
that, but with power comes responsibility and accountability. Fort
Dodge, a division of Wyeth, manufactures ProHeart 6 in the United
States. These vials of ProHeart 6 are then shipped to Canada and
distributed to Canada vets by Wyeth Animal Hospital. In the US there
have been recalls for ProHeart 6 due to varying factors. I believe this
recall was to be international in May, yet there was no actual recall
done in Canada. In the United States there have been three label
revisions, new package insert, Dear Doctor letters issued to US vets due
to reported adverse drug reactions. Why was this information withheld
from Canadian vets and consumers? Why did Fort Dodge, the sole
manufacturer of ProHeart 6, only make three label revisions for vials of
ProHeart 6 sold in the US? Why did Fort Dodge not send Dear Doctor
letters warning of adverse reactions to ProHeart 6? Why would
representatives of Wyeth Animal Health here in Canada not feel
responsibility to inform Canadian vets and consumers of reported adverse
reactions including deaths?

\"My vet or myself would never have allowed my seeing-eye dog nor my
companion dogs to receive this had we been informed of the possible
dangers. Two different executives here in Canada have told me that they
are not required to distribute this important information to Canadian
vets or consumers. Why not? Are we as Canadian consumers not entitled to
make informed decisions? Obviously not. In Canada our veterinary drugs
are approved and regulated by the VDD similar to the CVM in the United
States. The VDD is a division of the Health Canada system. I have
questioned the VDD several times \--.\"

MS. SINDELAR: Thank you very much.

MS. SIMPSON: Okay. Thank you.

MS. SINDELAR: Our next speaker is Laurie Rentas.

MS. RENTAS: My name is Laurie Rentas. I have no financial relationship
here with anyone, and in fact the only financial relationship I have had
was with the vets that I paid to have my dog die anyway. I am here today
because on February 5^th^ of '04 ProHeart 6 destroyed a member of our
family, our Yorkie Murphy, after a nine-month agonizing and ultimately
losing battle. My initial intention was to focus my time on her loss,
but based on the other tragic stories that came to my attention and
showed me that the impact of ProHeart was much worse and much bigger
than Murphy's case, I chose to address that.

We didn't want her sacrificed so that other dogs could be saved. We
didn't want our lives changed forever, and we most certainly didn't want
to end up a statistic of an unsafe drug and a pharmaceutical company
that seemed to be ambivalent however we are. And because we are, I want
this panel to know even more the horror stories regarding

ProHeart 6. I want to say right now that at no time have I ever or will
I ever claim to be a scientist, a statistician, or an expert regarding
the knowledge I have of ProHeart 6.

The totally voluntary and unsolicited data I am about to share with you
came from a website called CAPS. The president of CAPS created and made
available a ProHeart 6 complaint form because she knew of people who
suffered at the hands of ProHeart and wanted to see who else was out
there and going through the same thing. Complaints rolled in on almost a
daily basis. Keep in mind that at no time did anyone go out looking for
these people. They found CAPS because they were looking for answers, but
they found as did we that there was no going back once this poison was
put in your dog's body.

There are far more deaths than anyone was lead to believe, all which
came as a result of a product that was supposed to offer safety against
heartworm, and the veterinarians lead us guardians literally to
slaughter by misleading us as to the safety of ProHeart as the new,
convenient alternative to the monthly drug. But in reality, it was an
unsafe heartworm prevention promoted over the perfectly effective
products that had been on the market for years. We went to these
veterinarians because we trusted them to know more than we did regarding
heartworm prevention, and we accepted their recommendations.

There seems to be a denial factor here in these vets. Out of all these
reports that came in through this CAPS website, only 10 positive
comments were made by the guardians that their vet even tried to help
them or was at least empathetic and open to the possibility that
ProHeart could be causing the problem. Most vets wouldn't even engage in
conversation regarding the possibility. Guardians basically hit brick
walls trying to fix what was happening to their pets, and the brick
walls were Fort Dodge and the vets that we trusted in the first place.

I won't even address the thousands of dollars we have thrown away as a
direct result of ProHeart. There was a test for every symptom, and all
it took was a credit card from the guardian to carry it out. Yet
definitive answers as to those problems were never forthcoming.

So were the vets lied to? Who lied to them and convinced them of the
effectiveness and safety of this product? All of us in this room were
informed that the purpose of the hearing is to determine the safety of
ProHeart 6. ProHeart 6 is not safe. The comparisons against all of the
monthly tablets prove that. The numbers show unequivocally that there
are not the same degree of adverse reactions in the monthly prevention
drugs.

Unfortunately there are still people out there who are in the midst of
fighting what Proheart 6 is doing to their dog since it has only been
five months that it has been off of the market. So we know that there
are still dogs with this in their system. There was never the degree of
effort stopping the use of ProHeart that there was in couching us all to
use it. In fact, there are reports of dogs receiving this after the
recall.

Of over 60 adverse reactions, they came from over 35 states. There was
no rhyme or reason to the drug's effect on size, sex, or age. There's
practically equal numbers of both male and female. There are dogs from
age 15 down to puppies six-months old. Seven-years old was the most
common age reported for death in what we collected, with four-years old
being second. We have complaints from Chihuahuas and Yorkies to Great
Danes and to St. Bernards. 70 of the 174 guardians, which translates to
over 40 percent, responded that on that day the only thing administered
to their dog was ProHeart 6, 40 percent. But the most disturbing fact to
come of all these statistics is this: Out of the 174 voluntary reports,
80 of these dogs have died so far. Think about it, 46 percent.

If Fort Dodge truly feels their product is so safe then I question why a
company of your magnitude would offer thousands and thousands of dollars
in hush money if you have nothing at all to hide. One and only one
common denominator among all of this data? Right, ProHeart 6.

MS. SINDELAR: Thank you. Our next speaker, Janice Storey.

MS. STOREY: My name is Janice Storey, and my dog died in October of
2002. Two-and-a-half years I've been waiting for this product to be
recalled. Many thousands of dogs have been affected. I have in my
possession two other dog owners have asked me to cite the conclusions
that veterinary specialists after determining, after thorough
examinations and extensive testing, how ProHeart affected their dogs,
and the case numbers have been presented to the FDA and Wyeth. One of
them is in California, an attorney, and that case number is 80840-05.
The other one is a \-- the name of the dog is Pickles. The other one is
case number 200402016, Rusty, a six-year-old champion Doberman in
Dallas.

Also my dog, four vets, not one, not a single on vet would ever admit
\-- the product had only been on the market one year \-- that my dog
could possibly have been harmed \-- actually I was told could never be
possibly harmed by ProHeart 6. However, my new personal vet, I submitted
his x-rays which had a huge amount of spots on them, to him. He
submitted it to an utmost heartworm specialist. I can't say names here,
but he appears on the Wyeth front page of your website, so you would
know who that would be, and he is at Auburn University. So you all can
all figure it out. He looked at my x-rays and he said that it is
difficult for vets sometimes to look at these x-rays and determine if it
is in fact heartworms or if in fact it is cancer. So he looked at my
x-rays and he determined as told to my personal vet that it was
pulmonary thromboembolisms. Furthermore, my own dog's testing, the very
first vet that I took him to, he had written down PTE remarkable. I had
no idea what PTE is. I later found out it means pulmonary
thromboembolisms.

My dog had hidden heartworms, and he had tested 11 years due to being on
Heartguard Plus. Any monthly preventative out there is capable of making
the female worm sterile with prolonged use. The testing is inaccurate on
low female worm burdens. Therefore any dog that receives a ProHeart 6 is
at risk. I have documentation whereby the dog in Dallas, it cleared the
adult heartworms in 33 days and the microfilaria in 45. Has Wyeth ever
contacted this specialist? No. Furthermore, the personal vet of that
same dog, Rusty, heard from Wyeth one time. They have yet to have ever
been paid, and that was a year-and-a-half ago. But Wyeth will pay the
vets that don't speak out against ProHeart, and that is the problem the
public has. We can't convince our vets if they are brainwashed by Wyeth.
They are afraid of Wyeth. They buy products from Wyeth. It is very
difficult for us to prove to you. Furthermore, any of you vets here know
that in the clearance of microfilaria that it can create IMHA. You also
know \-- I have a study here from Japan, a clinical research data, a
published veterinary journal. It shows what happened to
microfilaria-positive dogs.

So, yes, I'm emotional about this. I'm mad about this. I am not going to
read to you everything. You can read it. You have the case numbers. You
can read what the vets concluded. I'm tired of the vets that promote the
product like Banfield who is going to acquire a lot of money because we
come in every six months and spend our money. This product \-- and I'm
mad at the FDA. They should have never approved this product. There was
not enough research done. Only 200 dogs in Australia for microspheres,
but that was extensive testing. It was in two veterinary clinics and
students were overseeing it. Why don't you all investigate the
microspheres?

Why don't you investigate what's really going on here? They are
obtaining research on our dogs, and they are using it to further their
vaccines in my opinion, and that testing can be tied to the fact that in
October of '03 they had a first injection for humans that they
announced. Okay? And in March of '04 they announced their affiliation
with TR and World Health Organization. So this isn't about just a
heartworm shot. You vets have been mislead. You are being used as a tool
to inject the dogs, and they pay for the tests and they win. We lose.
Our dogs die. We can spend thousands of dollars to protect them. So I'm
angry. I'm sorry, but I am angry.

MS. SINDELAR: Thank you for your comments.

MS. STOREY: So \-- thanks.

MS. SINDELAR: Our next speaker is Jean Brudd.

MS. BRUDD: Good afternoon, Ladies and gentlemen. Let me first state that
I do not have a financial interest or relationship with any group or
company or whatever. I paid all my travel expenses to get here. I jut
want to say that I am here today on behalf of my two diseased dogs,
Tasha and Nicki. They died during the peak period of 2002 due to one
shot of ProHeart 6. My survivor dog, Casey, is on the low end of normal.
Again, two-and-a-half years later, and his immune system was
compromised.

However, I am not speaking here today on behalf of my dogs. It's still
too painful for me to talk about two-and-a-half years later. Slow down
here. I just want to say that most of the people speaking this hour are
not a bunch of fanatics on the internet as we have sometimes been
called. We are here because we have been victims of ProHeart 6. Our dogs
took ill. Many of them like my dog died. Some may say that these are
just dogs that can be easily replaced, but not for us. These dogs were
and are our family members. For some of us our dogs are the children we
never had and never will have.

I am sure each of you in this room has bonded with a child. Perhaps it
is one of your own. Your love for this child is so great you cannot
imagine your life without him. Imagine a drug you agree to be given to
this child to keep him in good heath. Imagine this child adversely
reacting to this drug and there is no known antidote to counteract its
adverse effects. Imagine this child having to suffer through the adverse
effects for many months until the drug passes from his body, if his body
can live that long. Imagine the horror of watching day after day your
child seizing on the floor, or walking into walls, or not being able to
eat or drink, or urinating or defecating on himself, or blood coming out
of every orifice of his body, he is crying out in pain, and there you
sit powerless not able to do a thing to help him. All you can do is turn
over your child to the doctors, the so-called experts, and hope the
doctors can figure out how to treat him, because they sure as heck don't
know what is wrong with him, and it sure as heck cannot be the drug that
they administered to your child.

Your doctor won't admit it if he thinks it is the drug because he
doesn't want to be slapped with a lawsuit, and the manufacturer won't
admit it because they don't want to be slapped with lawsuits. Meanwhile,
you sit in desperation and pray that God fixes it all, brings you the
miracle you are so desperately praying for, but the miracle never comes.
You are faced with quality of life issues for your child who is never
going to eat or drink on his own, walk, talk, play again. So what do you
do? Do you let him suffer, or do you play God and pull the plug? Either
way your child dies, and all you can do is blame yourself because it was
you who trusted your doctor when he said this product was safe. But you
played a part in killing your own child. How do you live with yourself
for the rest of your life?

Welcome to our world. This is our own private living hell, the world of
thousands of us guardians who have our dogs, our family members,
adversely effected and even killed by ProHeart 6. If this happened to
your child would you sit idly by? We think not. This product is not
safe. You know it and we know it. The manufacturer will say that less
than one percent of dogs are affected, that it benefits more dogs than
it hurts. But when all the dogs in your household are affected by their
product that is 100 percent, and it was 100 percent in my household.

Fort Dodge, we want you to stop experimenting on our children. Stop the
killing. Stop this poison for profit. Members of the Committee, please
tell them to leave our family alone. Look into your hearts and do the
right thing by us and by our innocent, loving, animal companions.
Please, do the right thing. Thank you.

MS. SINDELAR: Thank you four your comments. The next speaker is Dr.
Martindale.

DR. MARTINDALE: Thank you. Other than purchasing Fort Dodge products I
have no financial connection with the company. I am a practitioner in
Denison, Texas. I own and operate a clinic for the past 36 years. It's a
companion animal practice, and we did start using ProHeart 6 when it
came out in 2001 and have progressively moved towards this drug as our
primary heartworm prevention. Since the beginning we have experienced
better compliance from our clients. It does fit well into our wellness
program where we see the pet twice a year. It is readily accepted by the
client, and we've had a marked decrease in the heartworm incidents over
the past two years, ranging between 45 and 55 percent, depending on the
year. Compliance was increased by sometimes as much as 60 percent in the
two years that we have used it. So in our experience it's been a very
effective heartworm prevention without any serious side effects or any
disease entity that we could directly attribute to its use.

We did have one small dog within 45 days after ProHeart 6 and
vaccinations with immune hemolytic anemia. Interesting enough, though,
that was the only case that we saw during the year. Whereas in previous
years we historically would se anywhere from three to five cases of this
disease.

Also I have had the opportunity to visit with many colleagues. My local
colleagues, colleagues in Oklahoma, Texas, and Louisiana over the past
few months before and after withdrawal. Every veterinarian that I've
talked to said they have not experienced bad side effects with the use
of the drug, and these veterinarians were giving anywhere from less than
500 doses to one veterinarian that had given 10,000 doses in Louisiana.
So my experience has been good. I think if this drug is handled, stored,
and administered correctly that it is a very effective means of
preventing heartworm disease. Thank you.

MS. SINDELAR: Thank you very much. Our next speaker is Dr. John Gay.

DR. GAY: Good afternoon. Dr. John Gay, a faculty member at Washington
State University. I am veterinarian and have a PhD in epidemiology. I am
the epidemiology representative on the American Veterinary Medical
Association's Counsel on Biologic and Therapeutic Agents. My comments
have been reviewed by fellow council members, and the Clinical
Practitioners Advisory Committee. The AVMA paid for my travel. I have no
financial interest in Fort Dodge Animal Health, and I am not engaged in
clinical practice.

The AVMA is a national association recognized as the primary voice of
the veterinary profession. We have some 70,000 members, which is 86
percent of all veterinarians. The AVMA's mission is to advance the art
and science of veterinary medicine in all aspects, from clinical
practice to food safety, to regulatory medicine to wildlife. We commend
the FDA for holding this meeting and thank you for the opportunity to
participate.

First, we believe a strong, science-based, transparent, systematic,
post-market surveillance system is critical to our patients, to our
clients, and to our profession. It provides important information that
our profession needs to maximize the benefits and to minimize the risks
for patients under our care. Our patients, ranging from finches to
elephants, and Pekingese to Great Danes, present with a wide range of
individual characteristics and live in a wide range of environment.
Because of this diversity we recognize that clinical trials required for
new drug approval cannot be expected to detect all combination of
circumstances and may lead to adverse drug experiences. We also
recognize we cannot avoid all risk, that virtually all drugs and
biologics have inherent risk as a consequence of their effectiveness. We
recognize that to minimize this risk we must continually strive to
improve our understanding of these and the conditions under which they
occur.

A strong system reduces two general types of errors. First, it has
sufficient sensitivity to provide early, clear detection of associations
between particular drugs and adverse effects in particular segments of
our patient population. In the long run, this is required to maintain
the profession's confidence in the drugs we use and our clients'
confidence in us. Second, it has sufficient specificity to reduce
problems with spurious false association between particular drugs and
adverse events in animals' lives. Again, this is required to maintain
the profession's confidence in and access to these drugs.

Critical to a strong surveillance system and thus to reducing these
errors is sufficient information. Increasing computerization of patient
records and internet access may provide several opportunities to
increase reporting. One opportunity may be as simply as including URLs
for direct adverse event reporting on every FDA approved drug insert.
Another may be developing procedures to upload event information being
routinely captured in electronic patient records, particularly in large
corporate systems. This is already happening with HMOs and other care
organizations in human medicine. Third, because the USDA is launching a
surveillance system for adverse vaccine reactions, sharing of data
between the USDA and FDA would improve the depth of comparative risk
information for both agencies. As drugs, biologics, and pesticides are
often used in combination, interagency collaboration including the EPA
would enhance the detection of adverse effects resulting from particular
combinations. Fourth, enhancements in the timely feedback of clinically
relevant information to practitioners would help communicate the
importance of reporting. Finally, it may be necessary for professional
organizations to further inform the members on the critical importance
of reporting adverse drug experience information.

To be as strongly science-based as possible, a pharmacovigilance system
should incorporate all of the steps for logically assessing the strength
of evidence for causality. The first step is using statistical analysis
to objectively determine the likelihood that any observed associations
are due to chance rather than due to cause. Unfortunately, subjective
assessment of count data for trends and clusters is fraught with danger.
Statistical procedures to determine how likely apparent trends in counts
or clustering events are due to random chance are well established.
Quantifying risk is an important component of this process. However,
reliably establishing and comparing risk requires sound exposure data,
which is not routinely captured in the current system.

Finally, to retain trust and to maximize cooperation, the system must be
sufficiently transparent to all stakeholders. Obviously the identity of
individual patients and clients must be strictly protected. That
marketing data providing for proprietary advantage must remain
confidential. But if any party loses trust or reduces cooperation,
animal health and ultimately the profession suffers. Again, I commend
the FDA for holding this meeting, and I thank you for the opportunity to
participate and to comment.

MS. SINDELAR: Thank you for your comments. Our next speaker is Connie
Dominy.

MS. DOMINY: Good afternoon. My name is Connie. I am from Georgia. I went
through snow, sleet, and pure hell to get here, and the mic just came
off the thing, but that's fine. I can improvise in five-minute period of
time. Let me say first that I am here of my own accord. I do not
represent any group, not have I received any monies from any group here.
I paid my own way. I am here to represent \--

MS. SINDELAR: \-\-- slide presentation?

