Number range CHAPTER

***Food and Drug Administration***

***Center for Veterinary Medicine***

***Veterinary Medicine Advisory***

***Committee Meeting***

***November 4, 2003***

PARTICIPANTS

[MEMBERS PRESENT]{.underline}:

John T. Waddell, D.V.M., Chairperson

Arthur L. Craigmill, Ph.D.

Sherman (Skip) W. Jack, D.V.M., Ph.D.

Deborah T. Kochevar, D.V.M., Ph.D.

John J. McGlone, Ph.D.

Lisa Nolan, D.V.M., Ph.D.

Marguerite Pappaioanou, D.V.M., Ph.D.

Anne M. Parkhurst, Ph.D.

Dennis P. Wages, D.V.M.

Richard R. Wood

[FDA, CVM STAFF PRESENT:]{.underline}

Amy Adams, Ph.D.

Eric Dubbin, D.V.M.

John Matheson, Moderator

Larisa Rudenko, Ph.D.

Aleta Sindelar, R.N.

Stephen Sundlof, D.V.M., Ph.D., Director

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

[VMAC MEETING]{.underline}

[November 4, 2003]{.underline}

**[PAGE]{.underline}**

***Welcome***

By Dr. Stephen Sundlof 4

***Brief Background for Today's Discussion***

By Mr. John Matheson, Moderator 12

***Risk Assessment Methodology***

By Dr. Larisa Rudenko, 20

***Summary Data from Animal Clones, Part I***

By Dr. Eric Dubbin 55

***Summary Data from Animal Clones, Part II***

By Dr. Eric Dubbin 67

**Conclusions for Animal Safety**

By Dr. Amey Adams 98

***Conclusions for Food Safety***

By Dr. Larisa Rudenko 115

***Questions for Clarification from VMAC and Public***

> By John Matheson, Moderator 137

***Open Public Comments***

> By Aleta Sindelar 157

***VMAC Deliberations***

> By Dr. John Waddell 193

***Concluding Remarks, Next Steps***

> By Mr. John Matheson, Moderator 216

**KEYNOTE: \"\-\--\" Indicates inaudible in transcript.**

**[M O R N I N G S E S S I O N]{.underline}**

9:02 A.M.

MS. SINDELAR: Could we have your attention to begin the meeting, please.
Thank you. My name is Aleta Sindelar. I am the Executive Secretary for
the Veterinary Medicine Advisory Committee. I would like to introduce

Dr. Stephen Sundlof, our Center Director, Center for Veterinary
Medicines. And welcome you all here this morning. Thank you.

***Welcome and Introductions***

***by Stephen Sundlof, Director CVM***

DR. SUNDLOF: Thank you and welcome everybody. We haven't had an advisory
committee meeting in a while and so it's really good to see a lot of
folks that we may not have seen for a while.

We are here, again, to talk about the cloning risk assessment that CVM
has been conducting as part of our orderly and transparent process of
dealing with one of these very complicated issues that is resulting from
modern technology.

Before we begin the discussions today, let me introduce the members of
the Committee. The Chairman is

Dr. John Waddell. If you could just signal with your hand. Thank you,
John. Corrie Brown could not be with us today. She represents pathology.

Art Craigmill, one of our new members from the University of California
Davis, representing toxicology. Skip Jack. Skip represents minor species
on the Committee. Dr. Deborah Kochevar, representing small animal
medicine. John McGlone, another one of our new members representing
animal science.

We have Lisa Nolan, representing microbiology. Mark Papich, who
represents pharmacology, could not be with us today. Marguerite
Pappaioanou, from the Centers for Disease Control and Prevention,
representing epidemiology. Anne Parkhurst, who we hear is in the house.
There she is. Hello, Anne. And Anne is representing statistics,
biostatistics.

And Dennis Wages, who is representing poultry medicine. And it looks
like something fell off the bottom of the screen. Oh! Richard. Dick.

(Laughter.)

It wasn't intentional Richard. We are particularly happy that Richard
Wood is representing consumers. He has represented consumers on this
Committee for many years. And we have asked him back by special request
to fill that very, very important role, since this particular issue has
so many consumer implications.

So those are the members of the CVM Advisory Committee, just to orient
people as to who they are. And I think before we move on, and I wanted
to get this in the beginning of the program, we have some awards to
present to our outgoing members.

And the first one I want to present, and I don't know if she is in the
audience, is Dr. Barbara Glen. Oh, she is here. This is a U.S. Food and
Drug Administration Advisory Committee Service Award presented to
Barbara Glen in recognition of distinguished service on the Veterinary
Advisory Committee. Come on up, Barbara.

DR. GLEN: Thank you very much.

DR. SUNDLOF: Thank you.

(Applause.)

DR. SUNDLOF: Our next plague goes to Dr. Anne Parkhurst. She slipped
out. Oh, there she is again. I keep losing you Anne for some reason.
Come on up. It says the same thing, for distinguished service in her
service on the Veterinary Medicine Advisory Committee. Thank you very
much. It's been a pleasure working with you.

(Applause.)

DR. SUNDLOF: And finally, Dr. Deborah Kochevar. We hate to see all these
fine folks leave us, but hope you have had a good experience with the
Committee. Thank you very much.

(Applause.)

DR. SUNDLOF: Okay. Just to orient you a little bit and give you some
context about some of the issues that CVM is wrestling with right now,
as new technologies develop and food safety issues and animal safety
issues come to our attention, there are really three areas. We are only
going to be talking about one of those today.

(Slide)

And the three areas are things like gene therapy. As you will recognize
most of these issues are also issues for human medicine. Transgenic and
the one, again, that we will be talking about today, is cloning.
Probably the most straight forward of those three.

CVM's primary responsibility in this area is food safety, which is
pretty much always our mission. We are also very concerned about the
safety to animals.

(Slide)

We have produced a risk assessment on cloning. We have circulated and
published a summary of that, in an

11 page summary. The overall risk assessment will come out later. Let me
just explain a little bit about the situation that occurred there.

We did receive a very large data set in June of this year. That data set
has been fully analyzed. But, because of the amount of information it
was just not possible to get the final report in the form that we
thought was suitable for publication.

We did not want to postpone this meeting as a result of that because we
basically have come to the conclusions that are represented in the
summary document. So we will be publishing the full risk assessment. It
will be somewhere on the order of 250 to 300 pages, largely tables and
appendices and those kinds of things.

That will be circulated for public comment. And no final decisions will
be made, of course, until that has undergone a thorough public review.

So, there has been a major effort going on within CVM to develop this
risk assessment. It is part of a larger process. I don't want to give
people the impression that this is the only thing that we are doing.

So, to provide some context, I will talk about the process by which the
risk assessment really fits into the overall policies and regulations
that the FDA will ultimately come to in determining what the regulatory
status is of cloned animals.

(Slide)

This started \-- the whole process really started with the birth of
Dolly the sheep. At that point in time we recognized that this
technology had the ability to be introduced into larger agriculture. It
did have many benefits that could be useful to agriculture.

And so we have been very much engaged with the scientific community and
the people who have been the developers of this technology to track the
progress of it as it moves closer and closer to actual
commercialization.

Once we understood that this was likely, this technology was likely to
become a much bigger than laboratory experimental science, we contracted
with the National Academy of Sciences. And the Academy, we asked the
Academy a number of questions, not only on cloning, but on transgenic
biotechnology as it applies to animals in general. And that committee
did produce a very valuable report that was published last year.

We took very seriously the conclusions and the recommendations of that
report. And one of the conclusions of the report and recommendations was
that we conduct a more thorough risk assessment, taking into account all
available knowledge that exists. And that is what we have tried to do.

Again, this is one part of the process, identifying the risks to the
food supply and the risks to animals is very important to CVM in our
mission to protect public health and animal health.

There will be other parts of this as we go along. And one of those will
be a risk management document that we expect to be published sometime
late Spring of 2004 that will take into account the finalized risk
assessment after the public has had an opportunity to review it and
comment. And then look at what possible regulatory options we have in
order to make sure that any risks are adequately managed.

So we are going to present today the results of that risk assessment.
The idea here and what we have said all along, is that as we reach
certain milestones in this process, that we will make all of that
information available to the public.

And this is part of that process. So that is what we are doing today. It
doesn't infer any final policy decisions on the part of the FDA. It is
merely to say this is where we are in our determinations. We want to
make sure that everybody has access to the same data. None of the data
that we will use in making our decisions are proprietary. They will all
be in the public domain. And so we want to make this as much a
transparent process as possible.

(Slide)

Here are the questions, some of the questions, that we will address
during the next, or today. And the question is do the risks experienced
by animals involved in the cloning process differ qualitatively from
those experienced by animals undergoing other assisted reproductive
techniques, such as embryo transfer and in vitro fertilization, some of
the techniques that are widely used in animal agriculture today.

(Slide)

The second question that we will be asking is, are the edible products
derived from animal clones and their progeny as safe to eat as the
edible products derived from their conventional counterparts. I think
everybody is aware that that is our critical area of concern.

(Slide)

Our initial conclusions would include, we want to get some idea about
the frequency of animal health problems. Although some of the problems
that have been identified from clones may be similar to those with other
assisted reproductive techniques. Is the frequency different? And does
that frequency, is the frequency of those abnormalities declining over
time as the technology improves?

Food from adult clones, again, are food from adult clones as safe as
those from conventional animals? We are using these classifications
based on age. So the question here really talks about adult clones
versus cloned animals that may be at earlier life stages. And that
discussion will take place today.

(Slide)

So based on what we have presented, what we will have presented here
today, have we adequately identified the risks relating to animal
health? We need to have your input on that.

(Slide)

And then based on what we have presented, have we adequately addressed
the risks to public health? Very simple questions, but have all kinds of
complexities built into them. So your review on this, as the Committee,
is extremely important to us.

I think it's extremely important to the public to get the expert opinion
of an outside scientific body such as yourself. And your expertise,
again, will help us make the kind of informed decisions that we need to
as a public safety regulation, or regulatory agency.

So, again, thank you and I look forward to a productive meeting. And now
let me introduce to you,

Dr. John Matheson.

***Brief Background For Today's Discussion***

***by Mr. John Matheson, Moderator***

MR. MATHESON: But before we get on with this show today, Aleta Sindelar,
our executive secretary, has a conflict of interest statement to read to
the Committee.

MS. SINDELAR: Before we begin our deliberations, this is important for
the public record to know that we have thoroughly addressed any conflict
of interest issues that may pertain to the Committee. And this is of
general matters. So as bureaucratic as this may sound excuse me for
reading.

> "The following statement is made part of the public record to preclude
> even the appearance of a conflict of interest at this meeting. The
> associate commissioner for external relations FDA has appointed Mr.
> Richard R. Wood, Drs. Deborah T. Kochevar and Anne M. Parkhurst as
> temporary voting members for this meeting.
>
> Based on the agenda, it has been determined that the Committee will
> not be providing advice on specific firms or products at this meeting.
>
> The topics being discussed by the Committee in open session are
> considered general matters issues. To determine if any conflicts of
> interest exist, the agency reviewed the agenda and all relevant
> financial interests reported by the meeting participants.
>
> The Food and Drug Administration prepared general matters waivers for
> special government employees who required a waiver under 18 U.S.C.
> 208. Because general topics impact on so many entities, it is not
> prudent to recite all potential conflicts of interest as they may
> apply to each member.
>
> FDA acknowledges that there may be potential conflicts of interest,
> but because of the general nature of the discussion before the
> Committee, these potential conflicts are mitigated.
>
> 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 upon.
>
> Waivers are available by written request under Freedom of Information
> Act. Thank you for this opportunity."

MR. MATHESON: Thank you Aleta. Good morning. My role this morning is to
talk with you about how we got to the risk assessment process. What
steps have been taken. And to provide some basic definitions so that we
are all working from the same background as we go through the risk
assessments.

Cloning of animals with known genetic merit. "Known" is the key word
here because of somatic cell nuclear transfer is the first process that
allows us to copy animals that we know their genotypes. We know whether
they will be male or female. We will know what the adult animal looks
like. And that is what makes it commercially possible or feasible.

(Slide)

Not all cloning is about productivity, although you will hear a lot
about that. The longhorn in the middle has been cloned because of the
horns, of its rack. It's a rack on a cow. And the two calves below it
are the clones.

You will also notice there are no poultry in this picture. Somatic cell
nuclear transfer has not been accomplished with poultry to any great
extent so they are really not a part of this risk assessment.

(Slide)

Our goal in this whole process of risk analysis with animal cloning is
to provide a science-based decision making platform of the future
decisions for risk management. To provide some education to ourselves
and to the public about cloning.

For the process to be transparent so that all data that we use in making
the decision is available to the public and they can understand how we
used it. And that we eventually establish a risk management process that
is proportionate to the level of risk, other than fit it into a
preexisting framework. We wanted to assess risk first.

(Slide)

As Dr. Sundlof mentioned, we have been going through this process now
since early 2000, late 1999, when it became evident that a number of
firms were becoming interested in commercially copying animals. Again,
this is just clones, or just copies.

We met with them starting early in 2000 and encouraged each of them to
publish safety data. Now, we were a little naive, I guess. The safety
data are hard to get published because there is a bias against boring
old safety data. So we did find out, the hard way, that there is this
bias in the literature against providing information that animals are
not significantly different from other animals. It just doesn't sell
journals.

At the same time when we were meeting with these firms, starting in
2000, we were asking them to not introduce these food products derived
from these animals or their progeny into the food supply. We made that
request public in July of 2001. And at the same time in 2000, we
contracted with the National Academy. So that process took two years for
them to make the report that was delivered partly about clones and
partly about the rest of the science based issues with animal
biotechnology in September 2002.

(Slide)

At the same time we co-sponsored with the PEW initiative on food and
biotechnology, a public meeting on animal cloning in Dallas. Many of you
were there in the audience. I don't think any of the advisory committee
was present.

We think that \--. Well, we know that the report was issued in June of
'03 so you can see that on the PEW initiative site as well as hear all
the presentations. They are all still mounted on the PEW site. It was a
live webcast.

In the meantime we were preparing the risk assessment and we are now
reaching the final stages. This advisory committee meeting is part of
the process to preview the risk assessment, which will later, we hope
soon, be available in its entirety for everyone to comment on.

So any comment period doesn't really begin until the full risk
assessment is out there. We plan to release it on our website, again
because books of this nature, it's about 300 pages long, will not be
published anyplace. You cannot get the full data sent or the full risk
assessment published in a journal for example.

(Slide)

Now some definitions. We have mentioned somatic cell nuclear transfer as
a term that we are applying to cloning. This is the type of cloning that
we are discussing here. It's the, you can read the definition. It's the
fusion of the nuclei of a diploid donor with unfertilized enucleated
oocytes. Say that three times.

(Laughter.)

Clone. That is an animal resulting directly from somatic cell nuclear
transfer. Or animal clone. You will hear that term used. We don't
usually try to say cloned animal because you really don't know when you
say cloned animal whether you are talking about the donor, the cell
donor, which would be the large horse in that picture, or the actual
clone. So we try to say animal clone or clone when we are referring to
the product of somatic cell nuclear transfer.

And cloned progeny are offspring of at least one parent who was a clone
that are sexually reproduced. So not a clone of a clone. But a sexual
reproductive product of the clone.

(Slide)

Again, just to remind we are talking just copies, not genetically
engineered animals. In our view these things occupy different risks
faces. We would do a different kind of risk assessment for the
genetically engineered animals.

(Slide)

This slide from Cyagra, thank you Ray Page, summarizes the process for
somatic cell nuclear transfer. One point to make here is that in the
second slide where it says "insertion of donor cell", if the donor cell
is a somatic cell, then you have somatic cell nuclear transfer. If the
donor cell is a blastomere cell from an early stage embryo, then you
have blastomere nuclear transfer. That is really about the only
difference between these two types of cloning.

Again, the blastomere nuclear transfer is an earlier process that is on
the market, has been in the marketplace and has been in our food supply
for a number of years. It was not particularly commercially successful
because you really don't know the genetic potential of that blastomere
cell. You don't even know if it's a male or female.