MS. DOMINY: Pardon?

MS. SINDELAR: Do you have a slide presentation?

MS. DOMINY: No, ma'am. I don't, and this is not at my five minutes,
okay?

(Laughter.)

MS. SINDELAR: We will give you your time for it.

MS. DOMINY: Okay. That's fine. I'm sorry. Would you please restart the
clock?

MS. SINDELAR: We will give you credit.

MS. DOMINY: Thank you. You know who I am, you know why I'm here, and you
know that I do not gain financially from any of this whatsoever. I don't
even own stock in pharmaceutical companies because I don't trust them
today, even though they are a big business and I'm sure I would have
monetary gains if I did.

By profession I am a psychotherapist and I have been in this field in
private practice for over 20 years. I have been able to be familiar with
product development and marketing statistics \-- or tactics, I'm sorry,
and post-approval safety data collection. My goal today is to challenge
the FDA and the Advisory Committee to simply do your job. You are
consumer advocates. The consumers are the animals, and they can't speak
for themselves. You are charged to do this to the best of your ability
and to not let politics, power, or greed intimidate your decisions. You
are to hold the manufacturers of animal products accountable for their
safety. I encourage you to look deeper than your soul and make the right
decision regarding ProHeart 6.

I have a comment about Banfield that I have heard today. Let me just
tell me that I went into our Banfield in Macon, Georgia six weeks after
the product had been recalled voluntarily. They still had the
advertisements up. That is not accountability. I'm sorry.

I remain firm in my belief that the symptoms my dog, Ready, who received
the ProHeart 6 injection who is an Italian Greyhound and a champion, he
received it and six months \-- over the whole six months he exhibited
symptoms, and I believe they were related to ProHeart 6. Fort Dodge
remains firm in its belief that their product is safe and science will
prevail. Well, ladies and gentlemen, I am telling you here today that I
believe that this product is not safe and science will prevail.

I have read the FDA report. I am appalled to think that Fort Dodge would
interfere in the reports sent in by veterinarians as being \-- referred
to them as being over-reactive and biased. I believe veterinarians
under-report adverse reactions. I believe that veterinarians are grossly
mislead by Fort Dodge and their sales representatives. You ask about
necropsy. By the time our animals get to that point we have spent major
megabucks, and that is the last thing on our mind.

When looking at all of this with a scientific perspective, I question
the validity of the initial studies presented to the FDA for product
approval. To have a valid study the sample groups should represent the
treatment time that this product is intended to work for. That at less
than 180 days does not represent the study validity or reliability. The
sample size was inadequate based on the projected population size and
the dosages that Fort Dodge projected to sell, nor was it representative
of a cross-section of the subjects that would receive this medication.

Another concern is the glaring absence of longitudinal studies of
significant sample size. It is interesting to note that the laboratory
trial subjects were destroyed. This is otherwise known as destroying the
evidence. In some areas this is a criminal activity. It is my opinion
that Fort Dodge has been negligent in their job to provide a safe
product. They have also failed in their job of apparently addressing the
issues, the data collected post-approval indicated. They have
categorically denied that the symptoms seen are not related to ProHeart
6. Denial of Fort Dodge is similar to that exhibited by the parent
company when they denied what Phen-Fen was doing to our population, and
we all know what happened with that.

So is this a systemic problem within this company? Maybe so. Is it a
trend? Maybe so. It certainly brings me and I hope the FDA and the
Advisory Committee to question Fort Dodge's integrity and their ability
to provide unbiased information to the FDA and consumers. After all, the
bottom line is profit, not safety or concern for our family members.
This creates the biggest bias reported here today, profits.

As late as October, 2004, Fort Dodge was still denying that my dog's
adverse reactions were due to ProHeart 6. I talked to the Fort Dodge
Representative. They told me that they had contacted my vet and they had
been told that his case had been closed because he exhibited no other
symptoms. Well, my little dog for seven months exhibited symptoms. They
didn't contact. They didn't talk to my vet. I talked to the vet. The vet
told me the same thing. Would you believe that? That vomiting and
diarrhea are not side effects of ProHeart 6. It's on your brochure. I
had tests done by \-\--. I had upper GI done. I had all kinds of stuff
done to try to rule out ProHeart 6 at my own expense, ladies and
gentlemen. Never did you contact. But yet you continue to deny, saying
that because his symptoms, his primary symptoms, occurred on the 11^th^
day \-- I've heard seven to 14 days, ladies and gentlemen. I have a copy
of his documentation with me. I encourage you to insist that more
comprehensive studies be done on existing data and surviving subjects.
Ready is alive. Let him be your champion.

One final parting thought. Until one has loved an animal a part of one's
soul remains unawakened.

MS. SINDELAR: Thank you very much for your comments. Our next speaker is
Georgene Paulauski.

MS. PAULAUSKI: My name is Georgene Paulauski. I'm a clinical specialist
at St. Anthony Medical Center. I'm a clinical educator for Indiana
University, and I \-\-- college. I have no financial gain. I filed an
adverse reaction report in December of 2003 after Cletius received a
ProHeart 6 injection. I was contacted by CBS-2 News in regards to what
happened to my dog. The segment aired. Fort Dodge gave their account of
what happened and published this both on the internet and through
mailings to your peer vets throughout the United States.

I would like to read to you an excerpt of what Fort Dodge printed about
my dog. \"Initial testing identifies some abnormalities. Hemolytic
anemia was a possible diagnosis. He was placed on antibiotics and
corticosteroids. The dog's steroid dose was decreased. Shortly
thereafter he presented not acting right again. After increasing the
dosage, the dog's condition improved.\"

Now I would like to show you and let you see in reality during the seven
months. These are the real facts, not what was published. Cletius
received ProHeart 6 on September 27, 2003. No other injection.
Immediately he developed a hot spot. Within weeks anorexia and became
lethargic.

(Slide.)

Looking at the first slide I have up, in Fort Dodge's word there were
some abnormalities noted. Anybody that knows a basic CBC, these are not
some abnormalities. There are grotesque. These are panic value levels.
This is the case of Cletius and hemolytic anemia. He is in your packets.
That's his number.

(Slide.)

Medical visits, we went through 45 office visits, two separate visits in
ICU stays at Purdue University, multiple emergency visits, surgery.

(Slide.)

He had 102 lab draws, multiple types and cross-matches, multiple
cultures including blood, urine, gastric, blood gas analysis, and ABGs.

(Slide.)

He had two ultrasounds, abdominal scans, numerous x-rays.

(Slide.)

This next page is hideous. These are the drugs it took to keep my dog
alive during his hemolytic anemia. I am not going to go through the
numbers. You can look at them and gasp.

(Slide.)

The fluids to keep him alive. Multiple keep opens, 0.9 normal saline,
lactated Ringers, Hespan, blood transfusion, Oxyglobin, potassium
chloride, Hetastarch.

(Slide.)

Due to all this multiple complications resulted. You can't imagine
anything worse on a hemolytic anemia than a dog starting to hemorrhage.
That is exactly what took place. The dog started hemorrhaging, vomiting
blood, tarry stools. At this time he also had grossly elevated liver
enzymes. My dog's appearance became grotesque. Pot belly, enlarged
liver, muscle wasting, the inability to walk, foot flop, swayed spine.

(Slide.)

Numerous attempts were made to try to wean Cletius from his
immunosuppressants while the ProHeart 6 was in his system. Every attempt
failed, and a lot of those attempts resulting in having to increase
doses of Pred.

(Slide.)

Eventually he became over-suppressed and leukopenic. I then had to deal
with bladder, bowel, and gastric infections, cystocentesis, diarrhea,
numerous antifungals, antibiotics, LONOX were added. Little did we
realize his over-suppression would finally become a turning point.

(Slide.)

After a lengthy conversation with Purdue and our vet, the debated on
whether to decrease the dose of the immunosuppressant or finally
withdraw it. The comment was made, \"If it is truly the ProHeart 6, we
should be able to remove all meds and this dog should do perfectly
fine.\"

(Slide.)

After him living on over 100-and-some medications weekly, on 6/2/2004
all meds were DC'd. I spent the entire summer rehabbing Cletius,
walking, swimming, rebuilding his muscles.

(Slide.)

He is since now symptom free and drug free for 209 days. He has gone
back to Interceptor without any incident. I am one of the fortunate ones
here today He is healthy, happy, and extremely active.

(Slide.)

As a point of interest, my dog did have mild skin allergies. This was
not his first injection. If you go back and look at your data, along
with the ProHeart 6 when I went to the vet he said, \"Is your dog
itching?\" If he was they gave him a shot of Depo-Medrol. Did that save
him from a previous reaction? Absolutely. The steroid protected him.

(Slide.)

The long-term effects of all the meds to keep Cletius alive are yet to
be seen, but what my family and this dog went through were pure hell. It
consumed seven-and-a-half months of our lives. I can't begin to tell you
the bills, the time lost from work, without a single dollar recovered.

(Slide.)

It is very disheartening to know after seeing the clinical trial data
after the fact I would have never have injected my dog with this knowing
what you have published as an adverse reaction. Can I just give a
closing comment? I say to Fort Dodge stop making excuses. You printed
fluff about my dog, not faxes. As for the paper, shame on you. The hell
that my family went through and what my dog went through? You continue
to create a facade. You put it out on your internet, published it \--

MS. SINDELAR: Thank you very much.

MS. DOMINY: Thank you.

MS. SINDELAR: Our next speaker is Paul Marron.

DR. MARRON: I do not have any financial affiliation with Fort Dodge. I'm
not a government employee. I have paid my own expenses to come to this
meeting. Members of the Food and Drug Administration, members of the
press, fellow veterinarians, fellow companion animal providers, pet
owners, thank you for this opportunity to speak before you.

As was mentioned, my name is Paul Marron. I am a veterinarian and a
practice owner at Battlefield Animal Hospital in Manassas, Virginia. I
graduated from Texas A&M University in 1985. I've been in practice for
20 years, four-and-a-half years with the Army Veterinary Corps and 16
years in private practice. We currently have five veterinarians in
practice at Battlefield Animal Hospital. We provide veterinary care to
almost 7,000 companion animals.

The veterinarians at Battlefield Animal Hospital have as their first and
foremost concern providing safe and effective products to insure the
health and well-being of our clients' pets. As such, we were excited
when a product became available that would not only improve compliance
for parasite prevention, but also significantly reduce parasite disease
and exposure to pets and pet owners. In July, 2001, we began providing
ProHeart injections to our clients. Since then we have given 2,357
injections with only two verifiable minor reactions to those injections.
During this period we have not seen any evidence of any increase in
disease conditions in the pets treated at our hospital. For our
experience it speaks for itself. ProHeart in our hands has shown itself
to be a safe product.

Before the introduction of ProHeart, our clients were faced with only
one choice in heartworm and intestinal parasite control. That was oral
medication. Though oral medication is effective, compliance has always
been a major issue. At our hospital, we remind our clients by phone, by
regular mail, by email, and during hospital visits to be sure to give
the oral medication to their pets. Even with our efforts and the good
intentions of our clients, compliance among our clients was at best 30
percent. Only one out of three of our clients' dogs were consistently
protected. That means a higher exposure potential for internal parasites
for our clients and their children.

As you know, transfer of parasites from our pets to us and our children
has become a very real concern, not only for the veterinary profession,
but to those of you in the regulatory professions. The Center for
Disease Control in a recent survey of animal shelters revealed that
almost 36 percent of dogs nationwide and 52 percent of dogs from
southern states harbor intestinal parasites. At least 3,000 to 4,000
serum specimens from human patients are submitted to the CDC, state
public health labs, or private labs for sero-diagnostic confirmation of
intestinal parasite disease. The CDC further recommends that practicing
veterinarians can provide an important public service by recommending
fecal examinations twice yearly and providing well-timed \-\--
treatments. The Companion Animal Parasite Control Council recommends
that fecal exams on companion animals be conducted two to four times per
year.

Ladies and gentlemen, the reason I provide these statistics is to inform
you that the use of ProHeart at our hospital has been one of the most
effective means in helping to follow the guidelines for preventing
internal parasitism in our pets and transmission to our clients and
their children. In our practice and with the use of ProHeart 6
injections done every six months, fecal exams are now availably done
twice yearly. In addition, it has helped to greatly improve compliance
for internal parasite exams and treatments. As a result of utilizing
ProHeart 6, our compliance for intestinal parasite exams, heartworm
tests and prevention has increased from 30 percent to over 80 percent.
That, ladies and gentlemen, is a significant improvement in protection
for our pets, our clients, and their children.

Members of the FDA, it is my opinion that the current risk assessment
strategy being utilized is flawed. The unfiltered reporting system
utilized to evaluate the safety and ultimate recall of ProHeart 6 has to
create confusion with pet owners, veterinarians, and the public in
general. On the one hand, we have thousands of veterinarians nationwide
who have provided tens of millions of doses of ProHeart with few
complications. And on the other hand, we have claims of a potentially
deadly drug. On the one side, I speak to my clients about the safety and
efficacy of a safe, convenient, and effective drug. On the other side,
they hear media reports and internet hype, opinion, and conjecture of
serious complications.

I encourage a revision of the current reporting system to insure that
review of drug safety is done by factually, scientific, examined
discourse and weight of evidence. Not with conclusions and actions being
taken as a result of the seriousness of the charges. It greatly concerns
me as a veterinarian that I have been told that there are those in
regulatory agencies who believe that, quote, \"Veterinarians cannot be
trusted to report accurately the adverse reactions to ProHeart because
they are simply trying to protect their own interests and are seriously
under-reporting the adverse reactions associated with ProHeart.\"
Unquote.

I hope that these reports are not true. First, this type of
self-promoting talk is grossly inaccurate and unprofessional. It is does
not encourage cooperation and communication. Second, it seeks to promote
an attitude of distrust between veterinarians and their clients.
Finally, I would like to restate that the veterinarians I personally
know have as their first and foremost concern for the providing of safe
and effective products for our clients and their pets. The goal of our
profession is to improve the quality of lives of our pets and improve
the client-pet bond while at the same time reducing the risk of disease
being transmitted from pets to owners and their children. As a member of
one of the greatest professions I again thank you for this opportunity
to address this Council.

MS. SINDELAR: Thank you for your comments. Our next speaker is Dr. Bob
Rogers.

DR. ROGERS: I'm Bob Rogers. I am a private practitioner in Houston,
Texas. I have no conflict of interest, financial or otherwise. I want to
applaud the FDA for the action they have taken to product the public by
the withdrawal of ProHeart 6. The adverse reactions that I witnessed in
my practice fall into three categories; neuro-toxicity manifesting in
the form of seizures, pulmonary symptoms including massive pulmonary
thromboembolisms resulting in death, allergic reactions including
hemorrhagic gastroenteritis progressing to disseminated intravascular
coagulation and death.

The following questions need to be answered before this drug is returned
to the market. Are these problems due to an inherent problem with the
drug moxidectin, instability of the microspheres, allergy to the
microsphere coating, or are they due to mishandling of the drug by
veterinarians or perhaps some of both?

If ProHeart 6 is injected through too small of a gauge needle or if the
bottle is reconstituted and then shaken vigorously after several nights
of refrigeration instead of swirled, could this cause disruption of the
microspheres? Could disruption of microspheres cause premature release
of the moxidectin, moxidectin overdose, and resulting seizures? Or could
this be an intermittent manufacturing problem?

We know moxidectin is a more potent filaracide than ivermectin or
milbemycin. In a letter I have from another veterinarian dated February,
2002, she says that her patient died from a pulmonary thromboembolism as
an adverse reaction to ProHeart 6. She states that Dr. La Roch at Fort
Dodge told her they knew ProHeart 6 could kill L4 and L5 larvae. Fort
Dodge did not send out a Dear Doctor letter to warn veterinarians not to
give heartworm to heartworm-infected dogs until November of that year,
nine months later. Does the death of L4 and L5 newly-emerged, young
adult larvae and possibly the death of migrating intestinal worm larvae,
all of which cannot be detected by available testing methods, post a
fatal risk to our patients? How can this risk be avoided?

How does ProHeart 6 cause hemorrhagic gastroenteritis? Is this due to
the death of migrating larvae, or is this a manifestation of allergic
reaction?

What is the cause of mast cell degranulation? Are dogs allergic to the
hydroxypropyl methylcellulose? Do these anaphylactic reactions result in
DIC? Is there a hapten somewhere in this formula that we don't know
about as was the case with diethycarbamizine? What is the cause of the
auto-immune reactions?

If microspheres are injected into a dog, do some of them enter the
circulation? What is the impact of circulating microspheres on the
kidneys, liver, and lungs? Studies have shown in other species that
microspheres can cause pulmonary hypertension.

Looking at the ADEs it seems a number of product failure reports and end
effects increased with time. Is this due to laxity of testing on the
part of veterinarians?

Finally I have a suggestion which could increase product safety. Unit
dosing has been widely mandated for human drugs. If this product is
returned to the market, unit dosing would help to prevent many of the
mishandling and storage errors.

I want to express dismay at the method in which this product was
marketed. Please help me to understand why a company would choose a
person whose presentations involve so much profanity? Dr. Whitford is
not a board-certified cardiologist, not a parasitologist or
pharmacologist. He has no qualifications. In his presentation he focused
on one point. Veterinarians will go broke due to competition from Pet
Med Express if they don't switch their clients to this product. He
stated that allergic reactions could be treated with Benadryl. Since
when is Benadryl the standard of care for DIC? He repeatedly said that
all of the adverse drug experiences reported to the FDA are not due to
ProHeart 6. For a company to deny all FDA ADEs is not responsible. He
did nothing to emphasize the need to handle the drug carefully and the
consequences of not following the label directions.

In my humble opinion, Fort Dodge is responsible for this mishandling of
this drug by veterinarians and the death of pets that have resulted
because they not only failed to warn veterinarians about the side
effects, they denied them, and the failed to adequately inform
veterinarians on the proper handling of their drug. This lack of
responsibility is no in the best interest of Fort Dodge, it is not in
the best interest of our patients, and it is not in the best interest of
the veterinary profession.

If this drug is returned to the market, the FDA needs to mandate that
Fort Dodge implement a thorough training program to insure clients are
warned and to insure that veterinarians are instructed on the safe use
of the drug. FDA mandated programs have proven very effective increasing
safety of drugs in past like Tilcomycin and Revolution.

Now Banfield has an excellent employee training program and \--

MS. SINDELAR: Dr. Rogers?

DR. ROGERS: Yes.

MS. SINDELAR: Thank you very much.

DR. ROGERS: Than you. Our next speaker is Stephanie Shain.

MS. SHAIN: Thank you. I'm Stephanie Shain. I'm here from the Humane
Society of the United States, and on behalf of our over 8.5 million
members and constituents, the majority of whom are pet owners I am here
today. As a matter of course, the Humane Society does not offer our
opinion on veterinary drugs. We choose rather to leave that to the
individual veterinarian and client relationship. We make an exception
for ProHeart 6 for two reasons. Number one, the enormous number of
animals that were adversely affected by this drug; and, number two, the
fact that it is a preventative drug and not something to treat disease.

I am lucky as an individual pet owner of four very healthy dogs that we
chose not to use ProHeart 6 when it was offered to us by our
veterinarian, thinking rather our monthly works, we know it's safe, and
a six-month injectable just seems too good to be true. We ask because
this is a preventative and because there are many known safe other drugs
that can prevent heartworm safely that this drug not be released back
onto the market. We think to do so is just simply reckless and too great
a risk for individual pets and their owners who will invariably suffer
from it. Thank you.

MS. SINDELAR: Thank you for your comments. Our next speaker is Kerry
Tuttle.

DR. TUTTLE: My name is Kerry Tuttle. I'm a veterinarian from Peoria,
Illinois. I have been in practice for over 30 years and am the director
of three hospitals in Peoria and Bloomington, Illinois. We have
approximately nine veterinarians working for us, most of whom have been
with us for over three years. In late 2002, being somewhat of a cynic
with all new drugs that come on the market because of problems that have
later been found once they have been presented, we did not begin
ProHeart 6 upon its initiation. Late 2002 we gave our first dose, and
since that time we have given approximately 6,000 doses. It represents
just over half of the heartworm prevention of the clients that we have
in our practice.

We offered our clients the choice of the once-monthly heartworm
medications and the ProHeart 6. In that time, since we began that, which
is over two years until the time it was removed from the market, via
three-day callbacks, the fact that we have three practices that are
relatively small practices, three doctors per practice, we feel that we
know our clientele reasonably well and our clientele knows us. If they
have a problem they tell us. If we think that they have got a problem,
we morally accept some responsibility to solve that issue, I think no
different than most veterinarians.

In the two years that we have given ProHeart 6, the 6,000 doses, we have
documented four adverse reactions. Of those two were transitory
digestive upsets, one was facial swelling, and one was hair loss at an
injection site. The only one that has maintained or has been a continued
problem has been the hair loss at an injection site. It didn't grow back
and probably is the size of a half dollar at this point.

Our efficacy as far as the drug has been essentially 100 percent.
Compliance on the part of the clients has been good. We do give them the
choice. We have advised them that there have been adverse reactions. To
each doctor they have their preference to their client as to which they
may provide voice inflection or at least provide which they recommend.
As I said, we are over 60 percent or slightly over half with ProHeart 6.
Art the time of the recall we had approximately 5,000 doses in stock. We
questioned whether or not to send it back. Shortly we decided that
immediately we would send it back because it was the right thing to do.
Since that time all we have heard from clients is, \"Don't you have an
extra shot of that around somewhere, Doc? We want it. It's great.\"

I empathize with the individuals here today who have had disastrous
reactions. We have not seen those, and I empathize with your group in
the FDA because you are getting certainly some diametrically opposed
information here, and I don't know you decide what's right and what's
wrong. Thank you.

MS. SINDELAR: Thank you very much for your comments. We have exceeded
the time allotted for the open public hearing. I would like to yield the
floor to Dr. Art Craigmill. Thank you.

**[Committee Deliberations]{.underline}**

**Dr. Arthur Craigmill**

DR. CRAIGMILL: Thank you, Aleta. We will spend another half hour until
we take a break. I think one-half hour. Is that your plan? Until 3:00,
so it is 45 minutes. I would like to at this time to return to asking
the committee if they have questions, and I think maybe in the interest
of efficiency we will simply start going around the table, and I will
skip people who have already talked and then come back for
clarification. So I would like to start with Dr. Aref please.

DR. AREF: I sort of have spread out questions from various places. On
page 18 in your \-- the document from Fort Dodge, it says that about the
carcinogenicity studies that the mice and rats that had the two-year
study that doses were lowered because mortality was increased. Then the
last sentence is that there were not compound-related findings in
hematology values, organ weights, or at macroscopic or microscopic
examination. There was no evidence moxidectin-related target organ
toxicity or tumorigenicity.

So for a lay person what does that mean? That you \-- I mean, you
obviously saw higher mortality, but you didn't see any symptoms or any
changes in the various \--?

DR. ROBB: I will ask Dr. Blasak to respond to the toxicology questions.

DR. BLASAK: Yes. Thank you. My name is Dr. William Blasak. I'm with
Wyeth Research, and the carcinogenicity studies were done in mice and
rats as they are typically done to assess carcinogenic potential because
it is a disease that tends to happen more in later years of life. Those
species have very relatively short life spans of one to two years. So
there are commonly used for that.

The way doses are typically chosen for those types of studies, they are
typically chosen on what is called a maximum tolerated dose. So you feed
\-- in these particular examples you feed the animals a certain amount
of the test article, in this case moxidectin, and you maintain them on
that diet. Now if that dose is too high generally what you will see is
you will see some kind of toxic effects. Okay? And the effects that we
saw were very typical of what is seen with moxidectin, and that is they
stop eating, okay, they begin to lose weight, and if you go on long
enough, okay, you have mortality in that study. Now obviously you cannot
study the carcinogenicity in animals that are no longer there. Okay? So
the reason of reducing those doses is that we were too high in those
doses. Okay? And so as the studies were going on \-- I think it was
within about the first month or so we noticed these decreasing body
weights in these animals versus control animals. Okay? So we reduced the
dose of moxidectin in the diet.

DR. AREF: Okay. So this was just a carcinogenic study so that you were
only interested if they got cancer?

DR. BALSAK: No. No, and at the end of these studies \-- so once those
doses \-- once the animals, if you will, stabilize at the lower dose,
okay, the study has gone on, the animals are monitored on a daily basis.
Okay? Then at the end of the study hematologies are performed, clinical
chemistries are typically performed, and a full histopathological
analysis of all the organs and tissues is conducted. Okay? And the main
reason to do that obviously is to look for tumors first of all, but you
also will find any kind of systemic organ or target organ toxicity in
those animals. So if there were liver lesions resulting from moxidectin
you should find them, if there were kidney lesions, et cetera.

And if I could add, it is not in the package, but we did a series of
pharmacokinetic studies to supplement what Fort Dodge had done. Okay?
And the reason we did the pharmacokinetic studies is we wanted to know
by the diet route how much moxidectin those rats were actually being
exposed to, because we weren't sure. We weren't sure how much would be
absorbed through the diet. Okay? And so we put those studies on in
November actually to help address some of these issues, and if you look
at what the rat consumed over the two-year period versus what a dog
would be given over a two-year period with ProHeart, that is four
injections, and you look at the actual exposure in the blood of those
animals to moxidectin \-- not just how much you gave them, but the
actual levels in the blood \-- those rats received about 860-fold the
amount of moxidectin that dogs receive in a two-year dosing regimen.
That is how exaggerated the moxidectin levels were in that study.

DR. AREF: So what did cause \-- I mean, that they didn't want to eat and
the weight loss?

DR. BLASAK: Well, you know, it's not uncommon in these effects. It is
not uncommon when an animal is taking in too much of anything. Okay?
There can be CNS effects. There can be effects on a variety of all
biological phenomenon where they will stop eating, and we know that
there is CNS effects of this drug. We know that from a variety of
different sources, let alone just the macrocyclic. But it is the
exposure of the animal to the drug that is really in question. Okay? So
if they were getting 860-fold the amount of drug over two years, if they
were getting more than that maybe that did cause some effects, but, you
know, the exposure differential there is so large that its relevance to
a clinical practice is really in question.

DR. AREF: But would a necropsy show anything?

DR. BLASAK: No.

DR. AREF: So if you do a necropsy on dogs who have gotten ProHeart 6 you
wouldn't see anything either?

DR. BLASAK: That's correct, and the dog studies for example, we have
done a whole series of studies in dogs. He longest term study was a
one-year study. Now this is a study were dogs were given again in the
diet moxidectin for one year. So they got to eat their chow every day
with a certain amount of moxidectin in it for over one year. Okay? And
at the end in those dogs, and absolutely a good case, they did not lose
weight. There were no adverse findings in life, and upon necropsy they
went through a very full necropsy, a very systematic necropsy where all
the tissues and organs were examined, and hematology, clinical
chemistries, all those sorts of things were looked at, and they were
actually perfectly normal. Okay? Now those dogs were exposed to 454-fold
the amount of moxidectin that a dog would be exposed to over one year.
That is how much the level was in those dogs. Okay?

Now in studies prior to that, you don't just start a one-year study
cold. You have to have previous information about how much you can give
dogs so that you don't go over certain amounts. Okay? So in studies
prior to that one, one-month studies and three-month studies. In those
studies indeed at doses even way above the dose we used for the 454
multiplication factor, you would have the dogs showing the same thing.
They would stop eating. Okay? They would have tremors. Okay? They would
become lethargic, a very similar picture. But upon necropsy in those
animals you don't see any systemic effects at all.

DR. AREF: But so it is likely if a dog was already compromised if you
gave that injection without knowing it was compromised for whatever
reason, it would not take that injection very well.

DR. BLASAK: Well, I can't speak to that. The toxicology studies were
done in very healthy animals and I can't speak to whether or not if it
is given to a compromised animal. I think it would certainly depend upon
what is wrong with that animal to start with about what would happen to
the animal. Sorry.

DR. AREF: I have another question. It's about a couple pages further on.
There is a field study mentioned on page 26 where client-owned dogs were
looked at. There were 374 dogs representing 84 breeds. 280 were ProHeart
treated and ProHeart 6 treated, and the others were \-- 94 were on
ProHeart oral tablets. On the next page they said that there were 12
other dogs were euthanized or died during the 12-month study, and those
were all from the ProHeart 6 population. It doesn't say anything about
any dog from the ProHeart oral population of these dogs. If none of the
ProHeart oral dogs died, there is actually a statistical significance in
the two populations' mortality rates at five percent.

DR. COBB: Dr. Rock, would you address that please?

DR. ROCK: Yes. We are talking about the field studies in the studies
that you are talking about, and in conducting these types of studies a
number of things happen. These studies are 18-month studies. Sometimes,
you know, dogs would get hit by cars. They are not in there. Dogs, we
had dogs that were lost in hunting accidents. We had dogs that ate
antifreeze, and a number of different things that happened throughout
the conduct of the field trial. The bottom line in the interpretation of
the experiments, both by Fort Dodge and by the FDA reviewers, is that
these deaths could not be attributed to the use of the product, either
the ProHeart 6 or the ProHeart tablet. ProHeart tablets at a very, very
low dose, three micrograms.

DR. AREF: Based on the clinical observation, but it is assumed that the
populations are equal except for the drug that they got? They should
have the same kind of mortality rate, shouldn't they?

DR. ROCK: We find that in the conduct of this type of study and in the
interpretation of these cases as I said, some were hit by cars, some
hunting accidents. There was antifreeze. We did have, you know, two
geriatric dogs. We had one dog that had congenital diseases which was
talked about already today. But it was the interpretation that these \--
that in both populations that there was not a correlation to the use of
the product.

DR. AREF: Right. But I am just saying that just from when you have two
groups of dogs who receive different drugs, there must be geriatric dogs
in the oral ProHeart medication group and there must have been those
that potentially could have been hit by cars and stuff. Were there none
of those that were?

DR. ROCK: Yes, there were. I mean, there \--

DR. AREF: There were \-\--?

DR. ROCK: Both populations basically reacted the same.

DR. AREF: Okay. Just because you mentioned only the 12 on the Proheart 6
\--

DR. ROCK: No. The incidence was basically the same for both treatments.
Remember the design of the experiment is two-thirds of the dogs are on
ProHeart 6 and one-third are on the ProHeart tablet.

DR. AREF: Yes. It just doesn't say anywhere how many of the other ones
died. That is the only \-- I mean, because you don't give any numbers
for those in the oral group that died then I was thinking that none of
them died.

DR. ROCK: Okay. I understood we were writing the report for ProHeart 6
to provide you information like that, but the two populations basically
responded the same.

DR. AREF: Okay.

DR. CRAIGMILL: We will move on and come back if you have one further.
Dr. Bennett, I would like you to have 10 minutes now.

DR. BENNETT: Right. Thank you very much. I want to actually focus a
little bit on the Banfield study a little bit. The way I look at it from
the FDA report there is about 12 million administered doses of the drug,
and the Banfield people said they have administered about 735,000 or
basically about six percent of all doses. What my concern was, my
question was of the 485 deaths that the FDA has that are reported
through the adverse event reporting system, how many of them come
directly from the Banfield program?

Then secondly in general with this nice adverse event reporting system
the Banfield field program has set up electronically, how many of those
adverse event reports from the Banfield system when straight down to the
FDA and when the FDA goes through their adverse event reports came out
of the Banfield system? So just some cross-correlation between what
Banfield reports and what the FDA reviews.

DR. NOVAK: So two questions, is how many \--

DR. CRAIGMILL: Please identify yourself for the record.

DR. NOVAK: Dr. Will Novak, Chief Medical Officer for Banfield. Question
one was I believe how many patient deaths did we have that were
attributed to ProHeart 6. We had zero. And the second question was how
many of the adverse events do we have that we have reported in our own
system are then reported to either the manufacturer or to the Food and
Drug Administration. We don't of course have a requirement to report
that through the system, and so I don't have an exact number. There are
a handful of the reports that we've had that would have been reported
with FDA. Anything that was reported with FDA goes through the normal
reporting process. I am sorry \-- have been anything that we reported
would have been reported to Fort Dodge Animal Health. They have of
course a requirement then to go ahead and report it on up through the
system. And so any of the reporting that we would have done would have
been something that we thought was above and beyond unusual after our
peer-review process medical record review and that sort of thing.

DR. BENNETT: See, the question I have is given these several Dear Doctor
letters and these package insert changes and the threshold for reporting
decreased over time as I understand from what people said because
awareness came up. It seems that if the threshold decreased over time
then the original reports we heard from the FDA was that people would
report differently at different thresholds. It seems to me a little
strange that as those thresholds came up that the Banfield system didn't
activate any different way than it had before, even though as you said
up front that there was an increased alertness, increased concern that
these things might be related. That initially they might be passed off
and then \-\-- it might not have been.

DR. NOVAK: Okay. I am not completely following the train of thought
there, but maybe to go through our adverse reporting system the way that
we have got it set up is it designed for an interim reporting system. So
we are then statistically tracking any variables that we would see for
each of the individual components of the vaccine versus ProHeart 6. So
we wouldn't particularly change the reporting methodologies going from
us to let's say Fort Dodge Animal Health, unless we saw a spike on some
change.

Now another example would be is that we may see a spike or a change on a
vaccine, a particular component of a vaccine. That would then instigate
that we would get involved with Fort Dodge Animal Health. Example,
looking for a batch of vaccine that maybe we think needs to be changed
out. So, and I'm not \-- the reporting system, I do have the same
concerns about the general reporting system when it comes to everything
that has been discussed today is that by nature if you send out a Dear
Doctor letter one would have a heightened concern about some things. We
have an internal medical advisory group that fields a lot of those
questions, and so we are \-- we got a lot more interchange between
board-certified experts at our main office and our doctors in the field.
So, you know, we are constantly looking at this thing internally.

DR. BENNETT: Well, okay. I won't go belabor the point, but the last
point I would make is that if you had a concern about the way the cases
were adjudicated between what you saw or when you reviewed the FDA
reports and there was concern that Fort Dodge didn't adjudicate them the
same way as the FDA did when there were cases to be adjudicated. My
question was why don't they look at the exact same cases that you have
in your data set that the FDA has and adjudicate them to see if you get
concordant or discordant reasons and discordant things. You could
adjudicate those even with what they have by matching them up by state
and dog size or something like that. There are some ways that \-\-- but
you are also going to report.

The last thing I wanted to bring up is the question that was brought up
from one of these speakers, was the issue about the handling of the
product. I think that is a point that I think when I look at the side
effects of ITP, IMHA, anaphylaxis, it raises a concern to me again of
the question of the single vial that somebody brought up as an issue as
opposed to the repeat use vial. Any questions about impurity related to
not actually the product, the drug itself, but the vehicle and the
stability? And I am wondering if the company has spent some energy to
look at the stability in terms of multi use as opposed to single use and
whether these adverse events that have been reported are associated with
vials that have been potentially out there more with more environmental
exposure than the other vials.

DR. COBB: I would be happy to address that question. Yes, the company
has expended a great deal of time and effort looking at various aspects
that you raise and they are very valid aspects. When we initially
received reports after the product was launched we in fact did a number
of practice surveys because we did notice a cluster effect in that a
practice in one city may report several reports. Neighboring practices
did not report any. And our first thinking was there may be something in
the handling, the storage, or the administration of the product. In
fact, people from our professional services and research groups went out
and visited practices, spoke to the veterinarians, to the technicians
who were involved in handling the product. They even spoke to some of
the pet owners to try to understand if there was any identifiable
predilection that would point us to something that precipitated a
reaction. We were unable to identify any patterns.

We certainly have conducted extensive stability testing on the product,
both in its primary presentation as two vials and also in its
reconstituted presentation. That has involved repeat penetration of
vials. It's involved storage of inverted vials versus upright vials. We
find that the product can be stored under normal usage conditions
according to the label without any detectible deterioration or change in
the product. We certainly have looked at what happens to microspheres
over time, whether there is different release of moxidectin as the
microspheres age. We do not find that in our testing, and I think a
comment was raised about the coating on the microspheres. I would stress
we don't coat the microspheres. The microspheres are manufactured from a
consistent granulation to insure a uniform distribution of moxidectin
through the glyceryl tristearate matrix.