(Slide)

So is somatic cell nuclear transfer really part of the continuum of
assisted reproductive technology? Or is it something different? Is there
something unique in the way of the hazards presented by this technology
to both animals or food that justifies special regulations? Or is it
like all the others that are listed here ending with blastomere nuclear
transfer. That is what "BMT" stands for.

Embryo splitting has been out there for some time, as well as in vitro
fertilization and artificial insemination. So that is really the crux of
the matter here. Is it part of the continuum or is it something unique
that we need to assess?

(Slide)

Presentations this morning will focus first on risk assessment
methodology. Dr. Rudenko will present that. We will have some data
summaries from Dr. Dubbin. I think we will have a break somewhere in
there.

We will also have animal health risk conclusions from Dr. Amey Adams,
who is in the audience. And then

Dr. Rudenko will return for a food consumption risk conclusions. We will
call them tentative conclusions at this stage. And that is really what
this morning will take. Then we will have lunch.

So with that, I will introduce Dr. Rudenko and we will begin the serious
business of assessing the risk of this technology.

***Risk Assessment Methodology***

***by Dr. Larisa Rudenko***

DR. RUDENKO: Well, good morning. My name is Larisa Rudenko. I am the
senior advisor of biotechnology at the office of new animal drug and
evaluation at the Center for Veterinary Medicine. I would like to thank
you all for coming today. It's nice to see so many friendly faces in the
audience.

(Slide)

I am going to start my talk first of all by thanking several of the
clone manufacturers who have graciously provided us with wonderful
photos that we have used here for visual interest. There is an
acknowledgment slide at the end. Unfortunately Dr. Bob Wall from USDA
fell off that slide. So I will reward him specially by calling him out
at the beginning. Those are his little piggies backs that you can see
back there.

As both Dr. Sundlof and John Matheson had said, this is part of an
orderly and transparent process that we are initiating here at the
Center for Veterinary Medicine, or rather continuing at the Center for
Veterinary Medicine. Especially on a topic of new technology that has so
much attention called to it because of the newness of the technology
itself and for other issues that surround it as well.

What do we mean by transparency and how do we initiate a transparent
process with the public and with you, the advisory committee? Well, a
scientist or a risk assessor sees transparency as making the rules
clearly available and understandable to everyone.

We need to define our terms. We need to show you our work. We need to
clearly apply the rules to our work so that you can see where our
conclusions are coming from. And then we need to tell you what we don't
know and what we do know. What we surmise and what we deduce.

And so what I hope to be able to do in the next

40 minutes or so is walk you through how we made the rules. How we
applied the rules. What we applied the rules to. The terms that we used.
What we know from the data. And what we don't know from the data.

I will be assisted by Dr. Eric Dubbin and Amey Adams in the actual
presentation of the data and the conclusions from it.

(Slide)

Again, as John has told you, we had a charge and that charge was to
characterize risks to animal health for animals that are involved in the
cloning process and to humans and animals from the consumption of food
from animal clones or their progeny.

As we said before, and we really need to emphasize this, this
specifically excludes genetically engineered animals. So there are no
trans genes involved here at all. The other point that is very important
to make as part of this open and transparent process is this is the
first step. This is the introduction and roll out of the risk
assessment. It is not a discussion of risk management.

(Slide)

So you all have seen this triad of risk assessment, risk management, and
risk communication. As part of our defining of terms, we are going to
tell you what we mean by risk assessment, risk management, and risk
communication.

(Slide)

Risk assessment, or the step that we are on right now, or more precisely
the step we are introducing to you right now, is science based. It
identifies hazards and risks. And we will talk about the difference
between the two in a couple of minutes. It's relatively value free, but
never entirely value free, because we do make assumptions, but we try to
be very clear about what those assumptions are. And finally, it provides
a framework for risk management decisions.

Risk management, on the other hand, which will come farther along in the
process, is the identification and evaluation of alternative strategies
and the selection among them based on some set of preestablished
criteria.

And finally, risk communication, which is part of what we are involved
in right now, is the interactive exchange of information and opinion
among scientists, among regulators and among the public. And we are
grateful that you are here to share this with us today.

(Slide)

So again, how do we approach this? Well, we had a statement of our
goals. We considered traditional risk assessment methodologies. We tried
to determine whether or not those would fit the issues presented by
cloning or not. We did a survey of the literature when we started on
this process and I became involved in it in about July 2002, I guess it
was.

We surveyed the literature to see what there was out there. And then we
asked some very fundamental questions about what hazards might be
involved in cloning and what risks might result from those hazards in
order to help develop a framework for what we were going to do. And then
we went back and reviewed the literature within that context.

(Slide)

So, in terms of starting out from a baseline, the first place to go
always when you are looking at risk assessment is to the National
Academy of Sciences who have published similar works on the issue.

In the right hand column you will see the four steps of risk assessment
that have been made, I guess, famous or infamous, depending on what your
position is, from the 1983 National Academy of Sciences Redbook.

Those four steps are hazard identification where you talk about what
might happen if exposure occurs. And exposure assessment determining the
extent and nature of the exposure.

A dose response evaluation, which is a toxicological review of the kinds
of effects you see at varying doses when you are exposed, or laboratory
animals are exposed to a particular substance.

And the risk characterization, which is a qualitative and quantitative
melding of the information that you gathered from the previous three
steps.

Well, in the 2002 report on animal biotechnology that the National
Academy of Sciences put out, they came up with a slightly revised set of
steps for risk assessment. The first one said, well, you have to
identify the harms.

The second one said identify the potential hazards that might come from
those harms. Determine what the exposure means and the likelihood of
exposure. That is fairly similar to the exposure assessment step. And
then quantify the likelihood of harm given that exposure has occurred.

Note that both of these approaches imply that there is a specific
etiologic agent involved. You are exposed to something. The amount of
that thing may change. That thing may cause bad things to happen.

(Slide)

Well, bear that in mind and now let's go back to our literature search.
When we did our initial survey we came up with about, oh, probably about
1,000 hits on our literature search survey, maybe 2,000.

By the time you went and threw out duplicates and so forth and so on, we
identified about 500 papers that might be relevant to animal somatic
cell nuclear transfer. Most of these papers describe the technology
development. We used this kind of a cell, we got this kind of fusion. We
used that kind of a cell, we got that kind of fusion. We applied an
electrical pulse that worked. We did a chemical pulse that didn't work.
Those kinds of studies.

Many of these studies, including many of the key studies that are cited
in reviews of cloning, especially reviews of cloning that address
adverse effects that are noted are actually on transgenic animals. And
that is not clear in many of these papers unless you actually traced the
papers back to their original citations.

The emphasis on these papers, as John had said, is hypothesis testing.
That is what journals publish. They want unique data where you test the
hypothesis or report on something new. There are very few surveys of
animal health. And those surveys that have been cited most often in the
press address transgenic clones. Again, and that is not always obvious.

So by the time we whittled down through there, we ended up using
probably about 100 papers in our overview of which probably 60 to 65
percent were completely relevant. We also investigated model systems for
the livestock species that we are interested in. And we looked at mouse
as a model system where there is a fair amount of publication.

(Slide)

So, harms, hazards and risks. What is the hazard here? The little jug
that the goat is climbing on, what is the risk? The little goat might
fall.

(Slide)

So, hazard is an act or a phenomenon that has the potential to produce a
harm. And a harm is defined as an adverse outcome, an injury, or some
kind of loss or detriment.

And, finally, risk, in this context, is the conditional probability that
an adverse outcome will occur provided that exposure has occurred. So
that is a quantitative \--. That definition can be incorporated into a
quantitative or a qualitative expression of risk.

(Slide)

So what were our challenges as we went forward in doing this risk
assessment? Well, we needed a methodology that was suitable for both
animal health and food consumption risks. That is not necessarily a
short order.

We have to get down to what the potential harms might be for both animal
health (AH) and food consumption (FC). Our pledge was that everything
that we would evaluate would be publicly available. That somewhat
limited what we could look at.

We didn't have a theoretical framework for cloning to start with. We had
no etiologic agent. We had only a technology change. We had no inserted
genes. No resulting gene products. And no postulated pleotropic effects
from insertional mutagenesis as one might hear from transgenic animals.

So there we were. That made the risk questions very difficult to
formulate and the absence of risk, or safety as we sometimes think of
it, difficult to prove. If foods appeared to be the same, if animals
appeared to be the same, how could we prove that? How could we limit the
uncertainty that came with that question or with the answers?

And, finally, what metric would we use? How would we measure risk? What
would our comparative group be? That is where we started from.

(Slide)

Well, we also started with a couple of baseline assumptions. We said if
animal clones were to be considered for food, they would not be
considered any differently, or not subject to any less stringent rules
than conventional animals would be subject to.

So we assumed that there would be compliance with existing regulatory
requirements for conventional food animals and for food derived from
conventional animals.

(Slide)

We also assumed, as has been the assumption of toxicologists and
physiologists for a very long time, that domestic animals consumed for
food do not naturally produce toxins in their edible tissues. And that
frankly diseased or defective animals do not enter the food supply. That
is conventional animals or clones should they approach the food supply.

If that is the case, and we have no transgenic inserts and we have no
frankly diseased or malformed animals entering, then the changes that
could be seen, that could occur in these animals would likely be due to
gene dysregulation or what are known as epigenetic changes. And because
by definition you can't see these changes, we called them subtle
hazards.

(Slide)

Now subtle hazards are something that are outside the conventional range
of food hazards as we understand them. I spent 20 years doing food
safety risk assessment and we never talked about subtle hazards before.

So what could those food hazards be if we were to postulate them? Well,
we could say there might be changes in gene expression as a result of
somatic cell nuclear transfer. And those might result in phenotypic
variability such as coat color, behavior, and longevity.

And if you look at any twin humans in the population you will see that
they have different freckle patterns. They might have slightly different
hair coloration. They have different fingerprints. Those are all the
result of epigenetic changes.

It's possible to postulate disruption of the immune function. And that
might be a risk to the animal or to the food supply and manifested as
increased sensitivity to pathogens. So we need to look for that.

And then the last thing are subtle changes in the metabolism of an
animal such that the animal has changes in its physiological set-points.
It compensates for those physiological set-points. But you might have
levels in tissues of certain substances that might be higher or lower
than you would expect. And that might pose some kind of a nutritional
risk to you. Because you might not get the vitamins that you are
expecting or some key dietary component that you are looking for.

So the next question we asked ourselves, well, this is fine. This is a
fine theoretical construct. We like this. But how would these differ
from subtle hazards that arise in conventionally bred animals?

We have epigenetic changes going on in conventionally bred animals all
the time even in twins. How would you detect them? And would these
subtle hazards pose actual risks to either the animals or to people
consuming food from those animals? And if there were risks, how could
you measure them?

(Slide)

So here is a little table that we pulled together that sort of worked
this through as a theoretical framework. The subtle hazard in the first
column across is a change in gene expression that could lead to change
in protein structure or function.

So the general risk to the animal, according to our framework, could be
postulated as toxicity of some sort, from very mild to reasonably
severe, due to aberrant protein expression. Protein can be an enzyme,
you can lose catalytic activity. A protein can be a structural protein
and you might have some kind of alteration in some \-\-- as the result
of that.

A hypothetical food consumption risk might be increased allergy to milk
because you have somehow changed the presentation of a key milk
allergen. Or changed nutrient content of milk because of a change in
catalytic activity, you are no longer manufacturing the level of thiacin
that you think you are manufacturing, for example.

These are the kinds of things we asked. I am not going to walk you
through the rest because they are pretty self evident.

(Slide)

So how did we develop the methodology? Well, we went through a number of
iterations. When I was first learning risk assessment I was told that it
was an iterative process. I said, yeah, yeah, three months. Well, a year
later we are still refining the methodology that we are using and it
really is an iterative process because data comes in all the way along
and you have to change assumptions based on the kinds of things that you
actually can observe.

(Slide)

We took a two-pronged approach to evaluating food safety. The first
approach we named the critical biological systems approach. I will talk
about that in a little bit more detail next. But it's based on the
premise that a healthy animal is likely to produce safe food.

The second prong is the compositional analysis. And it asks whether food
products from healthy animal clones or their progeny \-- if food
products from healthy animal clones or their progeny are not materially
different from those derived from conventional animals, then they likely
pose no additional risk.

If both of these requirements are met you can make a reasonable argument
that foods from these animals could enter the food supply.

Now the thing that is important to note about this is even though it
looks like these are two independent prongs, they are not. And they are
not because of the underlying biological assumptions that exist in both
approaches.

A healthy animal that is virtually indistinguishable from a conventional
food animal is not likely to produce milk or meat of a compositional
difference from a conventional animal. If everything is the same, then
you expect the same out. It's nice to confirm that. It's nice to have
the confirmatory composition data that demonstrates indeed that there is
no material difference between the products of those animals. But please
understand that these two prongs are mutually reinforcing.

(Slide)

So what is the critical biological systems approach? Well, it's
mechanistically derived. It's

HAACP-like in that it considers the life cycle of the animal in a
systems approach. It accepts somatic cell nuclear transfer as a
biological imprecise and inefficient process. We have a low rate of
animals coming out of the SCNT process. But, it allows for biological
repair or correction just as every biological system has a capacity to
do. That repair can be intrinsic or it can follow human intervention. We
call that medicine.

Its cumulative nature allows for the incorporation of both favorable and
unfavorable outcomes. So it's open to both positive and negative
results. And it's a suitable framework for characterizing both animal
health and food risks.

(Slide)

And this is what it looks like. It started out looking as a very, very
complicated wiring diagram. And we have trimmed it down to something a
little bit more manageable. And it consists of basically of five
developmental nodes. And the reason we did this was that remember we had
about 100 papers we needed to analyze. Going through them paper by paper
does not help you make a systematic analysis of the health of the
animals.

But giving yourself slots to put information into from each of these
papers allows you to cumulate and compare across different developmental
nodes of these animals.

The first stage is a self cell fusion through fetal development, a lot
of emphasis in the literature on these steps. And most of the papers
that you will find in the literature, if you do your own search, will
address this particular developmental node.

We have the perinatal development and functional period, which is the
period immediately preceding and following birth. We have juvenile
development and function, which is post-perinatal up to about to
pubertal period.

Then we address reproductive development and function, which we put a
lot of weight on, because the reproductive system is so complex and so
highly integrated that we felt if you had a correctly functioning
reproductive system that likely the animal was in pretty good shape.

And finally we considered post-pubertal maturation which was all of the
maturation processes that might occur simultaneously with reproductive
maturation, but did not specifically address reproductive function.

As you can see from the pink and brown call outs, this also allowed us
to identify points in the developmental process of these animals where
we might have a food consumption exposure. So you can see this framework
allows us to consider comprehensively all of the life stages of the
animal that are relevant to both animal health and food consumption and
allows us to cumulate data across studies in a systematic way.

(Slide)

As you know from looking at our executive summary, our draft executive
summary, we were able to draw some interim conclusions on animal health
regarding, based on the literature review using the critical biological
systems approach.

As I said to you before, with a few notable exceptions, most of the
information came in the first node of cattle. Several studies often
cited \--. Several of the studies that are often cited address
transgenic clones. And in some of these papers where we were hoping we
would get a lot of information, because there were several score of
animals evaluated, there was no individual identification of whether an
animal was transgenic or just a clone. So we were unable to make that
distinction. And, therefore, those papers became of extremely limited
utility for us.

There are very few animals that were just clones as the result of this
data set. And as we broke them into species, we realized that the
database was not enormously extensive.

And often there was cursory information on the health status of
non-neonatal animals. Again, because people are anxious to publish about
their neat and new cloning technique and how good the efficiency is,
there might be a throw away line somewhere in the discussion section
that says clone 753 aged uneventfully, went through puberty as expected
and gave a normal offspring. Well, that is not very helpful to
determining what the health and safety of the animal is. But it is
cursory information. You can't just throw it away. (Slide)

So the next steps. What were we going to do with this data set? Well, we
developed a wish list of information that we thought would be helpful in
assessing animal health. Like good scientists, good regulators, and good
transparent participants in the process, we went and gave presentations
to various professional society meetings and other public fora at which
various members of the cloning community and interested other public
citizens attended. And we had several conversations with several clone
producers.