As far as the carrier, we did extensive testing on the hydroxypropyl
methylcellulose. We sent quality assurance auditors into the
manufacturing facility to see if there was any possibility that the
product could be contaminated either during manufacture with something
else that was being produced by that manufacturer. The quality audit was
very favorable. All of our stability tests, sterility tests, have shown
that the product when used and stored according to label and under the
rigors of normal commercial use appears to be very stable. We brought
product back from the field. We tested it extensively, product where
dogs had been treated with that particular vial and had reacted, and we
could not determine any deterioration or change in the product that we
could attribute to a reaction.

DR. CRAIGMILL: If I may just interject one question here. Thermal
stability, did you test that? I'm sure you tested thermal stability of
the preparation of the microspheres, and could you comment on thermal
stability if perhaps something got a little too warm?

DR. COBB: Thermal stability is an issue, and at above 40 degrees
centigrade there can be a change in the matrix of the glyceryl
tristerate. Moxidectin also is temperature sensitive. It is a
fermentation product and like many fermentation products is temperature
sensitive, and temperatures above 60 degrees centigrade would be
expected to cause some degradation of moxidectin. They were not
temperatures that we encountered in our site visits to the practices.
The products generally were stored according to directions. We found
reconstituted products generally were stored in refrigeration or at
worst sat on a bench top for several hours. They were not exposed to
temperatures of 60 degrees centigrade that we could determine.

DR. CRAIGMILL: Okay. If I may follow it just a little bit more. So the
microspheres may become unstable if they are heated greater than 40
degrees centigrade?

DR. COBB: The microspheres may actually change their physical form a
little bit. The glyceryl tristerate has a critical temperature of 40
degrees C, and does change into a slightly different form and you may
see clumping of the microspheres if they are heated to greater than 40
degrees. That was one of the first things we looked at when we did our
field visits to see has this product been heat stressed, are the
microspheres a conglomerate in the bottom of the vial rather than being
free-flowing microspheres, and we did not find that.

DR. CRAIGMILL: So there is a visual representation that you can see. It
is a very visual \--

DR. COBB: It is very visual. They actually glue together in a big blob.

DR. CRAIGMILL: And so you can possibly give it if that had happened in
shipping or anything like that?

DR. COBB: They would need to \-\-- I think.

DR. CRAIGMILL: Okay. Thank you very much. That is what I was wondering.
At this point, I would like to move to another one of the people who has
not spoken yet, Mr. Jaffe.

MR. JAFFE: Okay. Thank you very much. I have a question for Fort Dodge.
The report that we were given that you had produced talked about
incident rates of adverse incident reports in \-- 10,000 doses sold. It
was a rate as to 10,000 doses sold. I guess I would like to know whether
you have some information about how many dogs were actually give
ProHeart over the two-and-a-half years that it was marketed and whether
you have done any calculations of sort of rate per 10,000 dogs for
example. I know that some of these adverse incidents you would expect if
they had multiple doses the chance of the likelihood of it happening to
be decreasing and so forth. Allergies and so forth if they had gotten
through the first dose without any adverse incidents. So I am curious if
you can tell us what information you have in terms of how many dogs have
actually been treated with ProHeart, how many dogs are repeat in terms
of the number of doses per dog that have been gotten since the product
has been on the market.

DR. HUSTEAD: You ask very interesting questions. The numbers of doses of
ProHeart which have been sold are about 18 million. We estimate that
about 12 million dogs have been dosed with the product. We get that from
interviews with our customers and analysis of marketing data which comes
into the company. We have not calculated a rate of adverse event report
per that number because the number is so highly skewed we don't know how
to evaluate it. So as has been presented, you need to be very careful
when you look at incidence rates so that you can draw any sorts of
conclusions with them. One of the things you have to do is have
consistent numbers, and the numbers of dogs is just not a number that we
can get a hold of with any consistency.

MR. JAFFE: So the numbers that are in the report are done on the 18
million figure, not the 12 million figure?

DR. HUSTEAD: They are the number of doses sold. That's correct.

MR. JAFFE: Okay. Thank you.

DR. CRAIGMILL: Anything else, Greg?

MR. JAFFE: No.

DR. CRAIGMILL: Okay. Let's move then to

Dr. Nolan.

DR. NOLAN: Hi. I wanted to ask Dr. Brown about the Fort Dodge assessment
of \-- how if you tried to reconcile what they found as remotely related
to ProHeart to your possibly related.

DR. BROWN: Well, I didn't really participate in training Fort Dodge in
the use of the algorithm, so I'm not sure how consistently it was
applied. But something that has to be considered is the initial
categorization as to assigning something else as a possible etiologic
agent. We apply that to the algorithm, which is weighted to take all of
that into account. So that as you go dog by dog, drug by drug, clinical
sign by clinical sign, you have the same consistent type of score that
\-- for a causality assessment that can be reached. If one considers
only that there is something else that could be causing that and
therefore you say it is unlikely or remote, then you don't apply that to
the weighted algorithm. You simply take those out as unlikely and
exclude them from the beginning.

DR. PETERSON: I have a question for Dr. Glickman. The study that you did
with the Banfield, you set up three groups of dogs that were on
heartworm preventive to include the ProHeart 6. Did you examine whether
or not there were any differences in the basic demographics among those
three groups? For example, age, breed, or gender?

DR. GLICKMAN: Qualitatively there were no differences. If you apply
statistical testing to them, there are statistically significant
differences, not surprising given the sheer number in some of those
groups of 700,000 or 400,000. You get very significant P values, but
clinically no. You are talking about perhaps a percentage of females of
52 percent versus 50 percent, but they come out. You know, you
traditionally look at it and say, \"Oh, wow. Statistically
significant.\" But I didn't see any clinical significance of that
magnitude of difference.

DR. PETERSON: Okay. Thank you.

DR. SAMS: Thank you. The preparation of the formulation for injection
involves a number of steps that are specified in the product insert, and
those steps appear to me to be somewhat more involved than for the
preparation of other parenteral formulations that are on the market.
Therefore it seems to me that there are opportunities for error in the
preparation, administration, storing and handling of the product. So my
question is, have any studies been done involving the intentional
mishandling in terms of either of the preparation, administration,
storage, or administration of the product?

DR. COBB: In terms of the detailed instructions for reconstitution, they
are there for a purpose because this product is a little different than
a reconstituted solution or a reconstituted suspension that is used in a
single treatment. We do have an approved shelf life of one month for
reconstituted product in the US. So it was very important to us to write
detailed instructions to be sure that this product could be used safely
and effectively within that time window. In some other markets are
reconstituted shelf life has been adjudged to be two months.

We certainly looked at what happens if you do it differently. If you use
too much diluent, and we do put a little overage of diluent in the vial
to allow the veterinarian to express any air bubbles that he may draw
into the syringe. You may a product that is marginally more dilute. If
you lose half of your diluent, if it squirts out of your syringe, you
may reconstitute a product that is somewhat more concentrated. But
certainly our \-\-- studies with ProHeart 12 show that three times the
concentration can be administered and used with safety in dogs.

There were questions raised as to why do we recommend that the product
be swirled after reconstitution, are the microspheres so fragile that if
you shake the product after constitution is this a problem. The reason
we saw swirl rather than shake is that if you shake it you end up with a
lot of air bubbles in there, and it means then that you have to put the
vial down and let it sit for perhaps 40 or 60 minutes to allow those air
bubbles to release themselves from the formulation. That obviously would
be a significant irritation both to the client and the veterinarian. So
we do recommend that you make sure that the microspheres are uniformly
suspended by that gentle swirling. But, yes, the product has been fairly
rigorously tested in terms of what we would expect to happen under
normal field conditions where people do get the dilution rate wrong or
they go to inject the dog and some of it squirts out and the dog is
under-dosed. We've looked at that.

DR. SAMS: Can any of the adverse drug reactions be attributed to any
mishandling of the product during its preparation, administration, or
storage?

DR. COBB: We have looked very meticulously many times, and we have not
been able to identify any adverse event related to drug mishandling or
poor storage by veterinarians. No.

DR. SAMS: Does Banfield conduct training programs specifically directed
toward the preparation of this product?

MR. : Will, did you hear that question?

DR. NOVAK: Yes. The question is do we have specific training programs;
and, yes, we do.

DR SAMS: And is that program applied uniformly across all of your sites?

DR. NOVAK: We believe so. As with 1,000 veterinarians you will always
have a little variation.

DR. SAMS: But there is a formal program?

DR. NOVAK: Yes. We have a web-based training program as well as when we
originally launched the product we did regional meetings. So we spent a
fair amount of time making sure that all of the steps of the process
were well trained against.

DR. SAMS: Thank you.

DR. CRAIGMILL: I guess it is my turn. I have a slide for Dr. Brown \--
slide \-- question for Dr. Brown. I would like to hear what the FDA
knows about the Australian experience with the ProHeart 12 drug in terms
of two major questions. One, is their adverse event reporting system
similar to ours; and, two, what is there experience with that drug?

DR. BROWN: Well, it is my understanding that in the different countries
around the world that the adverse event reporting systems are actually
somewhat different in terms of their collection and the way that they
are interpreted. Perhaps Dr. Post as Chairman of the VICH might be more
prepared to answer that.

DR. POST: Well, I will beg off on the VICH part, but it's just
different. Different populations, different systems. It's about it.

DR. CRAIGMILL: Can you comment about what they have found, seen, or in
terms of have they had a similar problem basically or any of the other
countries where it is approved?

DR. POST: No, I can't really comment on different countries, what they
have found or haven't found. I just know about what we found in the US.

DR. BROWN: I would just have to refer you to the websites for those
countries and to take a look at the numbers of reports that have been
received and what types of reports they are.

DR. CRAIGMILL: Just even one further question about obfuscation. Do you
know is the formulation the same as \-- it is a different formulation
being used, right? Or is it a different carrier?

DR. BROWN: I would be happy to answer that. The formulation in fact is
the same. We put three times as much mircospheres in the microsphere
vial. We put the same amount of diluent in the diluent vial. So the
product is administered at three times the does, three times the
concentration, but at the same volume.

DR. CRAIGMILL: Yes, Dr. Hustead?

DR. HUSTEAD: Well, I am actively involved in the Australian adverse
event regulatory arena as my area of responsibility is all countries
around the world. And it is my assessment that the adverse event
reporting system in Australia is actually very similar to the FDA's
reporting system. There are of course always differences, but those
differences are comparing vanilla ice cream and French vanilla ice
cream. The similarities are much more similar than the differences. And
as far as the adverse events that they have experienced, it is our
review of the events in Australia and here that they are highly similar

DR. CRAIGMILL: Okay. Thank you. My second \-- I have four questions, and
we will take a break at 3:00. My second question has to do with we heard
about the long-term studies that have been done with moxidectin per se.
I would like to know what acute and chronic studies have been done with
the actual formulations, multiple injections, one, three, five-X doses,
et cetera, for ProHeart 6. Can we have someone to cover that?

DR. COBB: Yes. I will ask Dr. Rock to cover that.

DR. ROCK: The safety program for ProHeart 6 actually covered three types
of studies. The first type of study is a safety study in the target
animal. Okay? It's a one, three, and five-X study, and there is a
necropsy of high-dose and then controls. If there is something for us to
look at, if there is a trend or something there, then we will go in and
do the mid doses.

DR. CRAIGMILL: Can I clarify? Is that a single dose?

DR. ROCK: That's a single dose. Yes.

DR. CRAIGMILL: Thank you.

DR. ROCK: Okay. We have also done a study in ivermectin-sensitive
Collies. In that study we choose Collies which are shown to be sensitive
to 120 microgram dose of ivermectin. That's approximately a 1X dose for
a 20 KG dog. We use a 1X, a 3X, and a 5X in that study, and we follow
those dogs for two days. We are looking for typical signs of toxicity
which would mainly be CNS effects. We follow those dogs in locomotion
studies, and we also follow immediate reactions to those dogs, and in
that study we saw none.

In a third study which was already talked about today, we identified
dogs that are naturally infected with heartworms. We determine that by
measuring the circulating levels of microfilaria. We then treat those
dogs with a 3X dose, a single dose of ProHeart 6, and then we necropsy
those dogs later on and look for abnormal reactions. We are also looking
for abnormal reactions immediately after treatment. If there is some of
the toxic effects that one might expect if we were having a mass kill of
adults, and allergic reaction or something to that nature, and in those
studies we were \-- we did not show any adverse reactions.

Just one step further in our discussion as part of \-- and Dr. Cobb
talked about it earlier today, as part of the ProHeart 12 program we did
do a heartworm-positive study with dogs that had 20 adult heartworms
inserted via the juggler vein, and looked at adverse reactions. In those
dogs we let those worms equilibrate for a period of 60 days I believe,
and then we treated them with a 3X of ProHeart 12, which was a 9X of
ProHeart 6, and there were no adverse reactions in that experiment as
well.

DR. CRAIGMILL: Do you have data from multiple injections of the ProHeart
6 in dogs?

DR. ROCK: We have a small, non-pivotal study in multiple injections. It
was in \-- it is in the FOI where we started out \-- one of the concerns
that we had at the beginning of the development program with ProHeart 6
was if we are going to have dogs on ProHeart 6, two injections a year
for a period of seven, eight years or something to that nature, what is
going to happen with each one of those injection sites? So we set up a
study which starts out with a fair number of dogs, but at each time
point after six months, after 12 months, throughout a period of time, we
will necropsy and excise those injection sites in a small number of
dogs. Whether it is two or four, we will go left side, right side, both
on the right side, and all different combinations. It ends up with a
large number of dogs, but it ends up with a small number of dogs at each
of the necropsy points if you are trying to cover all points. In that
study we determined or we observed that there was no adverse reaction to
multiple injections, nor was there any accumulation of the drug in the
body.

DR. CRAIGMILL: Okay. Being a toxicologist, one more question. Did you
run a test of the formulation using like a guinea pig,
hypersensitization model, anything like that as part of the initial
acute screen?

DR. ROCK: There were these types of studies way back in the discovery
phase when we were dealing with moxi

\-- with microspheres as a whole, and there was \-- we did not identify
any problem with the use of microspheres.

DR. CRAIGMILL: Okay. I will save my last two questions until after
break. We will come back and recommence at 3:15. Sorry. Aleta has
something for now.

MS. SINDELAR: I am sorry. Just for the purposes of transcription and for
the record, Dr. Tuttle has agreed to just make some comments which he
didn't make at the opening of his five minutes.

DR. TUTTLE: I apologize. I didn't announce. I have no financial interest
with Fort Dodge, a general drug distributor who provides not only Fort
Dodge products but all of our other products did pay my expenses here.

DR. SINDELAR: Thank you very much. Okay, 15 minutes please.

(Whereupon, a short break was taken.)

DR. CRAIGMILL: Okay. At this time I would like to ask Fort Dodge Animal
Health people again and Dr. Cobb probably and who will probably refer it
to somebody else again. It is a follow-up question to Dr. Papich's
question about the pharmacokinetic values. You mentioned the Tmax, the
time of maximal concentration was somewhat variable. The key point I
believe five and 14 days? The Cmax, the actual concentration obtained,
what type of variability did you see with that?

DR. COBB: The variability in the Cmax is not enormous. It ranges
generally around the order of five nanograms per ml, but we do not see
levels in excess of six. So it is quite tight Cmax, although the Tmax
may vary a little bit in individual dogs.

DR. CRAIGMILL: So you don't see why it swings in that, in the Cmax at
all. Interesting. Thank you. Dr. Nelson, whom I cut off at lunch, now we
will return with his questions.

DR. NELSON: Aa a clinician, I am more concerned about clinical cases,
and I would kind of like to return to these cases that were presented to
the committee as representative of some of the problems that were going
on. I guess one, the liver, since Dr. Brown was bring about the
pathology of the liver in these six cases, one of the things here, there
is only one case that actually has a level of what the ALT was. Mostly
it says it's elevated. Did you get actual, you know, values on these
cases? Or the report just came in elevated ALT?

DR. BROWN: That would depend. In most of them I would say that we do
have actual values, and there again they are considered elevated
reported by the veterinarian who is attending clinical that patient and
also referring to the baseline of the laboratory that that individual
practitioner uses.

DR. NELSON: Then also in those cases two were necropsy, one had a
biopsy. You were asking about pathology, and the third case we get a
biopsy, and this done like three or four days after the injection. The
diagnosis came back as chronic active hepatitis?

DR. BROWN: Yes.

DR. NELSON: And then on another case, case number five, necropsy was
approximately two weeks after injection, and in that one there was some
mineralization in the kidney tubules, which is more of a chronic kidney
problem? I guess one of the \-\-- today with these clinical cases is the
lack of information. In the neurological cases one of the things you had
in here on case number six, you talked about a CSF tap and then you
bring up a distemper titer of one to 80. Is that in CSF fluid or one to
80 in serum?

DR. BROWN: Oh. I believe that was in the CSF fluid.

DR. NELSON: Which positive titer and CSF fluid is pretty much indicative
of distemper, right?

DR. BROWN: Well, the laboratory said that could indicate vaccination
infection or exposure.

DR. NELSON: Did you have the titer of also serum?

DR. BROWN: No. That's the only titer we have.

DR. NELSON: Also there are some questions in here about health status?

DR. BROWN: Yes.

DR. NELSON: I thought it was interesting that it listed health as good
in a 40-pound Dachshund?

DR. BROWN: Oh. Yes, I found that rather interesting myself.

(Laughter.)

DR. BROWN: Actually in that circumstance obesity would be listed as a
concomitant medical problem and for circumstances anything affected
cardiology or the joints or the liver we would of course give that a -1
in the alternate agent category.

DR. NELSON: The other thing that is also not listed, and you talk about
concomitant use of vaccinations, it just says distemper. It does not
list whether it is distemper with lepto or without. Do you have any of
that information?

DR. BROWN: Yes, usually we do have that information, and for almost all
of these if it says it is distemper vaccine it is actually referring to
distemper adnovirus parvovirus combination. Usually with lepto unless
specified not.

DR. NELSON: So all the ones that say just distemper you had lepto
included?