(Slide)

One of the things we decided should come out of that is this wish list.
And the wish list basically said that what we would like to have are
species and life stage appropriate comprehensive veterinary examinations
and clinical measurements of blood and urine from these animals.

And we would like to have these veterinary exams and clinical
measurements at several developmental nodes because we have constructed
this lovely critical biological systems approach. And we thought if we
could get some additional data it would help us look across the data in
the literature and also evaluate what would get in hand.

And we also thought that it would be extremely useful to have necropsies
of animal clones that had died prior to use. And whose deaths were not
immediately attributable to normal events.

One of the things that I learned at CVM was that agricultural animals
are not laboratory animals. You don't get to keep your cows in a nice
plastic box in a rack in your animal handling facilities. Cows live in
barns. Barns have rails. Cows occasionally put their heads in the rails
and hang themselves. That is probably not a cloning related injury. That
is probably a cow related injury.

(Slide)

So we came up with, we went to various reputable animal diagnostic
laboratories and came up with a list of the standard tests that are used
to analyze blood both with respect to its chemistry and its cellularity.

And then we thought, well, you know, given this is the FDA, we have had
some experience with controversial subjects, there are some things that
people are interested in that maybe if we don't gather data on
immediately, we should at least reserve some blood samples for so we can
analyze later.

And in particular we looked at Serum IGF-I, we felt we would reserve a
sample for. Not because we have any apriori biological reason to suspect
that this is a risk. But rather because so much public attention has
been called to it. And also estrogen for the very same reasons.

(Slide)

So back to our two-pronged approach. And let's think about the
compositional analysis that we were looking for. Again, just as with the
animal clones we decided the regulatory requirements for foods from
animal clones must be met or exceeded regardless of whether they are
conventional or cloned animals.

So we would ask any of the foods to meet the requirements of the
pasturized milk ordinance. any USDA inspection criteria, the Center for
Food Safety and Applied Nutrition labeling requirements, and, of course,
our Center's blood residue requirements.

And if we were thinking about the compositional analysis, we would ask
that the constituents be within contemporary normal ranges for
variability for that food product. In other words, it would probably not
be appropriate to dig out a text book from 1938 that evaluated the
composition of milk from Wisconsin cows and compare California bulk tank
milk from 2002 to those values. That would not be an appropriate
comparison.

And finally that the identity standard analyses would reflect the
genetics of the animal that is being propagated. In other words, don't
compare meat from dairy cows to meat from Angus for example.

And the outcome criterion that we would be looking for from this would
be a statement that the milk or the meat would not be materially
different from conventional animals.

(Slide)

So we ran into a little bit more of a problem here than we had with the
data for the biology animals. And that was until this Fall. There were
no peer reviewed publications relevant to SCNT animal derived milk or
meat composition. There were none.

There are several reasons for that. One, very few clones have been bred,
are old enough to be bred, and to produce milk. Very few. There is
little impetus for the private companies who are doing this to publish
the composition of the milk, even though we might ask them for it.

And, finally, meat composition requires sacrificing the animal. We
called around to all of the meat testing laboratories that we could
identify and asked if any of these analyses had been miniaturized to the
point where we could use a punch biopsy for example.

And the answer was no. You needed kilogram amounts of meat. And at
\$20,000 per clone, that is a lot of money to pay to sacrifice an
animal. And then how many animals do you need to sacrifice in order to
have a good statistical survey?

(Slide)

So once again, we divide that wish list. And you can see for the milk
and the meat we decided that what we really needed to do was to
characterize the primary constituents of those products that would lead
to a potential nutritional risk. So we asked for proximate, plus test
vitamins and minerals for which meat or milk were a moderate to a major
source. And you can see those listed.

And we had asked for fatty acid profiles, which again would be of
dietary importance and would also, remember we said the two prongs are
neutrally reinforcing. They are not independent. If you can go through
this fatty acid metabolism and do all the fine steps that are involved
then chances are you have got a well functioning animal.

We asked for a protein characterization. Not for exact breakdowns on
each of the proteins because you don't eat meat and you don't drink milk
for the full proteins that are there. It's for the amino acids that are
there. So we had asked for an amino acid profile particularly
concentrating on the essential amino acids.

And, finally, for milk, the somatic cell count just to indicate that the
animal is healthy and see if we can move forward from there.

(Slide)

Well, lo and behold, coming out in this quarter's issue of "Stem Cell
and Cloning", is a study by Marie Walsh and her colleagues on the
composition of milk from dairy cow clones that were described by
Forsberg, et al, in a paper that we also used to look at animal health
that Dr. Dubbin will tell you about.

They looked at 17 clones derived from five cell lines that were cows
that were bred by AI. All right, so don't be confused here. The cell
lines are derived from animals that were bred by AI, but they went on to
make somatic cell nuclear clones from them. Two Holsteins and two
Holstein Jersey process.

And, interestingly also, there was one female progeny of a bull clone,
although they didn't specify the breed of that animal.

The comparators that were used in this analysis were approximately age
and lactation stage matched animals. They were not housed at the same
farm. And they were only softly breed matched. There were five Holsteins
reared at one farm and one Brown Swiss cow reared at a second farm. All
of these animals were fed different rations. Although the rations are
not described fully enough so that we can make some attributions as to
the effect they may have had on milk composition.

(Slide)

The analytes that Dr. Walsh and her colleagues evaluated looked in the
milk, were total fat, nitrogen, solids, lactose, PH, somatic cell count,
again an indication of the health of the udder from the animals from
which it came. An acid degree value, which is an indication of the
rancidity or the off flavor of milk. Several key elements. Several fatty
acids. And they looked at protein composition. You will notice that some
of those values, it's not your stigmatism, it's some of those analyzed
are in bold. And that is because they coincidentally happen to fall on
our wish list as well.

(Slide)

So here are the results of the Walsh study. All of the values from these
animal clones and the one grand clone, okay, that was the daughter of a
cloned bull, fell within either comparator or published ranges, with the
exception of strontium.

And the only reason for that \--. Or the reason for that is not entirely
clear because there is no published range. There is only a single value.
So if you have one value comparing it to another value doesn't give you
very much information. When you look at the paper you will see that the
strontium levels in the clones were lower than the published strontium
levels.

(Slide)

So Dr. Walsh and her colleagues concluded that the composition of milk
from somatic cell cloned cattle was similar to that from non-cloned
animals. And that the differences between clones and comparators were
likely attributable to differences in breeds, diets, or housing.

It's important to remember the number of animals in the study is
relatively small. But the results are entirely consistent with the
health data that you will hear about from Dr. Dubbin.

(Slide)

Next I want to go very quickly through the mouse literature. Remember we
said we were going to look at model systems where we had insufficient
information and rather than including that in our data summary, I will
tell you a little bit about it now, and include it in our methodology
discussion.

(Slide)

Mouse literature in many ways is very similar to the livestock
literature. It tends to focus on interesting outcomes rather than on
overall health surveys, for the reasons that John discussed, there is a
publication bias out there. It may provide insights into the underlying
biology, however, of the overall cloning process.

Because mice have relatively short generation times, these studies may
provide us clues to reproduction, longevity and agents related
phenomena. And it's interesting to note that some of the anomalies that
we have noted in mice are similar to the anomalies that were noted in
livestock. Others are very different.

So like every model system it's very important to interpret the results
with care. This is a model system. It is not a direct representation of
all of the other systems.

(Slide)

So what do we know about mice. Well, similar to livestock clones, mice
often have large abnormal placentae. I am jumping the gun a little bit
on what Dr. Adams and

Dr. Dubbin are going to tell you, but trust me there are some large
abnormal placentae in cloned animals. Some of these mice also have
perinatal respiratory difficulties either arising from cardiovascular
defects or birth related phenomenon.

There are, however, some distinctive phenomena that also have been
observed with mice. In one laboratory, one strain of mice that has been
generated using one cloning technique, animals have shorter life spans,
significantly shorter life spans than their donor animals.

Those animals appear to die from various kinds of liver pathologies.
Again, that however is limited to one laboratory in strain out all of
the data that has been observed. In another laboratory some of the mouse
clones have a very unique obese pre-pubertal phenotype that is
reproducible in that laboratory using that donor line.

(Slide)

So what insights do we have from the physiological mechanisms that may
be perturbed in all animal clones from the mouse model system? Well, we
know that placentation is affected. Without going into details there
have been a series of rather elegant studies that have asked the
question are these changes due to genetic modifications or epigenetic
modifications. When the entire report comes out you will see that this
group of scientists has done an elegant job of demonstrating that these
are epigenetic changes and not mutational effects.

That there is fairly rapid resolution of perinatal fragility, as Dr.
Dubbin will describe to you in the next half hour. And the most
important thing that the mouse data has taught us is that anomalies
noted in clones that are specific to cloning, in other words, an animal
that may have a genetic defect may propagate that defect.

But if there is an anomaly noted that appears to be cloning related,
such as the unique obese phenotype, that phenotype is not transmitted to
progeny. Reproducibly not ever in the publications.

So predicative interspecies extrapolation for specific endpoints or
outcomes should be attempted with caution. I think what we go to the
mouse studies for is some good understanding of what the underlying
biological systems that may be involved are. But to extrapolate from any
particular endpoint from mice to livestock is probably inappropriate,
just as it is inappropriate to extrapolate for example from goats to
pigs.

(Slide)

So what happened next? We are stuck with this set of papers that has
spurious, or not spurious, but very cursory information about animals as
they age. Don't really have a whole lot of physiological or biochemical
data. We are going out and hawking our risk assessment across the
country. And lo and behold, one company stepped up to the plate. And I
would like to thank Cyagra Incorporated for supplying us with an
extraordinary data set.

(Slide)

This data set is the reason why you are reading the executive summary
and not the entire risk assessment right now. Cyagra made these data
available to us in the Summer of 2003. It's important what they did
basically was to go out, try to identify every clone that they had
generated.

And as a snapshot in time, if you are an epidemiologist you can think of
this is as a cross sectional study and not a longitudinal study. Assayed
the health and took blood samples on all of these animals. It took them
long enough to do this, but they were able for a very small subset of
animals to get data on both the neonates and those animals a little bit
later.

They shipped us electronically that entire data set, including the
direct evaluation of the clinical chemistry from the Cornell Animal
Health Diagnostic Laboratory. And said, go to it. It's publicly
available. Do with it what you please.

So that is what we did. We analyzed it every which way from Sunday. And
what I would like to tell you about, or what Dr. Dubbin will spend most
of the time talking to you about that data set. Because it is the most
comprehensive and complete analysis of the health of animal clones.

Unfortunately it's only limited to cattle, and that is their business
decision, we don't have anything to say about that. But, that is the way
it goes.

In addition, we have received other data from other clone manufacturers.
It tends to be on specific endpoints and may be on different species.
With apologies to those clone producers, we have not incorporated it at
this time. But we will in subsequent iterations of this risk assessment.

So we decided to move forward even though we knew it would delay the
completion of the appendices and the decent proofreading a document of
300 pages in length would require.

(Slide)

So, finally, let me wrap up by telling you what the rules are that we
were choosing to apply to our risk assessment. Again remember we have
the initial criteria that the animals appear normal and healthy. Those
that exhibit gross abnormalities or disease are culled and do not enter
the food supply. This is not special for clones. This goes for food we
eat every day.

Meat and milk appear normal and neither exceed federal, state, and local
standards. Again, nothing special for clones. Same requirements that we
have had for other food animals.

(Slide)

We did something a little different. We decided to make our biases
transparent. Now there is no such thing as going into an analysis
without a bias. People can tell you that that is the case, but that is
not true.

So we decided that we would take the two extreme biases that could be
taken for clones. And we would bound the risk face in which we were
operating using those two biases. And by clearly identifying what those
biases are, we could be transparent about where the data was taking us
and how much confidence we would have in our conclusions.

So our first hypothesis is the more liberal interpretation that assumes
that clones are exact biological copies of the donor animal. And that
all you need to confirm that are confirmatory findings of health and
food product comparability to indicate that no additional risk is posed
by the consumption of these food products.

The opposite face, the other bound on this, is that animal clones may
appear to be biological copies of the donor animal. But subtle hazards
may have been introduced by the somatic cell nuclear transfer process.

To avoid additional risks above those posed by the consumption of foods
from conventional animals, comprehensive health and compositional data
are required to demonstrate that the animals are healthy. And that food
products derived from them do not differ materially from those derived
from conventional animals. So those are our biases.

Again, as was told at the beginning of these assessments, this is risk
assessment. This is science only. These biases are scientific biases.
They are not morale or ethical biases which are more appropriately
handled in the risk management component of this overall process.

(Slide)

We evaluated the weight of the evidence for animal health and food
safety based on the literature and the data that had been submitted.

(Slide)

We will state our conclusions regarding risk using the following
criteria. Any biological assumptions that we implied. Remember we said
it was relatively value free, but there were assumptions used in risk
assessment. The empirical evidence that we evaluated. The consistency of
observations among the animals of that cohort and across other cohorts
as well.

The degree to which model systems apply to that particular endpoint that
was being evaluated. And the consistency of that model system with the
data that we were evaluating.

We would state our uncertainties associated with any preliminary
estimate of risk that we might make. And then make an overall statement
of the confidence that we would have in that estimate.

So what you have here is a fully transparent decision making process
that identifies the two bias perspectives that you can take, where the
data that drove you with respect to that risk finding exercise, the
uncertainties that were still associated with it, and our confidence in
our estimates of risks for that particular endpoint.

(Slide)

Now it's important to understand what the limitations on any risk
assessment are. This is a qualitative comparative risk assessment. We
are not going to come out with a number that says meat from animal
clones is then many times more or less risky than conventional meat.

What we are going to do is compare these animals to comparators of known
or inferred safety. And the known or inferred safety that we are
comparing them to is the food that we eat every day.

The strongest conclusion that you can get out of this kind of a risk
assessment is likely to be as safe as. So what does that mean in the
context of animal health and food consumption? When we say a finding as
safe as for animal health, that means the cloning process is likely to
be as safe as other assisted reproductive technologies. That is our
comparator of known or inferred safety.

For food derived from clones the finding of as safe as means that food
derived from animal clones is likely to be as safe as the foods that we
eat every day.

(Slide)

Finally, we made some recommendations to decrease uncertainties. There
are always uncertainties associated with every bit of science. Risk
assessment, as I said, is an iterative process. We can always call for
more data. We can also be paralyzed by analysis.

So one of the things that we need to do is to, and that we will ask for
your opinion on, are the relative merits of additional data. And so that
we can then take those recommendations forward to risk managers so that
a transparent statement of risk tolerance can be made.

(Slide)

So we have been promising you this risk assessment. We are still going
to promise you. And the last little teaser here is what is the overall
structure of the risk assessment going to look like when it finally
comes out.

We want this document to be accessible to the entire public, from the
scientists to the layperson. To that end you have already seen the draft
preliminary executive summary.

The next chapter in the risk assessment will be a technology overview
that will review assisted reproductive technologies as they are
currently employed in the U.S. agriculture. A little bit about how long
they have been around. How much they are used, and what they are
actually like.

There is a short primer on hazard, risk, and cloning, most of which you
have heard today. A chapter on risks to animal health. A chapter on food
consumption risks. And a final closing chapter with overall conclusions.
There are several appendices which you see listed on the right hand side
of that slide.

There will be a comprehensive bibliography, including all of the raw
data that Cyagra submitted. Raw data. Individual animal numbers. And a
complete glossary so that anybody who is reading this document doesn't
feel that they are stunned by techno babble.

(Slide)

This risk assessment we believe has a great deal of value to us as a
regulatory agency, to the scientific community, and to the lay public.
It's a logical framework that is tailored to a specific question. It's a
systematic analysis of available data that have multiple uses.

It identifies clearly data gaps. It performs weight of evidence
evaluations that accommodate data, biological assumptions, biases,
uncertainties, and the degree of confidence that we have in the
conclusions.

And finally we believe that this gives all of the stakeholders involved
in the process a degree of transparency that we may not have seen
before. And this preliminary presentation of the executive summary is
the first step in that transparent process.

(Slide)

Finally, I would like to acknowledge all of the people who have worked
on this team. Without them, none of this would have been possible. And
with them we have, I think, come up with a unique product.

Dr. Amey Adams, you will see soon. Eric Dubbin, who has been involved in
things. Kevin Greenlees, who has been actively involved in the
preparation of the final document. Dr. Barry Hooberman, from our risk
assessment group. Dr. Wendy Jones, John Matheson and Christina Musgrave,
our consumer safety officer without whom none of the data management
would have been possible.

And finally I would like to thank our reviewers, Dr. Hungerford. Gail
Schmerfeld. Dr. Sherman.

Dr. Schoenemann. Jody Fleming, who was a summer student with us from
Rutgers. And many, many others at the Center and outside for all of
their help.

(Slide)

And finally to Ray Page from Cyagra for his openness, continued
availability to answer any questions about his data set. And to other
producers whose data we have not yet included.

And for photo credits, of course, we would like to thank Cyagra, Nexia,
TransOva, I think Jodie Palmer is here. ViaGen. Mike, thank you very
much. And Jorge Piedrahita. And of course Bob Wall, you get thanked
twice because you didn't end up on the slide. Thank you very much for
your attention.

(Applause.)

***Summary Data from Animal Clones - Part I***

***by Dr. Eric Dubbin***

DR. DUBBIN: Thank you, Larisa, for that overview and teaching us all
something about risk assessment and how this process is being evaluated.
My name is Eric Dubbin. I am a large animal veterinarian and I am a
member of the ruminant drugs team at the Center for Veterinary Medicine,
Food and Drug Administration. Just one second.

(Pause.)

(Slide)

This is a review of the critical biological systems approach and each
node that we used as developmental landmarks to couch our discussion in.
The first node, cell fusion through field developments. It's before the
calves are born. Then perinatal development and function around the time
of birth. Juvenile development and function.

Then when the calves go through puberty and have reproductive
development and function. And finally post-pubertal maturation where we
see how well the animals age as adults.

(Slide)

The overview of my presentation is we are going to do a species by
species evaluations. We are going to talk about key outcomes in the
critical biological systems approach context.

We are going to emphasize the data as it corresponds to the
developmental node and how it relates to animal health risks and food
consumption risks. We will also have a more detailed presentation of the
Cyagra data, which is the largest single data set and our most detailed
data set.

(Slide)

The first node is cell fusion through field development. This is the
period of highest risk for the developing clone where we can see failure
for the embryo to divide or implant. Defects in reprogramming. Problems
with placentation. There are problems in this node throughout all the
species we have evaluated.

The percentage of surviving this particular node is low and the data
that we have are limited for further assessment, but the data do help
set the stage for the next node.

(Slide)

With that I would like to talk about specifically about bovine clones in
the framework of the critical biological systems approach.

(Slide)

When we look at bovine perinatal clones what we see is that there are
really few laboratories, lots of data, but few laboratories with the key
studies. Another issue is that many of these studies discuss transgenic
clones and not just clones alone. And if you remember we discussed that
transgenic animals were going to be left out of this assessment.

So the number of actual "just" clones is relatively small, about 50 or
so. Most of the information on overall health is somewhat cursory, or as
Dr. Rudenko mentioned earlier, the passing discussions of the animals
were healthy after they got the information they wanted.

There are few physiological or biochemical studies with lab data and
blood data. And one thing we do see in bovines that the large offspring
syndrome is quite common. Large offspring syndrome, for those of you who
don't know, is a collection of findings where the calf, the neonate, the
newborn, is larger than expected for the breed.

There may be some placentation problems occasionally. Partrition may be
delayed. The calf is unthrifty. These calves might need support by nasal
gastric or oral gastric feeding and respiratory support with \-\--
oxygen and such. Most of these animals survive and Dr. Adams will
discuss this condition in more detail later and you can see my bottom
bullet there is not showing up very well.

(Slide)

What we see over and over again is that the newborn clones are
particularly fragile in the first few days. There is a higher incidence
of death early in the development of this technology. But we do see an
improvement in success rates as the technology itself advances.

In clones we see no qualitative difference relative to other assisted
reproductive technologies. Qualitating meaning the types of problems. We
do, however, very clearly see an increased frequency of these problems.
Most commonly LOS, which I mentioned previously. These calves tend to be
a little higher birth weight than their age matched comparators.

And you will hear the term age matched comparator over and over again
because it's important that when we use a reference, that the reference
we use is appropriate and age matching comparators or comparing animals
of similar age, similar breed, similar diet, similar farm background is
very, very helpful for a meaningful comparison.

We do see more common cardiovascular malformations more commonly. We
will see respiratory problems and flexor tendon contracture. Understand
that elevated birth rates, cardiovascular abnormalities, respiratory
difficulties and contracted tendons are not unusual to cloned animals.

(Slide)

So that is the perinatal summary of the literature. The next node I want
to talk about is juvenile development and function. This encompasses the
time in and around weaning, depending on the species because different
species are weaned at different ages.

(Slide)

What we find in the juvenile period in cattle is that initial
instabilities that were seen in the neonatal group tend to resolve. They
tend to lessen. We see problems less commonly in this group of animals.
Of all the literature, the 500 papers that Dr. Rudenko talked about, the
total number of clones in all of those papers were about 100 animals.
And in those 100 animals, only three deaths were reported in what
appeared to be otherwise healthy animals. So the numbers are not large.

In one study there was a description that growth hormone and IGF-I
levels were lower in the cloned animals than they were in the control
animals. The growth and general health was reported as normal.

And another study on behavior of cloned animals described their behavior
as normal and that their behavior actually resembles the donor. The dam
had, you get a personality type, and these clone offspring had a similar
personality type.

(Slide)

Continuing in the bovine juvenile node, we see a description of one
cloned animal with lymphoid hypoplasia that died at day 51. Again, this
cloned animal with this problem we do see conventionally bred animals
with lymphoid Hypoplasia as well.

In a study of Japanese Black Beef clones, of the 12 clones surviving the
perinatal period, which is a previous node, all of those 12 were healthy
and normal up to about a year.

In another study there were four clones derived from ear cells of a 17
year old Japanese Black Beef bull and the paper reported that they were
all alive and healthy at ten to 12 months. That the veterinary exams,
growth curves, and 30 day blood parameters were normal, although no data
were provided.

(Slide)

Continuing in the same node for cattle another study reported on 21
healthy appearing clones. And they took physiological measurements.
These calves had an elevated body temperature for a month or two. These
body temperatures were not responsive to non steroid
anti-inflammatories, with no abnormal blood work, per se. We can be
pretty sure these animals did not have some kind of infection causing
elevated body temperatures.

Some of the blood parameters or analytes that were analyzed were
initially unstable. They showed lots of variation and that variation
resolved within a few weeks. The basic clinical chemistries were normal.
And they also ran some hormone levels. IGF-I, IGF binding protein,
leptin, insulin, post prandial glucose. Those all were reported to be
normal.

There were some differences between the clone and the control calves
with their level of thyroxine, leptin, and IGF-II. But the paper
reported that those differences resolved in two weeks.

(Slide)

In summary, from this node of juvenile development, we do see
physiological instabilities. Fewer in this node than the previous. And
those from the previous one tend to resolve by the conclusion of this
time period in the clone's life.

The lab results that were generated showed an appropriate response to
growth and development. There are certain analytes that animals will,
well all animals including me and you, will have differences as animals
grow, as they grow. For example, calcium phosphorous and alkaline
phosphotates, which I will discuss later and you will see later. These
are growth related analytes. And animals with elevations of these are
generally beyond growing animals. And we will see more of that.

And obvious physical anomalies, things that looked abnormal were clearly
identified as abnormal. So, in summary, normal and healthy animals
behave and appear to function normally and are indistinguishable from
their comparators.

(Slide)

The next node is after these animals go through their juvenile
development they then go through puberty, God willing. That is what we
are looking for because we want to breed these animals. They are clones
with superior genetic merit and their job is to produce offspring with
superior genetic merit. So the reproductive system is important.

And as you might be aware, the reproductive system is an extremely
complex set of interactions. And we made the assumption we considered
that if a clone was able to successfully breed, that is it showed
breeding behavior, and actually reproduced, which is to calve or develop
offspring, that that would demonstrate that in the process of cloning
the animal still has maintained appropriate control of this extremely
delicate and sensitive process.

Success at this node indicates to us that the clones are genetically
well integrated because this process, this subtle delicate complex
process, is functional.

(Slide)

With that being said, the data that we have on the reproductive node is
quite limited. There might be a cursory mention, as Dr. Rudenko said
previously, a cursory mention of normal activity at the end of the paper
really designed to look at something else. And they do have this
information they included, but it's not detailed and comprehensive.

There is a paper where there was explicit evaluation of bovine clone
reproductive function. And this one paper reported that puberty occurred
somewhat later in the clones at 314 days on average compared to the
conventionally bred counterparts at 272.

These animals, the cloned animals, had a higher body weight at first
estrus of 336 kilograms versus the controls of 302. The authors
discussed that there is no difference in the cycle length, the average
cow cycle is 21 days, follicular developments and the hormonal profiles
like daily luteinizing hormone, follicle stimulating hormone, E2 is
estrogen and P4 is progesterone. These were similar between the two.

It is important to remember though that this nice data set really
centers on four cloned cows. So we are talking about four animals. The
bottom bullet, which is still readable, three of the four clones were
pregnant post artificial insemination. And four of the four controls
were pregnant post artificial insemination. The number of inseminations
wasn't reported. But artificial insemination, three out of four, is
really not that bad.

There was another report of some Holstein heifers that were cyclic by
ten to 11 months of age, which was in the normal range. We didn't
include that on the side because these animals, some of them weren't
transgenic and we decided we are not going to include transgenic
discussions in this. But, the fact that that was in the normal range is
interesting to me.

(Slide)

There were more reports, again, these reports, more of passing mention
of the reproductive issues. In one five clones were healthy and normal
and described as normally cyclic at one year of age. Cyclic means
showing signs of estus, showing signs of heat.

Our clone named "Gene," a bull, was reported as being healthy, fertile
and having sired calves by artificial insemination and in vitro
fertilization.

Another report of a clone bread via artificial insemination, rather,
conceived and delivered a calf described as normal. And another paper
described two Holstein clones in an abstract. The abstract mentioned
that the first post partum ovulations were delayed. That they had two
follicular waves, two per cycle, which is within the range of normal.
And these animals calved normally.

(Slide)

So, in summary, based on the data that we have, or rather on the review
of the papers available and the literature, we see that clones appear to
develop normally. That puberty was reached at a slightly delayed stage
of life, you know, some larger body weights and by days, slightly
delayed. But the reproductive function that was observed and measured
was described as normal for how it was measured.

(Slide)

The final node that we have and that we have reviewed in the literature
is that of post-pubertal maturation. Concept of lifespan. And that is an
important concept because we all know that Dolly died, was considered at
a younger age than we would have expected for an animal that was
pampered.

But the concept of lifespan for food animals is different than it \--
oh! Also, and Dr. Rudenko discussed the mouse model. The concept of
lifespan in food animals is different. And this may be a review for many
of you, but for those of you who don't understand or aren't familiar
with this, food animals come really in two types. There are brood
animals and there are market animals. Brood animals for breeding and
market animals for consumption.

Market animals are raised until the reach their market weight. They are
then slaughtered for food. This is about at 18 to 24 months for cattle,
and six to eight months for swine.

Brood animals are breeder stock. They are designed to produce offspring
year after year after year, as long as they are capable until they
become either infertile or develop a disease or lameness where they can
no longer perform.

Left by themselves, cattle, pigs, sheep and goats, could probably live
for up to 15 to 20 years, although they are usually culled well before
that time.

(Slide)

The technology is relatively new and few bovine clones have reached an
advanced age to have information on longevity. Also, in the literature
we have no reports of sudden abnormalities arising.

There is a report that a bull named "Second

Chance" \--. Hill reported that Second Chance as a neonate had diabetes
that was treated. The diabetes resolved. And the animal is now three
years of age, has normal body weight, growth, behavior, and as a bull,
all important semen production.

I am at the 10:30 mark. What do you suggest I do? I mean this might be a
good time for a break. I am about to go into the next thing.

(Slide)

The next section, a little teaser for you. My next part of this is when
I actually review the actual data, cattle numbers, health records, lab
data. And it's pretty interesting. I would like you all to be fresh
before I get into it. So, it's time to break. We will see you all at
11:00 o'clock. Whatever the agenda says.

(Whereupon, a recess was taken.)

***Summary Data for Animal Clones - Part II***

***by Dr. Eric Dubbin***

DR. DUBBIN: This is what we were waiting for. In the Spring of 2000, we
encouraged producers to publish data on the health of clones. Back in
the Fall of 2002, we presented our draft risk assessment methodology.
And then in the late Spring of 2003, we had an influx of new data from
the Cyagra company.

The Cyagra company clones cattle, or at least those were the data
provided. And in the data set were physical exams, medical records, and
this part about the laboratory data is key. These were systematically
collected laboratory data. Data collected on all animals based on the
calendar, not based on diagnosing a disease.

(Slide)

Since we received this set of clinical data, we reviewed them in the
context of clinical medicine. And clinical medicine uses something
called the problem oriented medical approach.

The approach is contingent really on an animal having a problem. And you
look at that problem and you take its history. And then you examine the
animal to determine if you can \-- the physical examination findings
will tell you anything more about, tie the history and the complaint
together so that you come up with a diagnosis.

This is also somewhat of an iterative process. We have all these
problems and you are not sure what it is yet, so you then run some
confirmatory tests. This is clinical pathology. So-called blood tests,
chemistry, electrolytes, the blood cells, and urinalysis.

And you use these lab data to help bolster your argument for what you
have done in your physical exam, your history, and your chief complaint.
That is the model under which medicine is practiced.

The point of this slide is that you must understand that lab work by
itself is not a free standing item. It is the context of the animal that
you use to judge the relevance of the lab work.

(Slide)

So clinical pathology, which is a very fancy name for "lab work"
complements the physical exam. It assists in the diagnosis. And lab work
has its downside, I shouldn't say downside, but limitations would be a
better word to put it.

The reference ranges that you use to determine if an animal falls in the
normal category are based on a population that the lab uses for healthy
animals. They take the lab values from health animals. They take the
mean at plus, minus two standard deviations and come up with a list of
normal values with 95 percent confidence. Meaning five percent of the
values you have may be okay, but out of the range just based on chance
alone.

So you can't scrutinize the data that every single thing is out of range
has a whole lot of relevance per se. Also what was the lab's reference
population . Many labs use healthy adult animals.

Another issue with clinical pathology is the concept of artifact.
Artifact is an unexplainable error that is caused by, for example, an
error at the lab, an error in collecting a blood sample, putting it on
the dashboard while you get a cup of coffee, then you take it away.
Artifact happens. Not that I have ever done that.

(Laughter.)

But, again, the point of this slide is to remember that clinical
judgment, the context, is still required when reviewing lab work.

(Slide)

So the data set that we received had 74 samples from clones. That is
split up into ten neonates, defined as less than 24 hours of age. 46
calves from the one to six months age group. And 18 calves from the six
to 18 month group. For a total of 74.

At the neonatal stage, seven calves from that stage survived and we
received blood work at the one to six month stage too. So there is a
repeat of seven calves. From comparators, we had 17 neonates, 47 one to
six months old comparators, and 21 six to 18 month old comparators.
These animals were age matched and very helpful for a reference point of
view.