DR. BROWN: Yes. In some circumstances we have the actual names of the
vaccinations used, and in others we don't.

DR. NELSON: And then also did you have, as I brought up earlier, any
information about previous heartworm preventatives in a lot of these
cases where there's gaps of two years?

DR. BROWN: In many of them we don't. Sometimes we have owners coming to
practices with all their previous records in hand. Sometimes they will
come and there is really no previous information available. If the
reporting veterinarian has been able to ascertain that, that would be in
the medical record, or we might call them and ask them for that
information. But if they don't have it, then they just don't have it,
and that does kind of obscure the possibility of has there been a
repeated exposure or has there been the possibility of a cross-reaction
across a class of the macrocyclic lactones. We are just not able to say
in those circumstances.

DR. NELSON: Well, I hate beat a dead horse, but the whole issue of
heartworm status is so important with these drugs. I mean, there is not
one of these drugs that we have not seen reaction in a
heartworm-positive dog, and then just the whole understanding of the
pathogenesis of heartworm disease. It was a little disturbing in going
through the CVM's report referring back to the 1999 guidelines and about
heartworms being found in the right atrium. When they break loose there
it is supposed to be in the pulmonary artery they are found, and also
the three-month disease cycle that we actually have two-inch worms in
pulmonary arteries at 90 days. So it is extremely important that the
heartworm status of these dogs and the prior preventative that has been
administered be known if you are going to try to predict any type of
anaphylactic reaction to \-\-- filaria.

DR. BROWN: Yes. We really would like to have that information, and as I
said many times we have called and asked please go back and try to find
it. Often they will send the entire record that they have to us, and it
is just not there. It really would be helpful if we had more complete
reporting.

DR. CRAIGMILL: Other members? Dr. Brown.

DR. C. BROWN: I have a follow-on to that. Not to sound like a little dog
at the end of a rag, but necropsy findings, histopathology, is there any
further data on that to be presented?

DR. HARRIS: I'm Keith Harris. I'm head of pathology for Wyeth Research.
I will try to talk loudly \--

MR. : \-\-- will get the microphone.

DR. HARRIS: Is that better? I'm Keith Harris. I'm head of pathology for
drug safety in Wyeth Research, and I guess this goes back to your
earlier question of how many necropsy and pathology reports we had in
the Fort Dodge database, and there were \-- out of the 616 animal in our
database, there were 165 necropsies. Out of those we had eight \-- there
were 85 pathology reports, and to the best of my knowledge all the
pathology reports went to the various consultants that were looking at
liver, CNS, immune-mediated disease, and that's how we divvied them up.
So I focused for example on liver, and I did look at a few heart cases
as well. Does that answer your question?

DR. C. BROWN: So you read the reports, but you didn't review the series
of slides?

DR. HARRIS: No. The only ones we read, the \-- we looked at the reports,
looked at \-- in my case I looked at \-- we all looked at the total
package, but we looked at the reports, looked at what the individual
diagnoses was made by the pathologist, then looked at their final
comments. The only case that I looked at slides or did we look at slides
was in two heart cases where I looked at sections from the animal in
trying to figure out what was going on in the heart.

DR. C. BROWN: Thank you.

DR. GROSECLOSE: Just a question on the series of studies that were
discussed just prior to the break. I had wondered whether those were
done pre-marketing or post-marketing, and how many animals may have been
included in those studies, and what was the power to detect any adverse
events in those studies should there have been any?

DR. ROCK: The safety testing was done during the development program,
and it is done to a standard design that was discussed with the Center
for Veterinary Medicine prior to initiation of the development program.

DR. GROSECLOSE: Okay. Maybe I can then direct it at the Center for
Veterinary Medicine. What power do those studies have based on the
sample size that you require to detect adverse events prior to bringing
these biologics to market?

DR. POST: We don't do a statistical analysis. It is all \-- oh, are you
talking about pre-market?

DR. GROSECLOSE: Pre-marketing, right.

DR. POST: I'm talking about post-marketing. I will defer that question
to Dr. \-\--.

DR. BARTHOLOMEW: I will try to address it, and the answer to that \--

MR. : Please identify yourself.

DR. BARTHOLOMEW: Mary Bartholomew from the Center for Veterinary
Medicine. I'm in the biometrics group and we review target animal safety
studies for the Center. The gentleman from Fort Dodge Animal Health is
correct in that there is a fairly standard study design that has been
used for companion animals, and the typical study size is four males and
four females per treatment group in each of zero, one, a three, and a
five-X study. The reason for using the exaggerated doses is typically
because the studies are fairly small and we are trying elicit the toxic
syndrome. So in terms of power we'd have to talk about what size
difference for what variable, and we look at sometimes for including all
the clinical chemistry, the hematology, necropsy variables, and some of
the in-life measurements like weight and feed consumption. We look at
probably 50 variables, so there is also a multiplicity issue there. But
that is the typical size. Sometimes that varies, but that is the
standard-sized study and I believe that's the size study that Fort Dodge
did.

DR. GROSECLOSE: Okay. Thank you. Just two more questions. The
microsphere technology, is that used in any other of your biologics at
Fort Dodge?

DR. COBB: No. We do not use that microsphere technology in any of our
other products.

DR. GROSECLOSE: And a question for Dr. Glickman. Could you review the
findings of your multivariant analysis of the association between
ProHeart and allergic reaction? There seemed to be a statistical \-- I
mean an increased risk of allergic reactions in dogs that were
administered

ProHeart 6, and you didn't mention it in your conclusions, and I \--.

DR. GLICKMAN: Yes. In looking at the multivariant model, well, what we
saw from just looking at rates was that there appeared to be an
increased rate of allergic reactions in the dogs that got vaccine
compared with the dogs that got any of the heartworm products. In fact,
this came out in multivariant analysis. There was this 150 percent
increase in the risk of allergic reaction in vaccinated dogs versus not
vaccinated. Both ProHeart and heartworm one monthly also were associated
with an increased risk of allergic reactions. In ProHeart it was
increased 38 percent, and heartworm one 12 percent. We probably didn't
see any increased risks for heartworm two because it is the more
infrequently used product, so the sample size was much lower. Had the
sample size been bigger, we probably would have seen an increased risk
rate as well. So we did see an increased risk of allergic reactions for
basically all of the heartworm preventives we studied, of course as well
as with steroids because of this use association.

But the interesting thing to me was then if you look at each additional
dose of ProHeart, the risks do not go up further. In fact, it was
marginally reduced.

DR. GROSECLOSE: Well, how did you account for say \-- I don't want to
belabor it, but, you know, a dog that had two versus three versus four
in your model?

DR. GLICKMAN: Well, we put that in, in the model. One dose, this was
\-\--. Zero would be no dose, then first dose, second dose, third dose,
fourth dose, and it went in the model just that way; and there was no
significant dose response relationship on the up side, and even on the
down side. It was sort of a negligible change in risk with each
additional dose.

DR. GROSECLOSE: Did you see any dogs that may have received one dose of
ProHeart who then received \-- went back to a monthly heartworm
medication subsequent to the first dose?

DR. GLICKMAN: No, we didn't track longitudinally in this case and
distinguish reactions to see if a reaction on the first dose would be
associated with a reaction on the third or fourth. It's interesting. We
have done a large study in this database with vaccines, which appear to
be more allergenic, and sort of the belief out there is, \"Well, if a
dog has an allergic reaction to our vaccine, either you shouldn't give
it again or you have to pretreat or whatever.\" And using this database
we have seen no larger risk with a second dose in a dog that had a
reaction the first time than in a dog that did not have a reaction the
first time. This is the first time we have been able to look at this
scientifically, and pretty much we are finding similar things with
ProHeart. It was a little harder with the oral monthlies because since
they weren't given in the practice it is harder to track, and owners
miss doses and you would probably not know about that if there is no way
to track it.

DR. MEALEY: Okay. One question about the mast cell tumor, the increased
risk that you found with mast cell tumors. Were any of those mast cell
tumors found at the injection site?

DR. GLICKMAN: That's a good question. We have not gone back to look at
two things, though clearly one should know whether it is at the
injection site or not, and, two, whether perhaps histopathologically
they differ, that is mast cells in dogs that got ProHeart versus mast
cells in dogs that did not get ProHeart. For example like we see with
fibrosarcoma in \-\-- when they occur at injection site they are much
more aggressive, et cetera, than if they are not. That has not been
done.

What we did do was to calculate how many dogs would we need in a
prospective study. For example, to detect this increased rate that you
see with let's say ProHeart with vaccine versus vaccine alone in the
incidence of mast cell tumor, and it comes out to be 600 \-\-- dogs per
group, so it is clearly never going to be done.

But what you suggested is absolutely right. One should go back now and
for those dogs who have histopathology, which most will, actually pull
them out and compare them, and also try to get more information on the
site of the tumor, which we did not do. Phil, do you want to say more
about the medicine?

DR. BERGMAN: Yes. Dr. Mealey, in reference to your question, my name is
Phil Bergman and the outside oncology consultant for FDAH. Of the 130
cases that we had available that I had available to review, there were
three dogs with mast cell tumor, and none were associated at the
injection site. Importantly, all three of those dogs actually had their
tumors occur with three weeks of injection of ProHeart 6. So suggesting
that there was no association with ProHeart 6.

DR. MEALEY: Second question is there seems to be a concern, and I have
some concern, that maybe moxidectin itself as the drug is maybe not a
cause of these adverse events, but potentially the vehicle. And in the
FDA documents that we got on page 11 there's a couple of statements in
there about letters that were made from the FDA to Fort Dodge Animal
Health about problems with manufacturing. There was sterilization
problems I think and dissolution time point and GMP violations
basically. I guess I want to know, is that a fairly common \-- are those
letters, citations, whatever they are, are they fairly common among
manufacturing pharmaceutical industries, or is that kind of an unusual
thing?

DR. : I don't know if I can answer how common they are, but it is these
letters were not really directly connected with adverse drug events.
They were just some manufacturing problems that were cited in an
inspection.

DR. COBB: Perhaps I can comment on those issues. The first issue related
to dissolution testing failure. Dissolution testing is conducted under
laboratory conditions, and it measures the consistency of a product
release. We put the product into a laboratory media and we measure how
much moxidectin is coming out at 1.0 hour, 1.5, 2.0, 2.5, and 4.0 hours.
Every batch of ProHeart 6 that is released passes that dissolution test
before it can be released.

On one occasion we did test some six month stability samples that had
been stored for six months and had already been released, and we found
that these two batches which were made from the one lot of microspheres
marginally failed our dissolution specification at 2.0 hours and 2.5.
The release specification was within specification at the 1.0 hour and
4.0 hour time limit. Despite that, it did not make specification. We
recalled those batches from the market.

However I would say to you that this is a manufacturing consistency
test. It tells you nothing about how the product releases in the dog,
and certainly a dissolution test that showed a slightly slower release
at two intermediate time points over a four-hour period would not be
expected to have any clinical impact.

The second issue in relation to the plant inspection and the warning
letter, I might ask Mr. Corcoran to comment on that. I believe that all
of those issues have been resolved and much to the satisfaction of the
FDA.

MR. CORCORAN: Yes. I'm Tom Corcoran with Fort Dodge Animal Health.
Countering along with Dr. Post's comment, the warning letter we received
is the first warning letter that we have received in at least over 10
years that I am aware of. Previous inspections have been absolutely spot
on, very few observations. We were having an inspection in December of
2003. The observations were mostly administrative type of observations.
We undertook a full retraining of our personnel, underwent an inspection
in October of this year and got a complete bill of health from the FDA.

DR. LUSTER: A couple of quick questions. You talked about immunogenicity
testing earlier and said you had done it, and I saw the post-clinical
data presented in the document. But what preclinical immunogenicity
testing were you referring to? You indicated you tested the moxidectin
separately and the microspheres separately. Did you test the formula as
it is used together?

DR. COBB: Yes. In our testing what we did was we ran a large number of
tests. Tests were run on the complete product, on the microspheres
containing moxidectin component, on the vehicle alone, on microspheres
that did not contain moxidectin, and we ran it independently on various
components of the vehicle. The vehicle carries several preservatives,

\-\-- and \-\--. They are preservatives that are commonly used in human
and veterinary pharmaceuticals. We have looked at those. We have looked
at the hydroxypropyl methylcellulose, and so that we did run tests on
the individual components as well as the microsphere component and the
total product as well.

DR. LUSTER: What was the test that you ran?

DR. COBB: We ran a number of tests. We looked at IGE and IGG levels in
dogs that had reacted and could not find any evidence that these
reactions were mediated by gammaglobulins. We did passive cutaneous
hypersensitivity testing and had very mixed results and not repeatable.
We did intradermal skin testing again with very mixed results and not
repeatable.

DR. LUSTER: So this is preclinical dog studies that you are doing this
immunogenicity testing on you are saying?

DR. COBB: These were actually done as a result of field reports of
adverse events, but they were done in laboratory settings.

DR. LUSTER: And also a little bit of clarification, but regarding the
\-- I was a little confused because the FDA people were talking about an
increase, showed some data in their talk as an increase in anaphylactic
responses after they were adjusting for market shares. Then you were
talking about a decrease in anaphylactic responses, or equal amount of
anaphylactic responses with ProHeart as there is with vaccine responses?
Can you clarify that for me? Is it more or less? And this is data
without obviously concomitant vaccine data.

DR. BROWN: Are you asking us initially?

DR. LUSTER: Yes. I would ask you first.

DR. BROWN: So you had wanted to know if we felt that there was an
increase in reactions, anaphylactoid reactions after \--

DR. LUSTER: Well, you indicated that there were \-- after you adjusted.
In your talk you adjusted for usage or for market share, and you said
that the actual rate of increase in anaphylactic responses in dogs that
took ProHeart without vaccination was three-fold or something like that?
Is that \-- did I get that number correct?

DR. BROWN: I think we might be talking about several different things.
One reference I made was to adverse events, full anaphylactoid events
over the marketing years, and we felt that there was a decrease in those
number of events after the label change in June of 2002. Although we
still do have a significant number of events. That was one factor.

I think the other was in Dr. Post's slide when he was showing you the
effect of was there a reduction in serious events after the minimum
residue solvent lots were put into the market, and he was showing that
in fact there were not. That we were continuing to receive high numbers
of serious events, even after those lots with minimum residue solvents
were in full market.

DR. LUSTER: I know you are being very careful and not saying any
numbers, but you did mention numbers in your

\-- at the conclusion of your talk.

DR. BROWN: Oh. That may have been when I was referring to the Fort Dodge
document? Talking about anaphylactoid \-- about allergic reactions with
vaccines versus ProHeart 6?

DR. LUSTER: Right.

DR. BROWN: Okay. Yes, that was referring back to Fort Dodge's narrative
that they submitted in which they showed that the reaction rate was I
believe 1.16 \-- 1.62 with \-- sorry, 1.26 with ProHeart 6 versus 0.4
with the Duramune distemper vaccine or a 0.5 with the Rabvac 3 vaccine.
Is that \--?

DR. LUSTER: That's right.

DR. BROWN: Right. Which makes the reporting allergy event rate for
ProHeart 6 two-and-a-half to three-and-a-half times higher.

DR. LUSTER: Well, that is how you got that number. Okay.

DR. BROWN: Right. That is on page 11.

DR. LUSTER: Okay.

DR. BROWN: That is on page 11 of my slides, but it is on page 37 to 38
of Fort Dodge's narrative.

DR. LUSTER: Okay. Now in the Banfield study, the Banfield spokesman said
that you saw approximately the same amount of anaphylactic responses
with ProHeart 6 as you did with vaccination. Is that true? Anaphylactic
responses.

DR. GLICKMAN: Yes, the rates were extremely low, 0.7, 0.4 per 10,000. So
they were extremely low for any of the products in terms of
anaphylactoid. Not for allergic.

DR. LUSTER: Just that it is easy. As I indicated earlier, it was easy.
It's easy to say this is allergy if a dog has a skin reaction and the
dog has anaphylaxis. It is more likely to be reported I would assume,
and it is quite a bit more obvious.

DR. GLICKMAN: Yes. I think in general regardless of which, even the
passive reporting, and certainly interactive review of the records.
Reactions that occur within the first one, two, three days, are much
more likely to be reported than reactions that occur later on because of
this association in time between the event and the product. You know,
just mentally one is less apt to associate the two. So there is much
more complete reporting I think for early events than there is for later
events.

Interesting, too, when you look at the \-- you mention the allergic
event rate of 1.26 that was calculated by Fort Dodge from passive
reporting. In the Banfield database we calculate a rate that is roughly
18-fold higher, and that is the first time maybe where we have a
comparison of \-- or a basis for stating what the amount of
under-reporting is in a passive system, and that is in a reaction that
is more likely to be recognized. So under-reporting, yeah, it might be
harder for the others that occur late.

DR. HUSTEAD: I would like to clarify as well that the number of adverse
event reports in the allergy category are going down each year following
2002, and there relative frequency is also decreasing as well.

DR. NELSON: I have one more question. I skipped over this earlier. Dr.
Cobb, you all talked about certainly

microfilaria were cleared approximately one week after injection, and
you know the effect against three month and four month old. Do you have
an data of actually how rapidly L3s, L4s, and L5s die?

DR. ROCK: In our heartworm-positive study which we conducted with
naturally-infected dogs there was a 97.6 percent reduction in
circulating mircofilaria at seven days, which increased to 98 at 14 and
99 from there on out through a 28-day study. One has to assume that if
they are naturally infected dogs that those stages of larvae would be
part of that population. If you look at the three- and four- and
six-month-old infection study, the retroactive studies where these
animals are being infected with microfilaria, the microfilaria are
allowed to mature for three to six months. Some of those microfilaria,
those larva stages are going to be the stages that you are concerned
with, too, and there was no as we discussed previously in a previous
question, there was no adverse reaction in those dogs as well.

DR. NELSON: I guess the question I am asking, do you know how long after
the administration that you actually start to see like an L5 die?

DR. ROCK: I don't have that exact number. No, I don't.

DR. NELSON: I was just trying \-\-- correlation with, you know, being a
clinical science or not.

DR. ROCK: True.