(Slide)

Again the data set discussed mortality. It discussed physical exams. It
had actual veterinary exam forms. It discussed clinical picture. It
discussed surgery. We saw some umbilical problems, which I will talk
about and describe in detail. And discussed how many animals were for
cull.

So before we look at the clinical pathology data, we want to take a look
at what appears, what I would call the big picture. What all was going
on with these cloned animals.

(Slide)

134 cloned animals had data on them submitted to us. Of these 134
clones, 28 of them were listed as being stillborn or having died or
euthanized by 48 hours of age. 11 calves were described as having died
from after that stage too, and there is typo, that is actually one and a
half years, or 18 months \-\-- were followed up.

The split of the 11 calves that died after that point, eight of them
died in the first month. Three died from one to six months. And none
died after then. You will see that the numbers don't necessarily, the
numbers on this slide add up. But, the numbers don't necessarily add up
everywhere you look. And the reason for that is we received the data in
two sets.

The first set was scrutinized very carefully. It has all of the lab
data. And that is the first 74 calves that were on the previous slide.
We have since received subsequent data on 60 more calves and it's too
good not to \--it's too good to have this, not to use it. But we can't
necessarily put them all in the same context. We don't have the same
level of detail on the last 60 as we do on the first 74.

(Slide)

So in further discussing the mortality listed in the data set, of the 28
that died in less than 48 hours, 11 were stillborn, 12 were euthanized
for abnormal development, defined loosely as sort of different problems,
and contracture means contracted tendons, or bent legs.

Two were actually infected with rotavirus diarrhea, a very common cause
of diarrhea in calves. And two animals succumbed to that. Three died
from unknown causes and their clinical picture is described normal. One
had a thickened placenta and pericarditis. And one had a moist umbilicus
and was depressed.

(Slide)

For the calves that survived over two days, those 11 calves, three of
them had umbilical problems and sepsis from those umbilical problems.
Three of them had gastro intestinal problems described as bloat
adhesions. And the rupture there is, evidently this calf ate some wood
chips and it had a bad reaction to that. And that is hard to attribute
to cloning.

Three of them had circulatory problems described as failure to, various
different types of circulatory problems. Failed to convert from fetal to
neonatal circulation and such. One animal had contracted tendons and was
not responsive to therapy. And one had an accidental trauma. As Larisa
described in the previous talk, it's hard to attribute trauma to
cloning.

(Slide)

So now we look at what kind of physical exams did we have in the data
set. And most of these, well these physical exams were submitted with
this set. And described 11 clones with musculo skeletal abnormalities.

Of these 11 clones, nine of them were described as contracted tendons
and these animals responded to therapy. One was described as having
thick withers, which is the shoulder blade area for those of you don't
know, an enlarged carpus, which is the front knee, and this leg deviated
laterally, which means it stuck out. And she was eventually culled.

And you will see this calf over and over again, because there is lab
work associated with it. And it will be mentioned, so you will get to
know her ear tag number by the end of this, I am sure. And the other
musculo skeletal problem was a dwarf with frequent bloat.

One clone was having described as having early mammary development. And
she was about four and a half months old. That is a little early for a
calf to have mammary development, but I can tell you that I have worked
with heifers for a long time and sometimes that just happens.

Two calves were described as having harsh lung sounds. Three bull clones
were described as having a retained testicle, which is, the term for
that is cryptorchid. And we thought this is awful curious. Maybe this
causes that.

And we further scrutinized the data. We found it was all from the same
donor and seemed to be some genetic link there and that is consistent
with what we think of in clinical medicine.

And one calf was described as having a cardiac arrhythmia. How often do
you have cardiac arrhythmia in calves in the general population? I don't
think a whole lot of calves are auscultated or listened to routinely on
a production operation, so it's hard to get a feel for that. It's not
common, but I have heard it myself.

(Slide)

One of the health issues that we see with this data set and we have seen
consistently throughout previous ones is that there are umbilical
problems. 41 of the 134 calves were described as having umbilical
difficulties. Bleeding, infection, adhesions. Two subsequently had cases
of pyelonephritis, which is an ascending bacterial, I shouldn't say it's
ascending, but it is a bacterial infection of the kidney.

Of these reported 41 problems, 29 of these calves required umbilical
surgery. The extent, whether it's umbilical extirpation, removing an
entire umbilicus, or simply a repair of an umbilical hernia, we don't
have that kind of detail.

Miscellaneous health problems, we talked about the rotavirus. I have
talked about the GI problems. The failure to transition to to fetal
circulation and hypoxia. And the two culls.

(Slide)

Now we have these actual blood. We reviewed the general clinical
picture. What kind of problems are we seeing? We have attribution of
each problem with ear tags so we know who is doing what. Now we have
lots and lots of blood data. How do we organize them? And how do we
decide what to compare them to?

(Slide)

This chart is a little busy, so I will walk you through it. We took data
from three different populations. That is the clone, the age match
controls and the Cornell Reference Lab.

We then compared individual analyte values from one population with the
range in the other populations. Counted the number of analytes that were
outside the range and made the comparison that way.

So, for example, let's look at the top row. For the six to eight month
old group, for clinical chemistry, ignore chart number. That is sort of
internal. 75 percent of the clones had their values within the range of
the reference range. So we would call that a 75 percent agreement,
loosely.

On the next column we compare the clones to age match comparators, and
you see that there is 99 percent agreement. 99 percent of the clones
have their blood values within the range exhibited by the age match
comparators. And we have actual raw numbers for you.

Out of 592 total blood samples, or total values available, 586 of the
cloned animals' values were within that range, which is a \-- that is
more than you would expect by chance alone.

And the final column we compared the comparator population, these are
the non-cloned animals, the regular old calves. And compared how they
stacked up against the Cornell reference range.

You can see that there was a 73 percent of the comparator, regular old
garden variety calves, where their ranges were within the Cornell range.
So you can see that the first and second column are almost identical,
which is that there is equal disagreement of the clones' comparators to
the reference range. But a very high amount of agreement with the clones
and their age matched comparators.

That tells us that we need to be comparing these calves to their age
matched animals. That is how we came to that conclusion.

But this chart illustrates something else that became evident as we were
reviewing the data. If you look at the neonates, and that is the bottom
row, and let's just take for example the hematology, which is the very
bottom row. I would like to thank Joanne for fixing this slide, because
I couldn't make this point without it.

That if you look at the hematology in the middle column, right there
(indicating) that 90 percent of the clone values were within the range
of the comparator values. That is pretty good.

But as you go up the column, you go to the next node, one to six months,
you see that 96 percent of the clone values are within the range of the
comparator values. And as you continue up you see that as, what should
we call them, six to eight months, or almost adults, market age or
getting close to market age, that there is almost 100 percent agreement.

So the other conclusion we can make is that the older the animals get,
the more stabilized their blood work becomes.

(Slide)

So now we have decided what we are going to compare and what we are
going to measure. Now the question is how are we going to present this?
How are we going to analyze it? What is going to give us a good visual,
quick view, and it will be something that is concise so that you can fit
it on one page, but it has to tell you something.

(Slide)

We came up with this approach. This demonstrates how we organized the
data to get an overall view of the sameness versus the differences.
Across the top, we have animal ID. That is an animal ID that we
attributed to the animals. We kept their actual identities or ear tags
to protect the innocent, or whatever. We didn't want them attributable
to that.

So, across the top are the CVM's, our animal identifier. The first
column lists the analytes that are measured, hematocrit, hemoglobin, red
blood cell count and MCV, mean cell volume, and so forth. And then each
black square indicates that for calf number 24, this clone's value for
hematocrit was within the range of the comparator. And when you look at
\-- so that is what the black square means.

What the gray square means is that it is outside the range. Because we
were strict. Boom. Inside/outside within point 01. Whatever it is. If it
was outside, it was not going to be a black square.

But some of these were so close. You know, if you have, let's say, a
glucose of 40 is the low, you have a glucose of 39, you are going to
make that a huge issue, or is that within \--.

So we said if something is within ten percent or within from a
practitioner's standpoint, within clinically close enough, we gave that
a gray box, which still means we didn't ignore it, but we didn't give it
the same weight as something that was truly out of range. Those are the
gray boxes.

Things that are out of range and obviously abnormal, this would be an
elevation, this would say that calf number 108 had an elevation of its
red blood cell count. And then down arrows would be, that is compared
with comparators, and that this calf 108 had an MCV lower than the
comparison population.

Asterisk are missing data. X's, which you will see in coming up slides,
are presumed artifact. We talked about artifact at the beginning.

If you look at the column on the far right, that is a summarization of
all the calves. How many had hematocrits out of range? Zero out of 18.
How many had hemoglobin out of range? Zero out of 18. RBC's out of
range. The term out of range doesn't really specify above or below. It's
just not a square.

And then along the bottom of the summarization is for calf number 24,
for example, how many analytes did she have out of range. How abnormal
was she? What kind of issues was this animal having? If you look, let's
say we look over at calf 108 again, two of her 17 variables measured
were out of range.

When you look at this slide, what we see is that of, and I did a little
math last night. I actually did it long ago, I just reconfirmed it. 294
boxes, 294 values to compare. Three arrows are out of range. That is 99
percent similarity between the cloned population and the age matched
comparators.

If I was to show you a box of say when we compared it to the reference
range, you would see all kinds of arrows and fireworks and things like
that, because there just wasn't a good match and it wasn't an
appropriate comparison.

(Slide)

So what questions do we want these data to answer? Generally, are these
clones and their comparators mostly similar or are they mostly
different? And if they are different, what are those differences.

Further, how do these animals respond to internal stimuli like stress
and growth and developing immunity and you know growth and things like
that. Or versus external stimuli like infection or heat or things.

Can these animals respond similar to their age matched comparators? And
do the blood tests give us any predictor. Is there some sensible blood
test that we could run that tells us, that predicts the future of this
animal?

(Slide)

We did notice some trends. The first trend is that growing animals, well
I will just call it what it is. We saw an age appropriate response in
the growth analytes. Growing animals, both clones and comparators, have
elevations compared to our standard.

Remember we are not going to use it, but it's still instructive to
determine, you see an elevated calcium level that is very high. You say,
oh, my God, what is the matter with this animal. Well, you find you are
looking at a reference range from the lab and not for the age matched.
And if you are age matched, you say oh, they are the same. Well, that is
because clones and controls both respond to the signals for growth by
increasing alkaline phosphotates. Increasing their calcium. Increasing
their phosphorus.

This indicates that the animals' metabolic, both bone growth pathways
are normal. That they are synthesizing Vitamin D. A functioning kidney.
A number of pathways that are responsible for this are functioning.

(Slide)

The second response we see is an age appropriate response in
immunoglobulin. Immunoglobulin is the prime component of globulin, which
is on the chart. That is an analyte that is measured. And it's also a
big word for antibody.

So we see that young calves, both clones and controls will have lower
globulins than their adult comparators. That is because young calves
haven't started producing antibody yet. They are dependent on the
antibody from the colostrum that they consume.

And as the colostrum wanes, their own body has to produce immunoglobulin
and we see in both the clone and the controls that they both do that
appropriately. So as would be expected for animals of this age group, we
see elevations, age appropriate elevations of immunoglobulin.

And to review the data and to actually see that light come on, you go,
wow, that is kind of neat. I wouldn't know what to expect.

(Slide)

So now I am going to go into essentially a blow by blow comparison of
the neonates, the juveniles, one to six month, and the pre-pubertals of
the six to 18 month. Comparing clinical chemistries and the
hematologies.

This is a little \-- well, I will just get to it. We have ten live
cloned neonates. 17 comparators in this chart. Okay. This chart
demonstrates a 92 percent agreement. That is 92 percent of the clones'
values were within the comparator range. That is actually, I stole that
from the slides previous where I discussed with you the numbers it was
based on.

If you look at the chart, I will try to make this fun. But, you will, if
you go down this column (indicating) we are looking for big numbers.
There is a big number. Boy, nine out of ten AST's are low. We see GGT
here. This is a typo. For those of you have the actually things, that is
actually six out of ten. Okay.

We see also the cholesterol is low in four out of ten. That iron has one
low and one high. Two out of ten out of range. And then hBA-random is
bile acids, which is liver, a measure of liver function. And we see here
that there are six out of nine. Nine, because one is missing.

So what does all this mean? We know that AST, cholesterol, bioacids and
GGT are often elevated in cases of liver disease. What does a low GGT
mean? Or a low AST? That is not entirely clear. There is some discussion
that since colostrum is high in GGT activity, that a low GGT may have
cholesterol issues. Well, then I would look to my globulin and I see my
globulin, which is antibody from colostrum, that globulin is right
there. My God, they are all normal. Normal globulins.

So I looked into it and found that there was one control calf that had
extremely low globulin. So that could have just been a spurious finding.
And that is one of the limitations of this type of comparison. Spurious
finds can affect the limits of what is considered normal.

So that is a summary of the out-of-range analytes. Mostly liver related.
Some of them may be colostrum related. I can speculate as to why these
liver values are low, but I won't do that. This isn't the place. You are
going to have to wait until the book comes out.

The calf here, 43, we see she has four analytes out of range. Low
bioacid, low cholesterol, like they all seem to do. And low chloride.
This is one of the calves that died of rotavirus.

Calf 79, you will see her later. In fact, you will seven of these later
because we have two time points and I will wait to discuss them then.

(Slide)

And hematology we see 90 percent agreement between the clones and
controls. 90 percent, still pretty good. Not as good as it gets as they
grow older.

If we look at the summary column, how many calves had analytes out of
range. And we see three calves had low lymphocytes. One of those calves
had rotavirus and died. Another calf with low lymphocytes had rotavirus
and survived. So there is no predicative value there.

Two calves had platelets out of range. What does that mean? The high one
died from diarrhea and the low one survived all the way to weaning.

(Slide)

So to summarize the neonatal data, that is a real brief overview. There
is a lot more to discuss, but I don't think this is the time and place
to get into the nitty gritty of each individual animal analyte, although
we do do that.

But to summarize what we found in the neonates, there were ten clones.
Two of which died. There was

92 percent similarity for the clinical chemistries and

90 percent for the hematology.

We did see liver enzymes that were different. And just to give you a
peek of the next node, those liver enzymes do normalize by the next
node. These animals do show the appropriate growth responses, both in
their growth analytes. I don't like to use, that word factor is wrong.
It should be analyte. And that was a typo that I didn't get a chance to
correct.

But the growth analytes and the immune analytes do show the expected
response for animals of that age. And as far as predictability is
concerned, showing you which animals had analytes out of range, that
didn't give a whole lot of predictive value. Remember that these
laboratory data still must be taken in the context of the whole animal.

(Slide)

Now this table is huge. We have 46 clones and 46 comparators. This is
the next node. The one to six month old group. And understand that a one
month old calf and a six month old calf, even though we have grouped
them together, are still \-- oh, boy. They still aren't identical.

So if we look at this chart, we can see, I will tell you what, I am just
going to walk \-- I am not going to point to the chart. It's in your
notes. But I will just describe.

The calcium, phosphorous and alk phos, growth related, still elevated.
Those tended to be the calves in the younger end of the group. We do see
creatinine out of range. I want to talk about it because people say why
do you ignore it. Well, it's low. What is the relevance of a low
creatinine? I don't know. I am not sure anyone knows in this context
what that would mean.

There are some low total proteins. Some are high and some are low. And
we see total protein on this chart, which is done in a chemistry
machine, the next chart is done by a refractometer and different calves
have values out of range. Once again indicating the limitations of what
your lab can do. Lab work isn't gospel. It's subject to interpretation.

I do want to point out that \-- well, those are the big findings for the
chemistry.

(Slide)

The hematology, it's interesting to note that none of these animals like
previously had a problem with their red cells or their white cells.
There is no anemia. No leucopenia or low white counts.

We do see on this slide that the mean cell hemoglobin concentration,
MCHC, four have of the 44 measured are elevated. Four red cell
distribution widths. I am sorry, three of 44, RDW's are elevated.

Now these analytes indicate red cell maturation, unusually used to
describe an anemic animal. What would cause the anemia? What do you do
with these values with an animal that is not anemic?