DR. RIDDELL: I guess I have a couple of relatively disparate questions.
Another thing that I do, I am involved with AVMA's Council on Biologic
and Therapeutic Agents. Currently I am being chair of COBTA, and I
appreciate Dr. Glickman's information about the relative reporting
rates. That is something we have been looking for. COBTA has expended
not a small amount of effort in the last couple of years to enhance
adverse event reporting by the practitioner through the USP network and
to FDA and also working with the Center for Biologics as far as
vaccines. We have also been working with that National Animal Poison
Control Center.

I guess I have and AVMA has always asked for a lot of these decisions to
be made based upon science, and it is a little bit frustrating to me. We
are having to ask people to make very weighty decisions with not a lot
of science out there floating around. So I am very intrigued by the
potential power in a database like Banfield's, and I had a question for
I think probably Banfield.

Is when an adverse drug event is reported, there must be a team to
evaluate it, and if so at what point will a trigger point be reached
that that would be reported to the sponsor, whereupon it would have to
go to FDA?

DR. CAMPBELL: Any adverse event at all, you know, is reviewed by our
internal group. If we believe that there is \-- you know, it relates to
the drug, then we report it.

DR. RIDDELL: But you don't have any specific trigger points, or it is
just a feel for the instance?

DR. CAMPBELL: There are specific trigger points. My two colleagues, who
would know that, you know, had a flight back to Portland this afternoon.
But I know there are trigger points. I don't know particularly what they
are. Larry might. Do you know? But I know a number of the \-- you know,
especially the anaphylaxis incidents and so forth, you know, that we had
ProHeart. We reported it and, you know, rolled into Fort Dodge's data
and then into the FDA data. Is that your question? We didn't have any
deaths, so obviously we didn't report any.

DR. RIDDELL: Okay. Thank you. One other question to Dr. Cobb. You were
pretty explicit in saying as far as the thermal stability of the
microsphere was 40 degrees centigrade. Is there any indication that
either a local or a systemic pyrexia would affect that once it is in the
animal?

The stability of the matrix?

DR. COBB: We have no information on that. We do know that under
laboratory conditions if that product is heated to 40 degrees it will
agglomerate and clump because there is a change in the form of that
glyceryl tristearate.

DR. RIDDELL: And if that were in the animal, how might that \-- I know
this is speculation. How might that impact the pharmacokinetics or the
dispersal of that product? Or is it in an animal system, in a live
system, not likely to occur?

DR. COBB: I really cannot speculate how likely those sorts of
temperatures would be consistently reached within an animal. What I can
tell you is that the release profile of moxidectin is very dependent on
the spherical shape and the diameter of those microspheres. So if those
microspheres become clumped, the expectation would be that there would
be a slower-than-expected release of moxidectin because the surface area
for release becomes smaller because of the agglomeration. That would be
my speculation.

DR. RIDDELL: The logical conclusion would be that would not lead to
toxicity but might lead to ineffectiveness. Thank you.

DR. CRAIGMILL: As chair I have one last question, and then I am going to
ask Joanne \-\-- if she will put up a slide because I would like to use
it. We do have some sort of discrepancies in data. Dr. Hustead presented
a slide which appeared on page five of our handout showing the total
adverse events reported by year for three different products by year
from 2001 to 2003, and I would like to just have some comments on these
data because they show a dramatic increase in the number of reports for
other heartworm meds. I would like to address this as a question related
to under-reporting and whether or not the simple awareness that there
had been some problems or things reported with relation to ProHeart has
also caused an increase in adverse event reporting. I will particularly
ask FDA personnel to plesae comment on this slide and what they think.

(Slide.)

Are these data correct that in fact ivermectin and pyrantel, the number
of adverse reports has dramatically risen as well as for milbemycin?

DR. BROWN: I would like to go ahead and address some of those if I may.
As I think you may remember from Dr. Post's slide, we do have a lot of
reports sent in across the class of the macrocyclic lactones. Now you
will see that there is a big change in the number of reports for both
milbemycin and the ivermectin pyrantel products.

One of the things that affected that was interpretation of the
regulations by various sponsors as to which reports they should be
sending in or not. When new interpretations were made clear to those
other sponsors, they then sent in the reports that they had not so
previously sent into us, and almost all of those \-- I would say all of
those were reports of ineffectiveness. Not just for heartworm disease,
but also for roundworms and hookworms. So that is something. They sent a
huge a number of those in all at once, and they went back to before the
year 2000 and it took quite a while to process them all in of course.

That is a second part of that, which is that reports initially are
triaged when they come in to the Center for Veterinary Medicine. We have
drugs that have been on the market for years and years and years, and we
feel that we have seen the types of adverse reactions, serious adverse
events that occur with them and ideally have addressed those concerns
already. For the newly-marketed drugs, we give those our priority. We
evaluate those as quickly as possible when they are received, usually
within a week, sometimes within a month.

But when we started to see back in 2003 that there were possibly
situations that there could be concerns of ineffectiveness or other
problems across this class of heartworm preventives, we went back and
reviewed the reports that were waiting for their turn. And we pulled all
the reports for all the heartworm preventives and reviewed all of them
so that we could effectively make these comparisons, and that can show
you these increases. Now Mary Bartholomew also has a comment to make.

DR. BARTHOLOMEW: I think it is perhaps fairer and more germane to the
safety discussion going on right now to see the next slide, to take a
look at the next one, then the effect of the increased reporting. Okay.
That's the one. Then some of the effect of the increased reporting has
been removed, and if you will take a look in the year 2003 then you get
a sense of for two drugs that have approximately the same percent of
market share what the adverse events are minus the ineffectiveness
reports.

DR. BROWN: And I would like to add also to that that of course these are
all the adverse events that come in, not necessarily the serious events
that come in. So perhaps you might see a great deal of the regular kind
of vomiting or diarrhea sort of reports coming in for those other
products as opposed to the more serious events we have been discussing
for ProHeart 6.

DR. CRAIGMILL: So basically what you are saying is that these data are
not really correct?

DR. BROWN: Well, I wouldn't say that they are not correct, but they are
not correct when you think of the severity of reports that are coming in
and considering the time period for which those reports are being
submitted. In other words, you are seeing a jump in reports for these
other heartworm products that have been on the market for years and
years. Suddenly the are submitted within a certain year, and evaluated
and entered into our system within a certain year. So from that
standpoint they are correct, but looking from the point that they are
going back for a number of years, just reported in one year, and that
they are not necessarily serious events but more likely to be the more
run-of-the-mill things like vomiting or diarrhea then I think that puts
it in perspective.

DR. CRAIGMILL: Okay. So many of those reports of adverse effects for
2003 for ivermectin pyrantel, and milbemycin are actually from past
years?

DR. BROWN: That's correct. That's correct. They may have not been
submitted because of a difference in the reporting regulations, or they
may have been submitted but have been waiting for their turn in
evaluation. Whereas the more recently marketed heartworm preventives are
evaluated completely within a week or a month. The second set of the
next most recently marketed would be getting the next priority, and
under normal circumstances these would be getting the lowest priority.
If you remember, we have seven people working part time to do these
effects, and we get more than 25,000 reports a year. We have to usually
let some of these reports wait their turn if we feel they have been out
long enough and we have seen enough of them so that we know we are not
getting any new information from them. But then in this circumstance
when our concerns became evident across the class, we felt we should
look at everything and get everything into the system.

DR. CRAIGMILL: Will you be looking to see in terms of adverse events,
serious adverse events, what fraction of those that are of that influx
that came in 2003 are actually from 2003 cases? In other words, are you
going to separate out the past history from the current situation to see
whether or not there has been an increase in reporting?

DR. BROWN: Yes. In our internal system, in our internal database we do
that. We do that by the correspondence date, and we can also search then
on the actual episode date. So we can look to see how many of those
occurred within a certain time period. And I think as you saw from our
slides, we then looked at all of those classes and the adverse events
for them during specific \-- the past three marketing years, which were
the first three years that ProHeart 6 has been out, and I think there
you could see really quite clearly that we simply don't have the number
of serious events for those drugs that we do for ProHeart 6.

DR. CRAIGMILL: And you feel those data are complete?

DR. BROWN: Yes. I do.

DR. CRAIGMILL: Okay. Could I ask for Fort Dodge?

DR. HUSTEAD: Sure. We believe the data is absolutely accurate. We
obtained it from the CVM, so we assume the data is accurate as
presented. We don't have any information as to when the events in 2003
for the other products actually occurred, because that is not part of
the data set that we asked for. As to seriousness, there is no
information in this data to know whether the events are serious or not.
So that conclusion cannot be made from the data presented. They are just
numbers of adverse events.

These are the lack of efficacy events removed, so these are the events
regarding safety.

DR. MEALEY: I have a comment on potentially what else may contribute to
maybe an increase in reporting for all of these macrocyclic lactones.
The discovery of a genetic mutation for ivermectin and macrocyclic
lactone activity occurred and was published in 2001 and then picked up
by, you know, [AKC Gazette]{.underline}, and [Dog World]{.underline} and
[Dog Fancy]{.underline} and then distributed by email all around, you
know, the world about some of this stuff. I get emails and I was really
getting a lot of emails during those times as well about any kind of \--
any macrocyclic lactone in any breed and any potential toxicity. I was
getting those at this time. So I think that that discovery generated
interest to some extent in these compounds again, and so perhaps \-- and
I have no data, but I am just saying perhaps \-- I am speculating \--
that may have contributed as well to maybe an increase in the number of
adverse event reports.

DR. CRAIGMILL: Any further questions from any member of the committee?

DR. TREPANIER: I have another question for Dr. Glickman then, because I
really think the Banfield study is \-- I think that data is so
important, but I think that is also important to look at it from as many
different ways as possible, and I think \-- I know you have done
multivariant analysis, but I think it would be important to look at all
the animals that got moxidectin and do actually a case control \-- a
matched case control comparison, same age, same health status, a very
important one, perhaps same breed. Because the patients that got monthly
heartworm may well be sicker, older, have other reasons to have
anaphylaxis or vomiting or diarrhea, and it really clouds the issue. It
seems like it is such a huge database. You can rely on the healthy dog
studies that were done pre-approval because they are such a small number
and it is clearly a relatively uncommon set of reactions. So is there a
way to look at that data? It seems like that would be very important.

DR. GLICKMAN: There are many ways to look at the data, and there are lot
of things that are attempting to do and should be done. In a sense doing
subpopulations at risk, is there a unique group of animals either by
their age, their medical history, or whatever, that would be more likely
to react to one of the monthly heartworm medications than to ProHeart
and vice versa. I agree with you. You know, you get a database this
size, this rich in information, there are so many things you can do, and
you have indicated another approach to doing what we tried to do by
adjustment. I don't know that one way is better than the other.
Certainly the two methods should give consistent findings. But the
tendency is when you have a database this large and have it over so many
years, rather than doing the retrospective approach like you are
talking, and matching and going back in time, it is to do this forward
analysis. The big advantage of doing it the way we did is we can come up
with an absolute risk, and incidence rate which gives you an absolute
risk. What is the likelihood that if an animal got something they will
have such-and-such reaction. Where if we do it the way that you suggest
we lose that, but we can compare relative differences.

DR. TREPANIER: But can we say from that data that the groups that got
moxidectin were same as the groups that didn't as far as \-- you said
you looked at that demographically, but it is not supposed to be used in
debilitated animals, yet plenty of clinically ill animals get monthly
heartworm preventative.

DR. GLICKMAN: I think the better way to answer that question is not for
me as evaluating the data, but from Dr. Campbell in terms of what the
protocols are for selecting dogs to receive, you know, oral versus
injectable heartworm. You may want to comment on that. In other words,
why would one animal get one product? Is it really up to the owner for
the most part?

DR. CAMPBELL: Well, you know, it is up to the owner, but it is also up
to the doctor. We believe that it is the doctor's ethical responsibility
to make a recommendation. Our doctors really believe that the best
efficacy of all of the heartworm medications is ProHeart because we know
that they got it, and so, you know, I don't want to, you know, embarrass
anybody the room by asking who has oral heartworm medications in their
drawer, but I will admit that I do, are overdue for my own dogs. So the
reality is our doctors primarily when it was available prescribed
ProHeart, not the orals, because it is a lot better product, and it is
really, really safe. You know, so does that answer your question? Not
really. Okay. So what was the rest of the question?

DR. GLICKMAN: But as far as I know from what I know that Banfield
practices and what I saw in the database, there are no deliberate
inspection criteria that a sick animal would get one product versus a
well animal would get another. The preferential treatment is for
ProHeart.

DR. CAMPBELL: Oh, absolutely not. If there was a sick patient we
wouldn't prescribe either one, you know, and what we look at are what we
believe are the barriers to care. You know, the things that stop people
from coming in and getting care. So, you know, over 60 percent of our
patients don't have to pay for office calls to come in because we want
them to come in if they are ill. So, you know, the doctor at that time
will see on the computer what has been prescribed for that patient, and
if they are on an oral medication they are going to say don't. You know,
don't give that until Buffy gets well. So, you know, I don't think we
are prescribing either of them, you know, if they are ill. Now the thing
is if you give ProHeart and the pet gets ill four month later, you know,
they have already in essence had it, you know, and so I suppose there is
more of a chance that an ill dog is going to get \-- has already got
ProHeart than it is they would get an oral medication I think. Isn't
that right, Larry?

DR. GLICKMAN: I think so. So I think the bias would be the other way.

**[Deliberation on Question One]{.underline}**

DR. CRAIGMILL: If there are no further questions from the committee, we
will go to deliberations and do a tally in response to these questions
that were presented to the Advisory Committee by FDA. What I will do is
I will basically do a tally and go around and ask individuals. We will
do one question at a time. We will start with the first question, which
is \"Based on the presentations and information provided is ProHeart 6
safe for use in dogs?\" We have been asked to provide a yes or a no
answer. Personally as a toxicologist I don't like the word \"safe\". I
say this every meeting. I want to say acceptable risk, so that is the
way I am going to answer it. You can go ahead and \-- go ahead with a
yes or no, but then please fill in afterwards qualifications, you know,
whatever. So what I will do is I will go to the members and then go down
the list, and Dr. Aref, Susanne.

DR. AREF: I have a hard time saying yes or no because I don't think we
have seen enough good numbers. I think CVM or FDA has provided the sort
of most \-- have included a lot of numbers that might be sort of on the
edge. I think that FDAH has excluded some numbers that they shouldn't
have. I had a hard time especially with the last table we looked at
where it looks like you have exactly the same adverse event for the two
top products in the table. So I would say at this point I would say no,
but maybe with further testing. I just don't think I can give an answer
based on the knowledge we have.

DR. CRAIGMILL: Thank you. Corrie, Dr. Brown.

DR. C. BROWN: Very difficult to answer that question. I thought the
Banfield data was excellent, and based on that it appears that ProHeart
6 is safe for dogs. The CVM reporting would indicate otherwise, but I
had some problems with that data in that much of it seems inadequately
documented with respect to cause of death, and the manner of reporting
seemed to me somewhat haphazard and a little subjective. So I would like
to see that data put into a more rigorous format before deciding.

DR. CRAIGMILL: I'm supposed to press you for an answer.

DR. C. BROWN: I would be inclined to fall on the side of, yes, it's
safe.

DR. CRAIGMILL: Thank you. Gregory Jaffe.

MR. JAFFE: I also have the difficulty in using the word safe because I
think safety is not absolutely and I think in the end. But I guess I
would answer the question if this sort of \-- if the question is asking
should this drug be back on the market tomorrow or not I would have to
say no. I think at this point we still need some additional data to
insure that it is safe for drug use. I think the data that FDA presented
does put that into question, and so it seems to me should err on the
side of getting more data before the drug goes back into use. I had
difficulty understanding the different data sets because I think they
didn't try to be comparative but tried to actually confuse. It would
have been nice if FDA had been able to put some rates down there for
rates. It would have been nice to better understand \-\-- reports. Both
groups were using different numbers of describing them differently so
that made it difficult. But it seemed to me there were enough adverse
incident reports that FDA identified to question the use of this, and I
think the voluntary recall should continue for the time being.

DR. CRAIGMILL: Thank you. Dr. Mealey.

DR. MEALEY: I don't envy the FDA for making this kind of a difficult
decision, and like I said before I think it is difficult to determine if
was the drug moxidectin that was actually the cause of some of these
things or if it was the carrier or vehicle. I think the data for the
liver, for some of the immune-mediated diseases, for the neurologic
diseases, it is very difficult to say one way or the other because they
were conflicting. They had data from the Fort Dodge that is very
different from the data from the FDA. But the anaphylaxis in both the
FDA and the materials provided by Banfield shows that anaphylaxis is
greater with ProHeart than it is with any of the other heartworm
preventives, and because, one, there are other \-\-- there are
alternative agents out there. Yes, ProHeart is comparable to vaccines,
but I don't \-- I think that is comparing apples and oranges. So I would
compare ProHeart with the other heartworm preventives out there and at
this point say that compared to those \-- well, obviously none of them
are 100 percent safe, but I would like to maybe see a little bit more
information there. And the fact that ProHeart is going to be
administered more often than vaccines makes me err on the side of saying
no, that it is not safe.

DR. CRAIGMILL: Thank you. Let's see. Dr. John McGlone.

DR. McGLONE: Well, thank you, everybody, for your presentations. I know
it took a lot of time to prepare. I was trying to figure out what the
facts are in this situation, and that is a difficult set to identify,
and I came up with three facts.

One is that mostly from the written material that the product, as with
probably almost every product, is toxic at very high levels. Not at the
levels that are sold commercially of course. So that's one fact.

Secondly, there seems to be multiple factors that interact with adverse
drug reactions with ProHeart 6. Most notably the age of the animal and
whether it has been vaccinated or not, and these interactions might help
explain some of the variability that is observed maybe.

The third fact, which is the fuzziest fact of all \-- they get fuzzier
as you go down the list. The third fact is that finding in the field are
highly variable, and that is not much of a fact is it, because it
doesn't say one way or the other what happened. But there are some \--
well, my characterization is that most of the reports from the field are
largely positive on its effects, but there are some significant negative
findings that cannot be ignored. It suggests a need for research to
understand what those interacting variables are and how they can be
managed through label change or training.