There are four of 44 in elevated basophiles. Basophiles are associated
with histamine and allergy. And what do you with just this alone, with
no clinical signs? It's hard to say what to do with these stand alone
numbers.

Mean platelet volume. Nine out of 41 are elevated. Mean platelet volume
is machine measured and it can be artificially elevated by clumping. I
don't know that, but side evidence from the slide that the pathologist
said that the morphology was good and the numbers were adequate and the
morphology was normal.

I do want to show that one calf, calf 100, right there (indicating.) See
calf 100? Two out of 16 analytes are \-- this is the only one that had a
real high white count. Like 26,000, I think, is what it was. This calf
had a raging umbilical abscess. Here is a calf with a disease responding
normally.

Remember in this group we don't see a whole lot of diseases. So we take
what we can get.

(Slide)

To summarize this group, 46 clones have blood work. There was 96 percent
agreement. Three in this age group, some of which remember we got a
second group of calves with no blood work. Of all the calves in this age
group only three of them were reported to have died.

96 percent similarity. Expected elevation growth analytes. And glucose
compared to the comparators. I do want to mention four animals from the
same cell line, one died of large offspring syndrome. This is not in the
blood data. This is in the health data. But it's instructive.

One died of LOS. One at about five months of age weighed 282 pounds. One
same age, 197. There is 90 pounds difference. And another one the same
age at 215, 20 pounds more. So we have one cell line with four, one
different outcome and three different phenotypes. And that is helpful to
understand what we can expect from this technology. And I already talked
about the cryptorchid calves.

(Slide)

This is a discussion of the seven clones that were present, we had data
on from both the neonatal node to the one to six month old node. I have
already discussed some of this. Just remember that there was liver
values. We discussed whether that was low liver values have no known
real cause. And then the colostrum deprivation.

(Slide)

We have one calf that had low lymphocytes and platelets. And that calf
normalized by one t six months. Calf number 79 had a number of analytes
out of range. And without going into great detail, we see that the
analytes analyzed at the neonatal stage actually corrected by the
juvenile stage, but had other problems at the juvenile stage. It was
eventually culled. This calf did have some problems.

(Slide)

When we look at the one to six month old group of those seven clones, we
see some interesting things. Four of them had real elevated glucose.
These were not within ten percent. We could not explain it that way. We
had to look into why.

When we looked at the urinalysis, we saw that there was no glucose in
the urine indicating no sustained elevation of glucose. We attribute
this probably to stress. If you have ever tried to pull blood from a
cow, they just don't just stand there and hold their arm out. So you do
sometimes see spikes in glucose in relation to distress.

Again, the alk phos and phosphorus. These animals were on the younger
end of the range, which were growing more.

The increased A/G ratio indicates low globulin. Again, these were like
six week old animals with internal antibodies dropping and endogenous
hadn't started up yet. Some with decreased \-\-- gap. And we don't know
what that means.

So these out of range values for this seven calf subcohort do not
indicate consistent trends other than what you would expect normal
physiological changes.

(Slide)

In summary, one out of range neonatal values improved by the one to six
months, the out of range values just described for the one to six month
old group. In context, when you look at the context, we are not
clinically of concern. And one of these animals was cloned, or was not
cloned, but culled later.

(Slide)

This is a discussion of the last group of data. The oldest one, six to
18 months of age. There were 18 clones in this group and 21 comparators.
There is 99 percent agreement between the clones and comparators. Again,
we \-\-- more would be, disagreement would be expected on chance alone.

I do want to mention three analytes that are actually within range, but
they have gray boxes. And I don't want to give them short shrift because
Dr. Rudenko discussed IGF-I and estrogen prior. We ran these analytes
and we do need to discuss them briefly.

If you look at the bottom last two rows, IGF-I has none that are out of
range but we have five gray boxes for IGF-I. I am sorry, that is four
for IGF-I and five for estradiol. IGF-I, it's slightly increased. It's
within ten percent of variation and one thing to keep in mind is to
speculate that these are animals of superior genetic merit. These
animals are designed to grow better. That may be involved.

The other thing to consider is IGF-I fluctuates. Its hormones are
released in a pulse. And you can have issues like that influencing. But
the value is very close.

With estrogen, the value is higher than the comparators but not higher
than say in the reference labs. Now, we already discussed that we want
to use age match comparators.

But the next step back from that is what other things can you compare
them to. And these estrogen levels are within that range. And estrogen
itself also has variability. It's pulsatile release. Its relationship to
the onset of puberty in these animals. We don't have that information to
determine if that is involved.

The other one I just want to mention, because there are a lot of gray
boxes is creatinine. And creatinine, there are seven gray boxes there.
They were all like, instead of 2.0, it would be 2.1. So close as to be
irrelevant clinically.

(Slide)

And the hematology, again we see 99 percent agreement. And we don't see
a whole lot of problems here. We see two calves with, two clones with
low MCV. And we see one calf, 108 here, MCV is mean cell volume. In the
context of no anemia it is hard to draw a lot of conclusions about what
that means on its own.

In calf 108 you see two out of 17 problems on this slide. On the
previous slide we saw five that are analytes out of range. And this calf
ended up being described as having been a dwarf and having frequent
bloat and was ultimately culled.

(Slide)

So to summarize this set, 18 clones, none of the animals after six
months died. We have 99 percent similarity and the IGF-I and growth
hormone were only slightly elevated but within published physiologic,
published ranges and physiological ranges.

As far as response to disease and predictability, well there was no real
disease and nothing to predict.

That is the summary of the data set from Cyagra for bovine. Now I do
have pigs and goats to talk about. And I will go through those next.

(Slide)

In 2003, Archer set out to determine what kind of variation is there
within a population comparing clones to conventionally bred pigs. These
animals were genetically the same age, breed. They were sex matched. In
fact, they were half sibs. They were very closely related.

(Slide)

The first thing that this paper, the researcher did was look at their
behavioral traits. They measured their food preferences, their
temperament, and time budgets, which a time budget is defined as the
amount time spent engaged in a particular activity in their pens.

They determined, the conclusion was that the behavior was no more
homogeneous than between siblings. There was a lot of variation. And
they behaved as conventional animals. That is to say that there was no
behavioral abnormalities.

(Slide)

They then went on to discuss physical traits to determine when comparing
clones and controls. For body weights they found no differences. That 27
week old clones and control animals were about the same age and within
the range for that breed.

As far as phenotypic variation, the teat pattern would be six on one
side and six on the other for most. One had six on one side and seven on
the other. And that is also within the range in a normal pig.

For skin, there was hair growth pattern. One had a unique hair growth
pattern with coarse hair. And I will show you a picture of that. And one
had hyperkeratosis, or thickened skin as seen on histology. The paper
doesn't mention if those were the same pig.

(Slide)

But if you look at this picture, you can see this pig with coarse hair
and this pig with smooth hair. And those animals are from the same
genetic line.

(Slide)

So that is an example of the phenotypic variation seen with animals with
the same genotypes. So we see also that large and small clones are side
by side. Again, same donor cell. And the smaller clone in the next
picture I am going to show you never reached the weight of the size of
the other clones.

(Slide)

And these two clones are from the same donor and they were farrowed,
that is born, by the same dam. You can see these. Again an example of
identical genotypes displaying different phenotypes. I discussed this,
the Cyagra data, with those four cows, one of which died of LOS and the
three others with different phenotypes.

(Slide)

We also had blood work which we reviewed they submitted. And this was
nice because this confirmed what we saw in the cattle, which is if you
look at Alk phos, not calcium for some reason, but phosphorous, those
two analytes were elevated in the young animals that were rapidly
growing and dropped off at appropriate levels as they got older.

And we see the same thing with globulins. This is a measure of immune
function that young animals have lower globulin and they get higher as
they get older. Same with the clones as the controls.

(Slide)

So in summary, in pigs, the clones and the comparators are relatively
indistinguishable. Via either lab values or with behavioral studies. We
see appropriate response in growth analytes and appropriate response in
the immune status, globulins and such.

We don't have the data on sheep. So I will skip those and go to the next
species, which is goats.

(Slide)

In a study, 27 transgenic and 70 non-transgenic goats, embryos rather,
were implanted into 13 recipients, an average of seven embryos per dam.

Of those five were confirmed pregnant at day 35. Of those five, four of
the recipients delivered five male kids and one recipient delivered one
female kid.

(Slide)

The birth weights and cotyledon numbers were not significantly different
from naturally bred goats at the same facility. Of the six goats that
were derived from this process, three of them died. One at 24 hours, one
at one month and one at three months. And those all died of respiratory
infections.

(Slide)

In another study we see 91 embryos implanted into eight recipients. Four
were pregnant at day 30 and delivered 7 female kids of which one died at
birth. 54 male embryos were implanted into six recipients. One was
confirmed pregnant and that confirmed pregnancy maintained and delivered
two male kids. One died at birth.

The point of this slide that all of the goats maintained pregnancy to
term, which is something that goats seem to be particularly good at.
Again, it's species difference that goats have.

(Slide)

The average birth weights were similar. And the average cotyledon number
was similar.

(Slide)

Half of the goats had poor suckling reflex and they were fed by
orogastric tube and that responded by day two, or resolved rather by day
two. These clones were described to appear healthy. The routine blood
profiles were monitored and described to be normal by one year of age,
although no data were submitted on that, I don't think.

And they described that these kids were within normal ranges for normal
growing Nigerian Dwarf kids.

(Slide)

In summary clones that survived the first few critical days of birth are
mostly normal and healthy.

(Slide)

The anomalies aren't qualitatively different from other assisted
reproductive technologies but there is an increased frequency. In the
perinatal node we see mortality, placentation, large offspring and such.
We don't see that this is necessarily common across all species.

In the juvenile node, we see less problems. Remember we talked that the
hormone levels are similar and the behaviors are similar. Mortality is
lower in the juvenile node.

In the reproductive and maturation nodes, there are no apparent
problems, although the data are sparse. And the growth parameters and
the fertility between clones and comparators are very similar.

Next I would like to introduce to you Dr. Amey Adams. She will discuss
what the data we have discussed tells us, what we can conclude on animal
safety.

***Conclusions for Animal Safety***

***by Dr. Amey Adams***

DR. ADAMS: Good morning. My name is Amey Adams. I am an animal scientist
and I work with Dr. Dubbin in the Ruminant Drugs Team at the Center for
Veterinary Medicine. And I will be talking to you today as he indicated
on the risk conclusions that we drew on animal health based on the data
that we had available.

(Slide)

And I will just remind you of Dr. Sundlof's introductory remarks. The
question that we started out with was whether or not the risks
experienced by animals involved in the cloning process differ
qualitatively from those experienced by animals undergoing other
assisted reproductive technologies.

We have all heard reports of increased incidents of health problems in
young clones and their surrogate dams compared to natural breeding. But
how did that compare with other artificial, I am sorry, assisted
reproductive technologies such as artificial insemination and in vitro
fertilization. Were they different in kind or were they different in
frequency?

(Slide)

Both Dr. Dubbin and Dr. Rudenko walked you through this slide. I won't
spend a whole lot of time on it for that reason. But just to show you
that we had slightly different interests when we looked at animal
health, specifically.

In the cell fusion through fetal development phase, as Dr. Rudenko and
Dr. Dubbin mentioned, this really sets the stage for the perinatal
period and the subsequent development of the young clone.

It also is, particularly in mid to late gestation, a time when we were
concerned with questions regarding the development of hydrops, which is
a late pregnancy condition that occurs in cattle and sheep. Whether or
not if in fact the fetus is not viable, whether the cow or sheep is able
to expel that fetus normal and return to cycling and normal reproductive
activity.

Then in the perinatal period we were interested in, we had concerns
about large offspring syndrome, as well as hydrops and dystocia. So we
looked at birth weight, the dam's readiness for delivery, the onset of
lactation, and mothering behavior, and newborn organ function and IGF-II
levels in the newborn clones.

And for the juvenile clones and for the later stages we were mainly
interested in the continuing development of the animal, of the animal
clone. How well it matured. Whether it came into puberty normally. And
it's continued health following those early stages.

And we also looked for information on the progeny of clones. And I will
just point out that as we progressed past the perinatal period, the data
became more and more sparse.

(Slide)

So just in general, these are the life stages and the animals that we
are looking at for the assessment of animal safety. And we will begin
with surrogate dams.

(Slide)

And as we sorted through the literature it became apparent that
different species experience different outcomes. As Dr. Dubbin pointed
out, we have a large data set on bovine clones.

Very little quantitative, if any quantitative, information on sheep. But
the qualitative reports that we have on sheep are consistent with what
we see in cattle and so we have grouped those two species together.
Whereas, goats and swine seem to experience much fewer problems.

And the studies that we reviewed indicated that there is an increased
risk of mid to late gestational complications such as hydrops, which is
a condition that involves edema of either the fetus or the fetal
membranes. Dystocia, which is difficult labor or difficulty giving
birth. And a few other reports of very few observations of other types
of complications, which I will discuss in a moment.

(Slide)

Hydrops, for those of you who are not familiar with the term, it's a
collective term referring to the excess build up of fluids in the fetus
or the fetal membranes. It is a rare condition in naturally bred and
conventionally bred cattle. It occurs at about one in 7,500 pregnancies
in the general population of cattle.

It is more common in in vitro fertilization, occurring at a rate of
about one in 200 pregnancies or

one-half of one percent of in vitro fertilized pregnancies in cattle.

Now because this condition is so rare in the general population of
cattle we realized that the majority of large animal veterinarians will
not have had experience in dealing with a hydrops pregnancy. And for
this reason we decided to contact some of the clone producers to discuss
with their veterinary staff their experiences with hydrops, both in
terms of its frequency of incidences and the pathology of the condition.

And one of the things that they indicated was that this condition can be
detected as early as the sixth month of pregnancy in cattle. Cattle
undergo a nine month pregnancy. So it would start to show up usually
late in the second trimester and from there on.

(Slide)

Another thing they indicated to us was that the degree of severity of
hydrops varies from mild to severe. Some cows will experience mild
hydrops. It does not pose a risk for either the fetus or the cow. She
goes through the pregnancy normally and is able to deliver a viable
calf.

On the other hand, there are cases of severe hydrops. They have been
reported in the literature. And if it does in fact progress, becomes
worse, and the pregnancy is not terminated, it often results in the
death of both the fetus and the dam.

The incidence we found as we reviewed the literature and as we talked to
cloning companies, the incidences are highly variable among
laboratories. And can range anywhere from as low as one-half of one
percent to as high as 15 to 17 percent, depending on what study you are
looking at, what laboratory you are looking at.

The data do indicate and the clone producers agreed that the risk of
hydrops is higher in clone pregnancies compared to in vitro
fertilization pregnancies.

And I just point out here that the Pace, et al, study, some of those
cows were carrying transgenic clones. But in pregnancies that survived
beyond 60 days, and there were 178 of those, 30 of those cows developed
hydrops.

Other clone producers that we spoke with indicated that the incidence
was as low as one in 200 or one in 300 pregnancies. So considerable
variability there.

(Slide)

And dystocia is a problem that occurs in all species of mammals. And
it's just difficulty delivering the calf or delivering the fetus. It's
most often caused by fetal oversize compared to the dam's pelvic
opening. It can also be caused by malpresentation, such as a breach
birth. Or in the case of twins or other multiples, when you have
simultaneous presentation.

In conventionally bred cattle, both dairy and beef, the incidence is
about four to six percent. And in sheep it's quite a bit higher. It's
actually ten to 30 percent depending on the breed.

(Slide)

In clone pregnancies dystocia is often the result of fetal oversize. As
we mentioned before large offspring syndrome, which I will get into when
I discuss the neonate. It is a problem for the dam because it can get
result, depending on its severity, it can result in retained placenta,
uterine infections. Can cause permanent damage to the reproductive
tract. It can even cause musculo-skeletal damage.

And in those last to instances, this could compromise the animal's
ability to return to the herd to reproduce. She may be culled due to
reproductive failure or other injuries.

And incidence of dystocia in clone pregnancies, as I mentioned, is
associated with the large offspring syndrome because these calves are
not able, are so large they can't pass easily through the pelvic
opening.

(Slide)

Some less frequently noted complications, and we don't have really any
numbers to go along with this, are poor or absent mammary development.
Absence or atypical signs of labor, also known as uterine inertia.
Agalactia or failure to lactate. And impaired maternal behavior.

These are more of a complication for, or a problem for the neonatal
clone than they are necessarily a risk to the dam. Although they are
happening to her, it has greater implications for the newborn.

If the cow fails to lactate that has implications for the calf's ability
to obtain colostrum, which is the source of passive immunity, it obtains
from it's mother. It also has implications for the calf's early
nutrition.

And it is also very important for the dam to interact appropriately with
the newborn calf or lamb by licking it, stimulating it to breathe, to
stand, to suckle and to form that maternal bond.

(Slide)

It is interesting that in goats and swine we have no reports of
complications in surrogate goats. And no reports about a hydrops or a
large offspring syndrome in either goats or swine surrogate females.

There have been some reports, based on our discussions with clone
producers and one study on clone transgenic swine, of lack of mammary
development, failure to lactate, and uterine inertia. And as I mentioned
those last complications are more of a problem for the neonatal clones
than they are necessarily a risk to the dam herself.

(Slide)

Let's talk about large offspring syndrome for a minute. Dr. Dubbin
touched on this. It was reported, it has been reported in in vitro
fertilization, blastomere nuclear transfer, which is early embryonic
clones, as well as somatic cell nuclear transfer clones of cattle and
sheep.

It's typically characterized as the fetus or newborn, which has a body
weight greater than 20 percent above the average weight for its breed
and sex. It's often accompanied by respiratory complications.

Sometimes the lungs are immature. They fail to inflate. Or, in case of
dystocia, the calf may wind up inhaling amniotic fluid, which sets the
stage for pneumonia later on.

There have been some internal organ defects reported, particularly the
heart and kidneys.

Musculo-skeletal defects, including tendon retracture and some joint and
skull malformations. And the calves are often slow to stand. And have a
poor or absent suckle reflex.

(Slide)

Large offspring syndrome increases the risk of dystocia. As I mentioned,
a large calf is going to have a hard time passing easily through that
pelvic opening in the dam. This is a source of stress to the neonate as
well as being a problem for the dam.

And it increases the risk of mortality and morbidity. Due to premature
separation of the placenta the calf is deprived of oxygen. It may be
forced to try and breathe and winds up aspirating or breathing in
amniotic fluid, which sets it up for respiratory complications later on.

(Slide)

Some of the complicates related to LOS are reversible depending on their
severity. Tendon, flexor tendon contracture, which is commonly noted in
these calves often resolves on its own or in response to therapy. Also
respiratory conditions are often amenable to treatment with supplemental
oxygen.

The incidence of LOS is also variable among the labs and can range
anywhere from eight to 50 percent depending on what study you are
looking at. And just to compare that to large offspring syndrome in in
vitro fertilized calves, they also have quite a wide range.

Anywhere from seven percent in an early study by Hasler, et al. And up
to 31 percent in the Kruip and den Daas study, which was a survey of
several European countries and a variety of assisted reproductive
technologies.

(Slide)

Based on the information that Cyagra provided us, the critical survival
period appears to be the first 48 hours after birth. Now the neonatal
death rate, and it's interesting whether we are looking at transgenic
clones or non-transgenic clones, the neonatal death rate in cattle
appears to be around 20 percent during that first 48 hour period.

In the IVF studies that were conducted in the

mid-90\'s, the range was 14 to 16 percent during this same period of
time.

(Slide)

Now we have far fewer data to look at in goats and swine. We have two
reports that were published which indicated mortality in neonatal goat
clones. They were both conducted by Dr. Keefer.

One kid that succumbed to a respiratory infection at one day of age. And
two kids that died during the process of labor. These were both twins.
Two surviving clones. We don't have any more information on those
animals.

There are few reports of complications in neonatal swine. Both Polejaeva
and Walker, et al., reported low birth weights, but it was just a
mention in passing. The actual frequency of these low birth rates was
not reported.

And we only have one report of physical deformity in a non-transgenic
cloned pig that was one out of 28 pigs, which was born with anal
atresia, which is the absence of an anus.

Now these problems have been noted in conventionally bred goats and
swine as well. But again because the numbers are so few, we really don't
have a way of comparing to decide whether there is any difference
between the incidence in clones versus the incidence in conventionally
bred animals of these species.

(Slide)

Let's move on to the juvenile period. And just generally speaking across
species for juvenile clones, most reports indicate normal growth and
development following the neonatal period.

The behavioral studies that have been conducted in cattle and swine note
no abnormalities. And results of blood tests, I mean we actually had
several papers on that as well as the Cyagra data set, indicate that
cattle and swine in this age group are mostly within the range of their
conventionally bred comparators, animals of the same age.

(Slide)

For cattle, this is mainly from the Cyagra data set where we actually
had some individual animal data, a few animals were reported to have
health problems. And most of these seemed to relate to congenital
problems that were observed at birth related to large offspring
syndrome.

There were two animals that had flexor tendon contracture that did not
respond to therapy. A calf diagnosed with failure to \-\--. GI tract
problems. Heart abnormalities.

But what really stood out to us was the large number of umbilical
surgeries that were conducted in this period due to enlarged umbilical
hernias and the like. There were 29 of those out of 134 animals.

(Slide)

Again, the data in goats and swine is rather sparse. We have one report
of two goats that died of respiratory infections during the juvenile
period. And one report, as Eric discussed, of hyperkeratosis in a swine
clone.

Both of these may be related to management. We know that respiratory
infections are a problem in goats. Hyperkeratosis most often is related
to a nutritional imbalance.

(Slide)

There are some other complications which may be associated with the
genetics of the donor. Eric, Dr. Dubbin, discussed these in brief.
Cryptorchidism, all of the calves from the same bull, from the same cell
line. And dwarfism. Both of these are problems that are related to a
recessive gene in cattle.

Hyperkeratosis in swine, I mention this same pig, because we really
don't know very much about the diagnosis and when it took place or
anything about the nuclear donors. But there is genetic recessive gene
that causes what is called dermatitis vegetans, which is a type of
hyperkeratosis in swine.

(Slide)

So for the puberty and reproductive maturity period, again, for pubertal
cattle, we didn't have any data at all on sheep, not even qualitative
data for sheep. So I will just talk about cattle for this period.

No health problems were noted. The data from Cyagra indicate that blood
chemistries in animals in this age group are normal. Most reports
indicate that heifers reach puberty, conceive and deliver healthy
calves. Again these are just cursory statements. Not a lot of
information there.

There was one study by Enright, et al., based on four cloned heifers
which indicated that these particular heifers reached puberty at a
slightly later age than their age match controls. But they were within
the normal range for their breed.

We don't have any detailed information on bulls. There have been a
couple, again, cursory mentions that bulls were noted to produce semen
and produce offspring. That is about all we have on that.

(Slide)

For other species, we have one report each on fertility of rams and buck
clones, male sheep and male goats, indicating that they were normal at
the age of puberty. And the Gauthier study in particular of goats looked
at fertility and sperm quality measurements and found those to be the
same as their age matched comparators.

And we have one report of a goat doe clone that conceived and delivered
normal offspring. No reports so far on reproduction in swine clones.

(Slide)

On maturity and aging, this is where we start running out of information
on livestock. Basically because not enough time has passed to be able to
evaluate this in these animals. We have several studies on aging in mice
that we looked at. One noted shorter life spans and increased health
problems in older mouse clones.

We also looked at studies of telomeres. And telomeres are sections of
DNA which are thought to be an indicator of aging because they shorten
as the animal grows older. Well we found that these studies were often
conflicting. Dolly was reported to have the same length of telomeres as
her six year old nuclear donor.

Studies in cattle have indicated that the cattle have telomeres that are
the same length or longer than their age matched comparators. And one
study by Kubota, et al., indicated that it depends on which tissue you
look at what the length of the telomere is. So we felt that it probably
was not a very good predictor of lifespan.

(Slide)

For offspring of clones, again we are very sparse on data. Mostly just
cursory reports that state, yes, they had offspring. They are normal and
healthy. No details available in farm animal species.

So, again, we looked at reports for mice. And we have two of them that
indicate that there were some abnormal clones that they bred. In the
case of Shimazowa, et al., they took clones that were born with their
eyes open that were abnormally large and had abnormally large placentas.
They bred them. They had normal offspring. The offspring were born of a
normal weight. They had normal placentas. And their eyes were closed as
they should be.

And the Tamashiro, et al., paper looked, again this was the obese
phenotype that Dr. Rudenko mentioned. That the clones developed. They
did not pass this phenotype onto their offspring.

(Slide)

So just to conclude, and again, I have broken these out into the species
because of the differences that we see across species. The critical
period appears to be late gestation through the first post-natal days
for both the surrogate dams and the clones. This is the time period with
the highest incidence of health problems and of mortality.

The risk of perinatal morbidity and mortality are higher in clone
pregnancies compared to other assisted reproductive technologies. Most
clones that survive this period appear to be healthy and similar to
conventionally bred counterparts. And so far no abnormalities have been
reported in the offspring.

(Slide)

For swine, we have a few reports of complications in surrogate sows.
They do not seem to be a risk to the dam. We don't believe them to be a
risk to the dam. Although they might be a problem for the neonates.

We have one report of deformity in a clone pig, anal atresia. It has
also been noted in conventionally bred swine. And so far no reports on
reproductive maturity of clones or the health of their offspring.

(Slide)

For goats, no complications noted for surrogate does carrying goat
clones. Very few health problems noted in the goat clones themselves.
Two deaths during labor. And three deaths due to respiratory infection.
They appear to have matured normally and produced healthy offspring.

(Slide)

So overall we would have to say that all the complications that we have
seen have been reported in studies of other assisted reproductive
technologies, particularly in vitro fertilization. The frequency of the
anomalies is increased relative even to in vitro fertilization.

The adverse outcomes that we have observed are more frequent in cattle
and sheep compared to swine and goats.

(Slide)

So just to remind you of the question that we posed to our advisory
committees is based on what we have presented, has the risk assessment
that we have done adequately identify the hazards and characterized the
risks relating to animal health.

And with that, I will turn it over to Dr. Rudenko to discuss food safety
consideration.

***Conclusions for Food Safety***

***by Dr. Larisa Rudenko***

DR. RUDENKO: Well it stands to reason that the talk on food consumption
comes right before lunch.

(Laughter.)

(Slide)

DR. RUDENKO: I want to remind the Veterinary Medicine Advisory Committee
that we do have a question to pose to you, just as Dr. Adams posed to
you. So the cloning risk assessment asked the following question. Are
the edible products derived from animal clones and their progeny as safe
to eat as the edible products derived from their conventional
counterparts?

And what we are asking you, in particular, is based on what we have
presented, has the risk assessment adequately identified the hazards as
we have defined them and characterized the risks, again as we have
defined them, related to food consumption?

(Slide)

I just need to remind you one more time what the criteria and
assumptions are that we are using in this evaluation. And then given
that we are running quite over time, I will go through these rather
quickly and get straight on into our preliminary conclusions.

(Slide)

Remember we dealt with a two-pronged approach. Two prongs are
interdependent but address food safety from two different perspectives.
One asks the question whether or not one assumes that healthy animals
are likely to produce safe food. And the other one asks questions about
the comparability of the composition of the food relative to
corresponding products from conventional animals.

Remember that unlike the animal health assessment, the critical
biological systems approach for food safety is looking for subtle
hazards. We are not looking to see whether an animal is frankly deformed
because our assumption is that just as conventional animals, those
animals will not enter the food supply. So, we are looking for subtle
hazards in these animals.

The compositional approach, of course, considers the available data.

(Slide)

Again, I want to remind you that this is a qualitative comparative risk
assessment. We are not looking for a specific numerical value associated
with risk. I will remind you that the certainty of safety is always
approached but never reached. Our goal is to get as close to certainty
as possible, always to be protective of the public health.

And that the strongest statement that we can issue in this risk
assessment, because it is a qualitative comparative risk assessment, is
that something is as likely to be as safe as, where our comparator is
conventional food animals.

And, again, so what does that mean? We are looking to see if the food
from animal clones is as safe to eat as the food that we eat everyday
from conventional animals.

(Slide)

We will present the conclusions just as we presented the methodologies,
species by species, except for bovines where we have the largest data
set where we will talk about a couple of life stages.

We will present to you a weight of evidence evaluation, summarize the
empirical observation. Make a comment about consistency with other
species. Try to identify what uncertainties we can. And give you some
indication of the level of confidence we have in those conclusions.

(Slide)

Okay. Remember that our underlying biological assumptions are that food
animals do not produce toxins. There are no introduced genes from other
sources. As I previously said, obviously malformed or diseased animals
are culled, do not make it into the food supply.

We are looking for subtle hazards. We have agreed that perinatal clones
may be quite fragile. And the other biological assumption that we have
that is backed up with data from a model system is the gametogenesis.
The process of creating sperm in egg in sexually reproducing animals may
clear the genome of inappropriate signals, reprogramming signals that
may result from somatic cell nuclear transfer.

(Slide)

So when we looked at the first developmental node, which was a cell
fusion and fetal development, we came to the same conclusion that Dr.
Adams came to for animal clones, which is that this stage sets the stage
for further development. But by itself it's difficult to extrapolate
from results that we may have observed here to food consumption risks.

We know that the probability of implanted embryos developing to
viability is quite low. But it appears to be improving as the technology
becomes more common place.

The animals are at high risk, developing animals are at high risk, as
can be their surrogate dams depending on the species.

We know that the lack of success here is likely due to two factors. One
may be technology. It may damage the oblast or the donor as you are
doing the injection or the fusion. And there are also biological reasons
for this, such as the incorrect reprogramming of the donor genome.

(Slide)

Now we go on to a species specific analysis. And let's start with
perinatal bovine clones. We will ascend in age to adults. Our
preliminary draft conclusions stated in the draft executive summary are
that perinatal clones may pose a limited risk for consumption as food.

The empirical data on which we based this conclusion is the consistently
reported relatively poor condition of these animals at birth and the
relative instability of their physiological parameters.

That doesn't mean we think they truly are a risk. But we cannot, based
on the data that we have available at this point, say that those animals
are indistinguishable from their comparators. And, therefore, they may
pose some small risks.

I want to make the comment right now that will be constant through the
rest of this analysis, and that is that we at FDA do not assume that any
clones will be primarily directed to the food supply. These are
expensive animals. They are difficult to produce. And therefore they
become extremely precious to both the producers and the breeders.

So it is unlikely that these animals will actually enter the food
supply. What is much more likely is that these animals will be used as
breeders and the progeny will enter the food supply.

So even though we go through the systematic analysis of clones
themselves, we want you to understand again that the probability of
these animals entering the foods supply is relatively low.

(Slide)

Now to go on to juvenile bovine clones. For this case we believe that
edible products from juvenile bovine clones are likely to be as safe to
eat as those from

non-clone juvenile cattle. We base this on the survey of the data that
Cyagra presented to us. And the consistency with the peer reviewed
literature.

Juvenile clones tend to be largely health and normal. They exhibit
appropriate physiological responses to developmental signals. And the
early physiological instabilities that we have seen in the perinatal
animals tend to resolve over and within this time period.

We were not able to detect any food consumption hazards in the
biochemical parameters that we investigated here. Either in the Cyagra
data set, the studies from Chavatte-Palmer, in which you saw levels of
IGF-I, IGF-II, thyroxin, and so forth, all resolved by the latest 50
days of age.

In the Archer studies of the pigs, in which all of the animals showed
age appropriate developmental signals, and no biochemical parameters out
of range with their passive related comparator animals.

(Slide)

So we have consistency here with the biological assumption that clones
will use the juvenile period to resolve any instabilities that occur
physiologically. Consistency with other domestic livestock species. That
is cattle and pigs. And consistency with the mouse model as well.