And the fourth fact \-- I said there was only three \-- is that the
levels of adverse reactions are low. They are low in the general
population and they are low in the subject animals here. So the risk it
seems to me doing \-- for some other purposes we use a qualitative risk
assessment, and that is what I am still thinking about from our last
meeting. It seems that the risk moves from very, very small to very
small when you use this product, particularly when you use it in
combination with certain other products and under certain circumstances.
So moving a risk from a very low number to a low number doesn't clarify
whether it is safe or not, because some people would not accept \--
would accept zero risks for their pets for example, and they wouldn't
like to move the risk from very, very small to very small. Other people
might be willing to take that risk in favor of some benefits.

I don't think that there is enough information to do a proper risk
benefit analysis for this product at this moment. I think there is too
much variation in reports from the field. That has to be understood so
that you can manage the risk a little better. So it depends on where you
draw the line on safe, whether you draw it at, you know, whether the
risk is moderate, or small, or very small, or very, very small. That is
why the committee is having a problem. So I would say in the interest of
the people who are highly motivated to not have their animals suffer
that moving from very, very small to very small is still a risk, in
which case I would have to say it is not safe at that level. Under other
circumstances it might be an acceptable risk, but not in the current
situation. Thank you.

DR. CRAIGMILL: Are you a lawyer, John?

(Laughter.)

DR. CRAIGMILL: Should I mark that as sort of a no at this point? I did.
Thank you. Dr. Nelson. Oh, excuse me. I haven't finished with the
committee. I haven't even figured \-- Dr. Nolan, Lisa.

DR. NOLAN: I thought it was a very valuable session. I appreciated
everybody's input. I was very touched by the folks who had lost their
pets or family members as they referred to them. They reminded us how
high the stakes are I think in this drug. For me, I found the evaluation
of the Banfield data to be quit compelling in support of the use of
ProHeart, but like Dr. McGlone and others before him, I am impressed. I
feel like it is relatively safe, but I would qualify that.

DR. CRAIGMILL: Thank you. Dr. Papich. That was a yes, yes? I got a yes
out of that, a qualified yes. All of these answers are qualified. We are
not going to have any straight ones.

DR. PAPICH: Well, we know that all drugs can produce some adverse
effects, but when I look at adverse effects produced by drugs I
differentiate between drugs that are used to treat a disease and drugs
that are used as a prevention in healthy animals. Drugs that are used to
treat a disease I think we do accept certain risks and we have a higher
threshold for those risks because we realize the stakes that are
present. But when a drug is used to prevent a disease and it is given to
an otherwise healthy animal, I think the bar is raised a bit and I think
we do have to have a higher standard. I also consider the nature of
those adverse effects. If it was something minor like loss of hair at an
injection site or something that is \-- that an animal can recover from,
that perhaps is acceptable. When it is the death of an animal it is not,
and I was compelled as was Dr. Nolan here by the visitors that we had
today and some of their testimony.

I think that not only do we need a higher standard in considering and
evaluating some of these products, but as a veterinarian I am a little
bit ashamed of the veterinary profession in the way they have reacted as
was cited today here. I think veterinarians could have handled this a
lot better. But considering all of the data available, I am inclined to
say no to this question at this time, but I leave the door open that we
still have a lot to learn. The Banfield data, although very good, I am
concerned whether or not we are relying too heavily on the Banfield data
in comparison with other potential sources of data. We don't know at
this point, at least I'm not sure, whether these reactions that are
possibly caused by the drug, caused by the vehicle, caused by some other
characteristic of the formulations. So there is a lot I think that we
have left to learn about this, and it is not a dead issue perhaps. But
maybe as we gather more data and learn more about this we will be able
to understand the nature of this, of these reactions.

DR. CRAIGMILL: Okay. We move now to consultants. Dr. Bennett.

DR. BENNETT: Okay. I think it is really a tough call as well, and my
question is for the second question. If we answer the first question and
say is it safe, does that mean we're not going to address the second
question?

DR. CRAIGMILL: No. In my opinion we are going to address it no matter
what.

DR. BENNETT: Okay. Because I am sort of qualifying as everybody else,
and I'm a qualified yes. I think clearly the cases, the reports are
dramatic and worrisome, and my biggest issue again, because I live off
of MedWatch databases and I look at these adverse events spontaneous
reporting system, and I put those at the level of \-- I go level one
through five. I put those at level five in evidence because of the
quality of the adverse event reports that come into the stars of
MedWatch database, and I know you have a difficulty with that, too. The
Banfield database had a little bit \-- had some value to me because of
the numerator/denominator issue, which is what I worry about mostly, and
I wish we had four more Banfield-like databases so I could feel more
comfortable that that was replicable around the country. I am concerned
that there is no other Banfield-like database out there. Maybe there is
or isn't. I'm not sure about that. If there were I would love to see it,
and otherwise I would say if I could see three more like that I would
feel much more comfortable with my qualified yes. But yes is the way I
put it.

DR. CRAIGMILL: Thank you. Dr. Luster.

DR. LUSTER: I thought the cases today by all the presenters including
the Fort Dodge people and the public and the FDA were very strong. I
just wish the data sets that they had or the way they could collect the
data was a little bit stronger and could make our answer a little bit
easier to come to grips with. But I think that from what I could tell is
that some of the endpoints that they are looking at, some of the
clinical manifestations, appear to look like there was an increase with
ProHeart 6. So I have to vote no at this point, although \-- and this
was especially related to the anaphylaxis and \-\-- type responses,
although the incidents were really small, but they seemed to be
prevalent there. Particularly in the sense that there are other drug
alternatives other than ProHeart 6. Saying that, and probably what
everybody else is thinking as well, but there is really a need here to
conduct some sort of risk benefit analysis, particularly considering
that there is an apparent high level of noncompliance with the tablets.
But that data wasn't presented. It was just a general percent. I have no
idea what the noncompliance would be with ProHeart 6. I mean, I know if
you go in and tell your vet will give it to you, but not everybody is
going to go in and get a shot all the time. So anyways, I am saying at
this point it is a no.

DR. CRAIGMILL: Okay. Dr. Groseclose.

DR. GROSECLOSE: Well, I appreciated both the testimony and the
presentations by the various presenters and would agree that the quality
of the data is really lacking to make any sort of decision. My vote is a
qualified no mainly because I think there are data available. I think
the clinical trial data that was presented suggests that there is really
an adequate sample size to really answer most of the questions that are
presented, and the Banfield piece is really a \-- it appears to be sort
of a retrospective look at a large population but is suggestive of low
risk, but is not \-- it doesn't have the quality of evidence that a
clinical trial would have. I think the post-marketing surveillance by
both groups, both the FDA and Fort Dodge, really are inadequate to
address the question as well. I mean, they are basically numerated data
and it is hard to say what the source of some reports were. We just
didn't have that information. So a qualified no at this point.

DR. CRAIGMILL: Dr. Nelson.

DR. NELSON: I, too, want to make a comment that with the pet owners that
were here we all sympathize with them. We went into this business
because our pets are important to us, too, and when it is your pet it
doesn't matter what the statistics are. If it is your pet, it is 100
percent.

Also the American Heartworm Society has not taken a position on this,
but being a member of the society I am privy to lots of information from
around the country, have veterinarians call us about the \-- or email us
about this particular product. And over a year ago when questions were
coming up, or two years ago, you know, I spent a fair amount of time
answering questions and also reviewing databases like on VIN and see
what the comments are, calling colleagues, calling professors,
universities, and trying to in my own mind find what kind of incidence
is out there. And the more we looked, the more I looked, especially when
the veterinary professionals are saying it was nine to one no problems,
and there was \-\-- a problem.

There was mention about this being a preventative drug, and we need to
hold it to a higher standard, and I will agree to that point partially.
When you look at the number of heartworm cases that we see every year,
when you look at the statistics on compliance and those people who
purchase monthly preventatives and the 60 to 75 percent of the doses
being given and the rest sitting in the draw. The number of cases that
are going around out there, you also have to look at the number of
animals that are getting heartworms and suffering and dying because of
lack of proper preventative administration.

One of the things this product did was to address that issue. It also
helped us address it other ways. My own particular practice, you know,
when we started giving the injection we started sending reminders of the
injection. We also started sending reminders for all the preventatives.
But still we would find just the compliance rate was not there with the
monthly pill.

Then also, you know, talking about making the decision based on the
information provided today and provided in the reports, and when I
review the clinical cases that are supposedly representative of the
situation, I just see too many other possibilities for causes. While
there is no 100 percent safe drug and no 100 percent effective drug, I
would have to say a qualified yes.

DR. CRAIGMILL: Dr. Peterson.

DR. PETERSON: I have the advantage of having heard most of the other
folks give their opinions so I can better formulate mine I guess. I
think it is important to keep in mind that the system that CVM has in
place is a passive surveillance system, and I think it did its job from
the standpoint that a passive surveillance system really does no more
than raise the index of suspicion, which I think it did in this case. I
think the data that speaks most appropriately to whether or not we have
a safe situation, and I would also comment I don't like the word safe,
but I have a little bit different perspective on that. I think the wrong
question is being asked. I think people are making decisions based on at
some level, an unknown level of what is safe and what isn't safe. I
think a more appropriate question quite frankly is \"Relative to the
other products out here how does this product compare?\" I think that is
a little bit different question, but I think it is the more appropriate
question. I know it is not being asked, so I will answer the one being
asked. But I just want to make that for the record, that comment.

There were comments made relative to the increase in anaphylaxis as
being a contributor to some people's decision. I think there is given
the real world data and given how this preventive is administered, I
think strongly biases any difference you would see and any increase in
terms of anaphylactic reaction. As practicing veterinarians I think we
all know the potential to see a more immediate anaphylactic reaction I
think was well described, and you tend to see that when you administer a
product that is administered by injection as opposed to something that
is given orally and you don't even know in fact when it is given,
whether or not there was an association with their oral medication. It
is more easy to determine a point in time association with an
injectable. I think that tends to bias people's perspective on what is
cause and relation here.

My feeling is that the Banfield data is really real world data, and I
know as an epidemiologist I really don't know any other way to find out
whether anything is at increased risk for causing problems, particularly
relative to other medications that are designed to do the same thing
other than a real world situation. I will grant you the data is not
perfect, but I would also point out that that data, at least in the
field of veterinary medicine, is very rare to have available to us. I
think everyone here is familiar around the table with the veterinary
literature, both in research and the clinical literature in terms of,
you know, case reports of literally 60 to 100 cases, and that is
generally pretty good. What we are dealing with here is hundreds of
thousands of real world cases. My feeling is that that data very
strongly demonstrated that there is a lack of safety, however you want
to define it, across all three drugs that were tested. I think it also
demonstrated that there really wasn't much difference among those three
drugs, particularly when you take into affect what may be contributing
to the use of an injectable versus \-- in terms of the reporting system,
particular with reference to anaphylaxis relative to the oral
medication.

So I really don't have any problems in making the decision that the
answer to this question is yes, because I think the bigger question that
needs to be answered is what is the relative safety of all of these
types of medications. And I would tell you I have had some experience on
the human side sitting on the Advisory Committee for Immunization
Practices. I have seen the pictures of the babies who have died because
they were attributed to deaths attributed to immunization for human
vaccines, and while these are possible, I think what you have to do is
you have to do some type of a risk benefit. Make a decision. I would
propose to you also that I don't think that we are every going to have
in the next one, two, even three years, definitive answers that will
satisfy everyone to the question of whether or not something was safe.
So my answer, and I don't really have any reservations based on the data
I have seen, my answer to the question is yes.

DR. CRAIGMILL: Thank you. Dr. Riddell, Gatz.

DR. RIDDELL: Well, I would like to thank all the parties involved for
the material they presented to us, the presentations they made today,
and for the people who came and gave the personal stories. My
congratulations for having the strength to do that. When I try to
evaluate decisions that I have been involved with that deal with topics
like this, in the end it comes back to doing everything you can in a
science-based mode. And granted science is not perfect and that is
always going to be a difficult thing with something that is very
subjective like this. I understand some of the comments about holding
preventatives to a higher power, but yet we still have to remember that
every pharmaceutical agent that we put in an animal has potential to
have very powerful effects, whether it is very new and cutting edge or
whether it is old. So those are concerns I think we \-- there is not
going to be \-- obviously there is not a perfect adverse event reporting
system. Otherwise we wouldn't be sitting here talking about this. But I
think there's several strides to be made in that direction.

Looking at the same thing for the risk benefit analysis, but the risk to
a patient whose owners do not do better than the average for compliance
in heartworm-infested areas is pretty severe. So when I look at that,
look at all the possibilities, and look at what seems to be \-- not
being an epidemiologist, but judged by other people's evaluations to be
the best data and the best science that is out there, that being the
Banfield data set, I would have to say a qualified yes.

DR. CRAIGMILL: Thank you. Dr. Trepanier, Lauren.

DR. TREPANIER: Well, I also think the Banfield data is important. I
think one piece that is missing from that data is a 30-day phone call to
these clients to confirm that there were no adverse events in that time
period, and we don't have that. We have a three-day phone call and then
really relying on the owners to come back to them if there is a problem.
And I do believe there is a lot of power in that data set. It does
appear that these reactions are rare. It does seem from what the FDA
presented that there does seem to be a higher signal in the patients
that got ProHeart, and it may be because of the way it is administered
and the way it is monitored. But these reactions when they occur can be
catastrophic, and I also agree that there is a higher bar for a drug
that is used in a healthy, young animal where there's no other problems
and then death is a potential side effect.

So I would have to say no since the burden of proof is on the company to
prove that it is safe to a reasonable level, and I think when you look
at relative risk you really need to put this drug in the context of how
much extra protection is it going to give versus oral medications, which
do appear to be safer at least based on the FDA data, and I think that
is something that needs to be looked at. If this drug really truly does
save more lives from heartworm then there may be a risk that can be
accepted. So I do think that a more rigorous risk benefit analysis is
really important.

DR. CRAIGMILL: Thank you very much. Am I supposed to vote, Steve? Not
vote; give my assessment to this answer.

DR. SUNDLOF: (Nodding head.)

DR. CRAIGMILL: First of all, Last night about 8:30 Aleta came with a \--
yes, Dr. Sams is not voting at this time. Last night about 8:30 Aleta
handed out a package, double-sided copy of public comments. For the
person who wrote in here that he thought that his comments would not be
read, they were but at least one member. I went through all of these,
and I am sure many of the others did, and there are some very touching
personal accounts of having lost pets. Having lost pets of my own I can
relate to them very dramatically.

The drug in question here has basically been tested thoroughly according
to all the FDA requirements, and the FDA accepted it on the basis of all
those requirements on the studies that are normally done by any new
animal drug to satisfy safety, effectiveness \-- that's the most
important things. That said, the number of case reports, there is no
question that there have been a large number of adverse reaction reports
on this particular product that have come in. Why do we have such a
discrepancy between the FDA opinion of this and what is going on with
the company's opinion of this? I don't know how to resolve that issue. I
find it difficult to juggle those, and I am not sure whether even if we
locked them in a room for a couple of days they would come to the same
conclusion with the same data \-- although it is an interesting idea.

(Laughter.)

DR. CRAIGMILL: When I review these data and again as a toxicologist I
look at things in terms of acceptable risks, safety being an acceptable
risk. For some people it is unacceptable. A risk is basically a
probability of an adverse reaction occurring or an adverse event. For
the people whose dogs were affected that risk was one, and they have
suffered the consequences and it has been awful. For thousands of other
people who have used the compound, have had it, that risk was zero. It
is acceptably safe to use this drug? I would give a qualified yes to
that in my opinion, but I also will have some further comments when I
get down to the section on safety concerns. Basically everybody here has
said we need more data. How are we going to get more data if we don't
have the drug being used? We are not. If this a drug where we can state
there are acceptable risks and possibilities for gathering more
information to further define those risks more effectively, that is why
I am going to give it a qualified yes at this point. I love being last.

**[Deliberation on Question Two]{.underline}**

At this point I would now like to \-- again we will go through the ranks
here and ask the following. \"If there are remaining safety concerns
with ProHeart 6, what additional avenues of research could be explored
to mitigate and/or prevent the adverse events?\" In other words, what do
we need to do? And at this time Dr. Aref has been able to listen to us
and formulate her answer. So one more round.

DR. AREF: I am not sure that \-- I mean, I get worried about the
multiple logistic model sometimes when \-- I don't know that all of the
aggressors would be completely not correlated. I mean was the modeling
investigated for that? So, I'm sorry, this should have been a question
before. I mean, possibly somehow all these different data gatherings
ought to be somehow put together to make for \-- well, I don't know. The
data is so confusing and not adding up somehow. Further research with
further clinical trials maybe. I don't know. But that seems to be the
only option if the drug is going to be accepted at some point, or since
we are only doing qualified yeses and nos.

DR. CRAIGMILL: Thank you. Dr. Brown.

DR. C. BROWN: Well, I would like to suggest some things that can be done
with the existing data, and that would be to take a closer look at the
cases that have occurred and to really dissect out the other confounding
factors. In particular administration of other vaccines at the time.
What brand of vaccines were they, what was the \-- how many times had
the ProHeart 6 prior to that. So that would be from an epidemiologic
sense.

But then I would also like to see a better follow-up with the animals
that die and a correlation of the necropsy and histopathologic findings
with the clinical disease and also the time frame post-administration.
Does it all fit together with a toxicologic pattern, or are some of
these deaths due to something else and they are being report as adverse
drug events, but really they are spurious incidents?

Then the third thing would involve some proactive work on the part of
Fort Dodge Animal Health, and that would be the moxidectin
administration, the ProHeart 6 administration at the same time as
creating a febrile illness in a dog to see what those levels are. You
mentioned that with a clumping at 40 degrees there would likely be a
decrease in blood levels, but do we really know that? Thank you.

DR. CRAIGMILL: Thank you. Gregory Jaffe.

MR. JAFFE: Being I guess the one non-veterinarian medicine doctor here
on the panel, it is hard for me to talk about the avenues of research
that might be explored. But I think I would say that one of the things
that might be done here is the Banfield data has been reviewed by Dr.
Glickman, but it hasn't been reviewed by FDA I don't think and they
haven't had a consultant analyze it. Since there is a lot of data there,
it might have somebody else do it, a different analysis of that data.
Especially taking in some of the comments that other panel members have
said today, might be able to come up with confirming that information or
providing additional data about the drug. So I think that would be a
useful thing to do. I think if you were to continuing using it there
might be additional conditions that might be put on it if the agency
decided to do that. Maybe it shouldn't be given with a vaccine at the
time to get rid of some of these possibilities of something else
happening. Maybe there should be a follow-up for the veterinarians to
fill out with the patients afterwards to bring in data to the agency in
a certain percentage of the number of vaccine \-- the number of shots
that are given so that we have some affirmative follow-up. So I think
there are ways that if one is to continue giving the drug that they
could get additional data at the same time and also get rid of some of
the variables that seem to skew what we have in terms of the data now.
But I think also having some of the parties look at each other's data
some more might help get some additional information.

DR. CRAIGMILL: Thank you. Dr. Mealey.

DR. MEALEY: Not being an immunologist I am not sure that I can help
anymore here except for maybe some more experimental investigation into
the potential causes for anaphylaxis. Not specifically with moxidectin,
but maybe with the vehicle. I would love to see another independent
data, group of data. I have some concerns that there may be a bit of a
conflict of interest with the Banfield data. Maybe collective
information from veterinary institutions, from the colleges of
veterinary medicine collectively might give similar quantity of data as
the Banfield data. And I would like to see more data on the efficacy and
compliance of ProHeart versus some of the monthly. That has been one of
the criticisms, that there is not good compliance with the monthly
heartworm preventives, and I guess I would like to see data that it is
easier for people to come in to a veterinary hospital twice and get an
injection than administer doses of heartworm medication at home.

DR. CRAIGMILL: Thank you. Dr. McGlone.

DR. McGLONE: Well, as I might have said, I don't think there is really
enough data to do a risk benefit analysis. But it seems to me that Fort
Dodge Animal Health is highly motivated to collect such information, and
the nature of that is really you need three kinds of studies. You need
some basic studies on mechanisms. You need a large-scale clinical field
trial, because I don't believe the 280 dog study was large enough to
show even a small incidence of some of the problems that have been seen
in the field. Maybe you won't see any even if you have 2,000 dogs, but a
larger study would have a greater chance in such a thing. Then I think
you need a prospective epidemiology study. You need to start from
scratch and agree on what you are going to collect and collect relevant
information for a long enough period that you have confidence in the
data. Perhaps from more than one Banfield-type organization.

I do think that there is an inherent problem in veterinary medicine. I
can say that because I am not a veterinarian I guess. In that a lot of
veterinarians including my veterinarian that takes care of my dogs sell
the drugs. And when I go to the physician, he doesn't sell the drugs. In
fact, he gives them to me for free, and then I go to the drugstore and
buy what I need. So the physician doesn't have the kind of conflict of
interest that veterinarians have. So that is kind of problem, because
the members of this committee are asked to declare and live up to these
positions, but the people in the field don't have to hold to the same
standard. So basically we have a general problem with getting quality
information in just a retrospective sort of way. So if you start from
the beginning and set it up where that is not an issue, then you will
get a larger quantity of data that is of higher quality.

Then when you have that, I think a change of label if appropriate \-- it
might not be appropriate \-- and training of people in how the product
is used and delivered would be appropriate. I think that when you have
the label change and the training organized, then you can do the risk
benefit analysis and you will probably see that it's a wonderful product
from the point of view of the company. Thanks.

DR. CRAIGMILL: Thank you. Dr. Nolan.

DR. NOLAN: Well, it seems to me this drug addresses a real concern in
heartworm prevention and with other \-- prevention of other disease, and
that is compliance. If it is used it can really lead it looks to me to a
decrease in a terrible disease. It would seem to me that risk benefits
analysis would be dead on and very helpful in evaluating this drug.
Unfortunately I am not a statistician, so I can't say what that
involves. I would also wonder if it is possible to do some kind of
follow-up study, a 30-day callback in the future to see if we can do
some long-term stuff on it.

DR. CRAIGMILL: Thank you very much. Dr. Papich.

DR. PAPICH: We have raised a lot more questions than we have answered,
and I think there is lots of room for some other investigations. I agree
with the comment that somebody brought up earlier that if this drug is
not available anymore there is not an ability to collect more data.
However, there is data for which we have records. If it is possible, it
would be very helpful to try to mine data that \-- other than the
Banfield data that would perhaps be of some consistency that we could
use to compare, and I think that would be helpful. Whether that is
available or not, I'm not sure.

In the presentation one of the things that I found one of the most
interesting was the relationship between the onset of some of the
adverse effects that have been reported and what seemed to coincide with
what would be a peak drug concentration after administration. That is
one of the reasons I had asked some of the earlier questions about the
kinetics and the release of the drug. That seems to me to be a
relationship that we shouldn't ignore and could be explored further,
perhaps looking at a larger group of dogs and looking at variability and
release of the drug after an injection and looking at other conditions
that may affect the release in a group of dogs. Pharmacokinetically it
might be helpful.

Of the reactions that have been seen, I think there are some of them
that appeared in the record such as malignancies that are I think
perhaps red herrings. I don't think that this drug probably leads to
malignancies, and it is possible that some of the elevations in liver
enzymes didn't have much to do with the drug. But the reactions that
appeared immunologic in nature, those are \-- and those were the largest
group it appeared. Those are ones that I would hope that someone with
better immunologic background than I do could think of some ways to
explore that.

Also in dogs that have had reactions, if it would be possible it would
be fascinating to explore potential genetic relationships among the dogs
that have had similar reactions. We have experts on our panel who are
better experts in pharmaco-genomics than I certainly am, but I think
they would agree that pharmaco-genomics is in its infancy in veterinary
medicine. But we do recognize that there are genetic relationships among
the dogs that have certain types of reactions, and if that could be
explored among the dogs that have had reactions to this drug, that would
certainly be worthwhile.

DR. CRAIGMILL: Thank you, Mark. Dr. Bennett.

DR. BENNETT: I'm thinking back on the experience I had with the
immunologic side effect with \-\-- products which we just reported, and
it was very rare, but it was immunologic and it lead to some responses
from the FDA that I think were very insightful. The kinds of things that
the FDA did then was \-- one is they elevated the warning to a black box
warning, which I know you don't have here, but a black box warning does
raise a level of awareness and reporting also in the public sector to
build a higher level. Second thing they mandated in the other countries
besides the US where the \-\-- was a formal prospective
pharmaco-vigilant study, a large-scale one, and it was formal and it was
prospective. I thought that was also a useful thing. The third thing
that they mandated as well and is important is I think the vehicle is an
important issue, and I think that became an issue with the other
product. It raises concern about the vehicle, and I think the vehicle is
something that we got some insights from you that there is some question
about the vehicle. And it leads me to think for instance if the study we
heard from, those people are more rigorous with the vehicle, with the
product, than the other people in the community, that may be a
differential reporting rate. That maybe \-\-- reporting for the study
that you commissioned, and high lights because they did say you have a
formal educational effort out there. You have got a web-based
educational effort out there, and the same thing with the other product
is what happened. The FDA and the other countries, the other countries,
the regulatory authorities, did mandate formalized and a more rigorous
approach. I thought that one speaker from the outside requested that
they think about a single use file had an interesting point. It would be
interesting to know if a single use file would actually get us to the
point of being a little bit \-\-- with the vehicle.

DR. CRAIGMILL: Thank you. Dr. Luster.

DR. LUSTER: I am actually an immunologist by training, and since I'm an
immunologist I tend to think that most \-\-- drug reactions are really
systemic allergy in disguise. Which is very hard to, as the drug
companies can tell you \-- pharmaceutical companies can tell you that is
hard to identify and test for, and also is a major problem for many,
many pharmaceuticals. But one of the tests that are currently being used
which I think is worth exploring is the simple test which I think most
FDA centers use as a guideline. The test now is a \-\-- assay of the
various materials. I would think that the drug itself is technically not
to be extremely allergenic, but you would think that the materials, the
microspheres, have been shown some of them to act as almost like an
antigen depot. So that they are really serving as a continuing expulsion
of the antigen, almost like an adjuvant. So that is \-\-- to cause more
of an immune-type response if that is what is occurring. But there are
ways to test for that, and one is the \-\-- assay. One can do
immuno-pathology to look for immune deposits on tissues and things like
that. So it can be done, and if that if that is the case, I mean, there
is also some of the pharmaceutical companies have developed \-\-- to
remove that antigenicity, and they can do masking for example. A lot of
the materials used for imaging for example in humans can tend really to
be antigenic, and they put what they call masks on it so the immune
system no longer recognizes it as antigenic and they can be used. So
there's some potential opportunities there. That's all.

DR. CRAIGMILL: Thank you. Dr. Groseclose.

DR. GROSECLOSE: Thanks. I think there are some things that you can do
with no new data. One, I would follow up on the recommendations to do a
risk benefit analysis and try to model that based on what we know. I
mean, I do think the issue of compliance is a real one and it would give
us some better idea of the value in terms of the risks. Also I would
second the recommendation for a case control study using Banfield data.
I do think that would be a good use of that data set and to review \--
have FDA sort of review the study design to insure that it can answer a
few more questions. I also think there is a need to try to resolve the
disparate data that we have. Essentially there were three case
definitions for these adverse events. There is the Banfield definition,
the FDA, and then the Fort Dodge, and those data are now out and
available and are generating a lot of heat. I would think it is probably
worth some effort to try to resolve those.

In other words, perhaps get reviewers and more than one reviewer per
case to try to use at least a common case definition and try to see what
we can come up with there. Ideally you could combine data from various
clinical studies that have been done and some sort of a meta analysis,
but I don't think that is possible just based on what I have heard about
the types of studies. I don't think that those data can likely be
combined. But it might be something to think about in the future, that
one design study so that you could combine those data. I think, that may
take us certainly closer to perhaps me closer to a qualified yes. But
the prospective issue, you know, this is apparently the only microsphere
technology out there, and I think that should be evaluated through
prospective studies if at all possible with the same size that is
adequate to try to address that issue.

DR. CRAIGMILL: Thank you. Dr. Nelson.

DR. NELSON: Allow me to comment about the veterinarian selling the
product. It doesn't have anything to do with the research, and we
discussed all the other areas. We can take the data we have. But whether
the veterinarian is selling ProHeart or selling Heartguard or
Interceptor, it is really not a \-- you are selling one or the other. So
the economic benefit is there. There has been speculation about
veterinarians \-- and I had to say this \-- that have been going more
for ProHeart because trying to eliminate the internet pharmacies. You
know, I can't speak for every practice, but our particular practice in
general, you know, we have always been willing to match prices. In fact,
when it came up as an issue, we reviewed these major internet
pharmacies, and actually it was a pretty good eye-opener for me. It
allowed me to raise my prices, because I was cheaper than most of them.

(Laughter.)

DR. NELSON: And I could do it in good conscious and still be cheaper.
But as the data I would like to see, we know that these class of
compounds do have very potent activity against both microfilaria and
immature heartworms. I would like to have a little bit better idea of
actually what effect the drug has on the L4, the L5, how quick it dies.
Could this be correlating to the reaction? We know when these
microfilaria are acting \-- microfilaria, excuse me. When these larvae,
L3s, L4s, L5s, die they can produce immunological responses as we are
seeing with most of these cases. So that was some data I would really,
really like to see.

DR. CRAIGMILL: Thank you very much. Dr. Peterson.

DR. PETERSON: I have to be forgiven for thinking like an epidemiologist
again I guess, but typically what happens with epidemiological
population-based studies is you go from something like a passive
surveillance systems which identifies the potential for an excess of
disease or an excess of risk or whatever, to something like a
cross-sectional study which was done with the Banfield data. Based on
that, typically the next step is really not necessarily a case control
study, but something that is done prospectively. The problem with
prospective studies, particularly in this case, is it doesn't appear
there is going to be any more data in the future to collect. Secondarily
the other problem with prospective studies, and it is probably even
worse in veterinary medicine than it is in human medicine where this is
the typical way things are done, is there aren't going to be enough \--
there isn't going to be enough money to do an appropriate prospective
study. There will not be enough cases collected, and Dr. Glickman
pointed out that for some of these rare occurrences you would literally
have to have well over half-a-million cases to identify anything that is
excess risk if you are making comparisons between groups. So at least
from an epidemiological perspective I don't think there really is going
to be any more data that is going to add to the ability to make a
decision relative to safety.

I think one other thing, and since some of my other colleagues have kind
of touched on this also, I think we need to keep in mind I think \-- and
this is true of human medicine as well as veterinary medicine. I think
as practitioners of veterinary or human medicine I think many times we
don't do a very good job for a variety of reasons of communicating risk.
I think we tend to some degree to either have clients who let us make
the decision, or we try to influence them for a variety of reasons, some
which were given round the table. I think we are going to be faced with
these same kinds of problems in the future relative to whether it is
this particular drug or whether it is other drugs. Whether it is drugs
you use to treat, whether it is prophylactic medications, I think it is
the same issue. I think we have to be very, very careful about putting
things in perspective. Otherwise we are going to be faced with these
same kind of issues in the future. The same is true with human vaccines,
the same is the true with veterinary vaccines, it is true with all types
of prophylactic medications. There is nothing that is 100 percent, and I
think what happens a lot time is I think people have expectations that
because a veterinarian or a physician is prescribing or recommending
something there is a certain degree of safety that goes along with that.
I think that is true, but I think it needs to be communicated so that
actually the client is making the decision for their pet in terms of
whether or not they feel the risk is worth is. I don't think you can
make guarantees, so I think yes. Since I gave a yes to the first
question, I am having a hard time coming up with any recommendations. At
least from the perspective of an epidemiologist that is gong to add
additional information in terms of answering the question.

DR. CRAIGMILL: Thank you. Dr. Riddell.

DR. RIDDELL: I guess at the risk of sounding like an ogre, when you deal
with a set of reactions that might by the World Health Organization be
classified as rare or very rare, to get any kind of statistical power
you are going to have to have large populations exposed to that, and so
that suggests that I might be advocating using a population \-\--
experiment. That is not the case. However, we have a product that may be
potentially valuable and the compliance they shoot for, a very real
disease in the canine population. We also need to know if it is safe,
and several other good questions about its efficacy and the impact of
the microspheres on the immune system. They are all really important,
but I think at some point in time to get the numbers that we are going
to need to be able to truly evaluate this, it is going to have to go
back into general maybe educated use, and it might be that we might have
to be required sponsor-initiated educational program for those users
that would not be unlike what a current sponsor has to do for the human
potential ill effects from \-\--. While that is a bias that is taking a
group that biased towards using it, making them responsible, and I think
they are responsible for making sure that appropriate data for cases of
adverse events reported and followed up on I think is probably only one
of the true ways we have going to have to evaluate this. I don't think
that the data sets like Banfield other than Banfield are going to be out
there.

DR. CRAIGMILL: Thank you. Dr. Trepanier.

DR. TREPANIER: I also believe that a prospective study is ideal,
although because I think the pet owning population is very sensitized to
this drug, you may not be able to find a lot of people willing to allow
their dogs to receive it. Also it would be very expensive. So I was
trying to think of ways to work with the data that is available to try
to get more information about perhaps mechanisms and is there a safe way
to label this drug and make it \-- a safer way to label this drug.
Certainly I think doing a meta analysis is one thing to consider. There
are certainly other large computerized veterinary networks like VCA. The
Animal Medical Center is also a very large practice. There might be ways
to mine that data in a manner that is similar to Banfield that you have
other data sets that could confirm or conflict with what was reported
from Banfield. Also if you are trying to get at mechanisms, certainly
the anaphylactic reactions may be very different from the convulsions.
They probably are. But if there are serum \-\-- from these patients that
have had convulsions, do they have very high moxidectin concentrations?
Or if there are CSF or brains from these patients. So are some of these
patients having abnormally high release from this drug. I know that
C-max concentrations were very narrow in initial studies, but that was
with a very small group of dogs. We are talking about outliers here. We
are expecting to have outlier responses.

Then the other issue of microfilaria being present and possibly
triggering anaphylaxis, is there a way to go back and look at heartworm
endemic versus heartworm non-endemic areas and see if instances of
anaphylaxis is different in those two groups. Because that may be away,
a less expensive way to try to get at that information.

DR. CRAIGMILL: Thank you. For my own comments, basically everything has
been covered pretty much by all the other panel members. I think that if
possible a retrospective case control while it might not add a whole lot
to the data might be reassuring. That a prospective study with a very
large clinical trial would be probably the only way to put this issue to
bed, and that such a study would need to be \-- the protocol would need
to be agreed upon in advance by FDA and also Fort Dodge. In other words,
work together to figure out what you need to answer this question if you
are going to do that. In that, that would require the use of the drug in
a large number of animals, and to do that I think a very good public
education and informed consent program for the owners would be
necessary. Because even at low rates, one out of 10,000, if that one is
yours it is still a rate of one, and people need to know that is a risk.
If you are completely risk adverse you need to warn people away from
using this compound, or probably just about anything in that regard.

The other last \-- first of all I should say that I am academician,
which means I don't have to have practical ideas.

(Laughter.)

DR. CRAIGMILL: It would seem to me that this issue is looking on the
horizon for all heartworm products now that the awareness has been
raised, and that this might be something that a consortium of the
manufacturers of these drugs ought to get together and work on them
together, even though they are competing on the sales. Why don't you get
the data together to show that these products really are safe, or let's
say acceptably risky to use.

I don't have any other comments at this point. Aleta, is there anything
else we need to do? So we will turn it over to Dr. Sundlof for the
benediction.

DR. SUNDLOF: Thank you, Mr. Chairman. I just want to thank you and the
committee and all the folks who have participated in this today. As you
see, these are very weighty decisions that we have before us. In my
imagination I was hoping we would get a clear signal.

(Laughter.)

DR. SUNDLOF: But realistically I was prepared that we would not get
that, and that appears to be where we are. So we will take the comments
back to CVM. We will certainly have a thorough discussion based on what
we heard today from this group, and we will come to some conclusion.
Hopefully we can take into account especially the answers to the second
question that I think laid out some very attractive possibilities for
further investigation in this. So again thank you all. I know it was a
lot of information that you had to go through in a very short period of
time, and with the weather and everything it was wonderful that you
could all make it. A few people didn't. So thanks again, and I wish you
a safe trip home.

(Whereupon, the meeting was adjourned at 5:14 p.m.)