We have relatively few uncertainties about this time period. The data
set is relatively large. Due in large part because of the rather large
data set we have in the literature on cattle and this time period as
well as the Cyagra data set. And it is entirely consistent.

So therefore our confidence in this estimate is relatively high. And the
comment that we would like to make again here is that these animals are
unlikely to be primary producers of food.

(Slide)

Finally getting to adult bovine clones. Our preliminary conclusion here
is that edible products from adult bovine clones are likely to be as
safe to eat as those from non-clone adult cattle. Again, the empirical
basis on which this conclusion arises stems in large part from the
animals from the Cyagra survey where healthy adult clones were virtually
indistinguishable from the comparators.

All of the earlier physiological instabilities in the populations of
animals have been resolved by this time. The literature results are
entirely consistent with this, even those studies in which physiological
parameters have been taken and cattle show complete resolution of any
instability by 50 days of age. And there are quite a number of studies
that take a look at this.

The information that we have on reproductive function is, as previously
stated, perfunctory. But it does indicate normal functionality.

So here again we have consistency with the underlying biological
assumption that as clones age, they become more physiologically stable
and function indeed as copies of their donor animals. There is
consistency with other domestic livestock species and the mouse model.

We have relatively few uncertainties here. Although additional
reproductive data could confirm the cursory reports and we would again,
as we have done from the podium in many other times, asked producers of
clones who have such data to make it available to us.

(Slide)

Our confidence in these conclusions is quite high for the reasons that
we have discussed. Again, I remind you that these clones are unlikely to
enter the food supply as meat for economic reasons. But milk from adult
clones may enter the foods supply from lactating breeders.

(Slide)

So remember I talked to you about bounding the risk space and trying to
be very systematic about identifying where our biases might be and where
we started out and where we ended up. This is our internal self-check on
ourselves.

We started out from the hypothesis two, which as you remember, was the
bound that said animal clones may appear to be copies, but you really
need comprehensive data to prove that.

And so what we did was we went through a rather comprehensive database.
And based on those data, we decided that the weight of evidence moved us
from hypothesis one to hypothesis two.

(Slide)

Swine. Our preliminary conclusions regarding the safety of consumption
of food products from swine clones is that edible products from those
animals are likely to be as safe to eat as corresponding products from
non-clone swine.

Now the data set here is a bit more limited than it is for bovines. And
I know that some of the clone producers who have clone swine have
submitted some data to us and we have not had a chance to evaluate that.
These conclusions are drawn independently of those submitted, but
non-evaluated data.

The swine cloning appears to be technologically a little more difficult
than cloning cattle. But piglets generally appear to be healthy when
they are born. The Archer studies from the Laboratory of Jorge
Piedrahita indicate that the behavior appears to be age appropriate and
entirely normal. As do the health and the physiological measures, which
appear entirely normal within the range of closely related sibs and
reflective of normal developmental function.

So we feel pretty confident in saying at least for the animals that we
have been able to look at, they are not materially different from
comparators.

Here we have consistency with biological assumptions, other livestock
species. And I am sorry there is a missing mouse model here too. It is
entirely consistent with the mouse data. This data set, because it's
smaller, causes a few more uncertainties for us. It would be nice to
have additional data on reproductive function of these animals, because
we really have none.

And the confidence in our conclusions is tempered by the size of the
data set. It would be nice to have as much data as we had for the
cattle. But the data that we do have is entirely consistent.

The Archer studies are indeed compelling. And they increase our
confidence in the estimate. But still we do not have the same level of
confidence as we did in the cattle. And again I remind you that clones
are not likely to be used as meat and we don't get a lot of milk from
pigs.

(Slide)

So we started out with an initial hypothesis of two. Again, you know, we
needed more data. We needed a fair amount of data to show that these
animals didn't just appear to be copies. And the weight of evidence
moved us to about a hypothesis one minus. We are pretty comfortable
saying that there are good copies, but we would really like to have a
little bit more data for pigs.

(Slide)

We have nothing at all on sheep. So we will move right to goats.

(Slide)

Our preliminary conclusions on the safety of food products from goat
clones is that they are likely to be as safe to eat as corresponding
products from non-clone goats.

Again, the empirical basis for this decision is from a small but
entirely consistent data set. Goats appear to be extremely cloning
friendly. Their behavior appears to be age appropriate and normal.

Health and physiological measures appear normal and reflective of normal
developmental function. There is one small, but detailed, study of
normal reproductive function. And remember we said we put a lot of
weight on good reproductive function as an integrative assessment of the
health of the animal.

(Slide)

So here we have again consistency with underlying biological
assumptions. Consistency with observations in other livestock species.
And, again, the mouse model got left off this slide.

And we have some uncertainties with this data set. And I think they are
a little more, our uncertainties are higher than they are for cattle,
but different from the uncertainties that we have for swine.

We believe that we would have more certainty in our conclusions if the
\--. One of the things that Dr. Dubbin didn't tell you about, in large
part because of the shortness of time, and because the data are
preliminary, is that there is one abstract out there in which there are
some physiological data similar to the ones that you have seen for
cattle and pigs. It's extremely cursory. It's in abstract form. It
hasn't been published as a peer reviewed publication. That is
tantalizing but not probative.

So we would feel much better if those data were indeed published or made
available to us. Unfortunately it's a business decision not to publish
those data at this point. And so our confidence would be increased if
those data were indeed released to us.

And, again, we just want to comment that goat clones are not likely to
be as major producers of milk, although it is entirely possible, but
milk from lactating breeders would enter the food supply.

(Slide)

We have gone here from hypothesis two to hypothesis one. We have
relative \-- and this is a little bit higher than our swine, because of
the very high weight that we placed on the reproductive function as
indicating normative integrative function of the animal.

We based that on biological consistency that we see among species. A
small but high reconfirmatory data set. And the weight that we placed on
the reproductive function.

(Slide)

Now progeny. These are the animals that are likely actually going to
become meat and from whom we will likely obtain milk, should these
animals enter the food supply.

Our preliminary conclusion here is that edible products from the progeny
of healthy cones are likely to be as safe to eat as those from
conventional animals.

Now you notice I didn't say as progeny from conventional animals,
because all conventional animal are progeny. We don't start talking
about the initial animal and then descend down.

The biological assumption on which we relied quite heavily is that
gametogenesis naturally resets abnormal epigenetic signals should they
occur in the clones themselves. And much of our confidence here comes
from the mouse data, which is more extensive than any of the information
that we have in livestock, which as we have said over and over, tends to
be cursory.

(Slide)

Again, the data from livestock is cursory. There are very short mentions
in papers. Such and such an animal was bred, progeny or normal. Or you
will hear in conversation we have bred this bull, we have bred this
heifer and the calves are great. But we don't actually have the data in
hand to analyze.

We do have compelling data from the mouse model and it is compelling. We
have a limited report of comparability of bovine milk. Remember I told
you in the Walsh study, there was one animal that was the progeny of a
bull clone. And that cow gave milk that was comparable to the comparator
animals.

And we have limited reports of reproductive function of progeny goats.
The Gauthier study that both

Dr. Dubbin and Dr. Adams mentioned, had one sexually reproduced
offspring of a goat clone. It was a male. And it seemed to be entering
puberty at about the right time and behaving appropriately.

(Slide)

So that is where we are based on the critical biological systems
approach. The first prong of our

two-pronged approach. Now let's get to the second prong.

(Slide)

The compositional analysis of bovine milk is considerably more limited
than the data base that we had to work from from animal health.

There is one peer review study that I have discussed with you. There is
one abstract that we didn't discuss that had cursory mention. The peer
review study is entirely consistent with the prediction that animals
that are virtually indistinguishable from comparators will likely
produce milk that is similar to the comparators.

One of those animals, as I said previously is the progeny of a clone.
But we have a small sample size. Any differences that do occur or that
might occur could be due to breed and husbandry differences. It was not
a particularly tightly controlled experiment.

But, again, I remind you that studies conducted in agricultural
environments are not as tightly controlled as studies that are
conducted, for example, in laboratory animals. And this is, after all, a
survey and not necessarily an example.

So more data would really increase our confidence and judgments
regarding whether or not material differences exist between the milk of
clones and their progeny and conventional animals.

(Slide)

So we started thinking about well, if we could get the comparative data
that we wanted, what would we ask for and how would we look at it?

So the first question I asked, because I am not a dairy scientist by
training was what is milk. I went around the agency and asked, "What's
milk?" And the Code of Federal Regulations states that

> "Milk is the lacteal secretion, practically free from colostrum,
> obtained by the complete milking of one or more healthy cows."

This also applies to sheep and goats.

(Slide)

And then we asked well, what is meat? How do you define meat? Well the
Code of Federal Regulations says it's,

"The part of the muscle of any cattle, sheep, swine or goat, which is
skeletal \..." And you can read the rest. And it does include lips,
snouts, or ears.

So given that those are the regulatory definitions that we have, we
frankly don't have any chemical formulas that define either of these
commodities. And it's important to note that they are indeed
commodities.

They are not specialized products that have a certain set of specs. The
Pasturized Milk Ordinance tells you that you have to have a certain
amount of milk fat and things like that, but it doesn't tell you
anything really beyond that.

The other thing that we know is that we fortify milk with Vitamin D. So
don't go looking for Vitamin D levels in milks.

(Slide)

What else do we know about meat and milk? Well a survey of the
literature and a fairly extensive survey of the literature including
various USDA databases indicates that the composition of meat and milk
can vary significantly, even within the same breed. Even within the same
animal, depending what stage of lactation it's in. Depending on the
season, the climate, the diet the animal is receiving, the age of the
animal. And with respect to milk, where it is in the lactation cycle and
how many cycles of lactation it has had.

So even for experimental purposes, as I tried to tell you before, it's
very difficult to control the conditions under which you obtain milk
from animals to do a good comparison.

So, it doesn't really look like exact compositional analysis is
practicable. We just don't know how to define the comparator for a
complete tightly controlled chemical analysis. So what could we do that
would be practical, informative, and give us a good handle on risk?

(Slide)

Well the first thing we decided to do was to narrow down the comparators
we could use to compare against. And we asked the question, well, do you
want to compare it against, do you want to compare cloned milk or cloned
meat against genetically closely related animals? For example, the half
sibs that were in the Archer study that you heard about.

That would tell you what the effect of cloning was on that particular
breed or genetic background. But how would you account for normal
epigenetic variability in the comparator population? We already know
that if you give a lot of methyl equivalents to certain animals, they
will have different levels of gene expression, than if you feed a diet
that is low in methyl equivalent.

How would you do the statistics on this particular analysis? So okay, we
answer the question on what \-- that is one set of questions that we
could ask. As you can tell we like to bound our questions from both
sides.

The other way to look at this is to look at commodity products. What we
eat and drink every day. So we could look at comparisons to bulk tank
milk, which is what you get when you got to the Giant or the Safeway. Or
when you go to the butcher shop.

So that would provide a more extensive comparator range for conventional
counterparts. But then how do you account for the variability in the
comparators? How do you know that the beef that is at your Safeway, you
have two packages of beef in your Safeway. One of which comes from an
Angus from Texas and the other of which comes from a black cow of mixed
parentage grown in Virginia. They are going to differ.

(Slide)

So again we come back to the issue that we discussed previously. To look
at whether or not there is a food consumption risk. What are the actual
hazards we are thinking about? And for us here, the question was one of
nutritional risk.

Remember we are not introducing anything new into these animals. So we
don't have to worry about the presence of some exogenous substance. We
are looking to see is this milk or meat providing you the same dietary
equivalents that you are receiving from conventional foods.

And as you may remember, we came up with a short list, not terribly
short, of analytes that we believe would cover most of the dietary,
major dietary requirements that are met from milk and meat.

If any clone producers are out there, we would really like to have some
more data on this.

(Slide)

But what I really want to ask the Advisory Committee is a provocative
question. Given the highly detailed physiological information that we
have on some of these clones, what would be the additional scientific
merit in obtaining a lot of compositional information on milk, on meat?

I am not saying we shouldn't get it. But what would be the relative
merits of doing that and how would it increase our level of confidence
in our preliminary assessment of food safety if we had those data?

(Slide)

So having asked you that question right before lunch, you can ruminate
on it while you eat.

(Laughter.)

I would like to make some concluding comments. First of all, it is
important to remember that these are preliminary conclusions drawn on a
complete analysis of the data that we currently have in hand, of the
data that we have current analyzed, which does not include all of the
data that we have in hand, which will be incorporated in the subsequent
iteration of the draft risk assessment.

Our preliminary conclusions based on the data that we have evaluated so
far with respect to food safety are that edible products from normal
healthy clones, or their progeny, do not appear to pose increased food
consumption risks relative to their comparators.

We have relatively high confidence in this conclusion based on empirical
evidence from bovine clones, consistency of responses from other
species.

(Slide)

With respect to progeny, our preliminary conclusions are that edible
products from cloned progeny are likely to be as safe to eat as products
from non-clones. Again, based largely on biological assumptions,
compelling evidence from the mouse model, limited but consistent
observation in domestic livestock.

We believe it would be very useful to have additional data on the health
status of progeny and the composition of meat and milk. As we believe it
would likely increase the certainty of our conclusions, but we wait for
your advice on that as well.

Thank you all very much for staying a little late for lunch. I hope you
enjoy it and come back this afternoon for our discussions.

(Applause.)

MS. SINDELAR: This concludes our morning session. Restaurants within
walking distance are listed on a flier that are on the registration
table outside the door. Please return at 1:30. Thank you.

(Luncheon recess was taken.)

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

1:37 P.M.

MS. SINDELAR: I hope everyone had a very pleasant lunch. This portion of
the meeting is seeking clarification from VMAC and the public. Any
questions regarding the talks that have been presented this morning. And
I am very fortunate that Dr. Matheson has agreed to be a better
moderator at this time for directing these questions to the appropriate
person. So, John Matheson, please. Thank you.

***Questions for Clarification from VMAC and Public***

***by John Matheson, Moderator***

MR. MATHESON: Maybe from the Advisory Committee, do we have questions
about the presentations this morning or things about the data that we
can ask the speakers while they are up here? Yes, Rich.

MR. WOOD: I appreciated the clarity of the presentations. I anticipate
the comments that will come later. I was confused in looking at the data
that was provided, when it described how different terms were being
used, if we were comparing apples to oranges or apples to bananas. And I
wasn't real sure.

It was said that the comparison note with the clones was going to be
with ART's, assisted reproductive technologies. But then I heard one
study or two perhaps, the Cyagra study where it was presented as
comparing the clones with comparators. And were those comparators a
tease or was that data looking at the general population in those goat
statistics?

DR. RUDENKO: I think, and I will let Dr. Adams finish some of this. It's
important to understand that where the comparator is being placed. For
the food safety, for the overall analysis of the Cyagra database, the
comparator was the approximately age and breed matched animals reared on
the same farms.

The question that was being asked with respect to the qualitative or
quantitative differences in the adverse outcomes that were noted in
cloning were done in the context of other assisted reproductive
technologies. Do you want to add anything?

MR. WOOD: From our perspective we are concerned about trying to drawn
conclusions when comparing clones to another technology. And we find it
more helpful to compare clones to the impact of husbandry systems within
the general population.

So I wasn't sure how to draw what conclusions at that point. And that
may be something that you want to address in the final draft.

DR. RUDENKO: Thank you.

MR. MATHESON: Dr. Craigmill.

DR. CRAIGMILL: I was just wondering if in the process of doing your data
comparisons you found any cases where it was possible to compare the
clone with the nuclear donor. Any information in terms of physiological,
health status, or compositional factors.

DR. ADAMS: In terms of health status, the only information we have is
one study that was done, it's actually a behavioral study, from the
University of Connecticut, where they compared the behavior of the four
clones they had to the donor as well as to age match comparators.

DR. CRAIGMILL: Swine?

DR. ADAMS: Pardon me?

DR. CRAIGMILL: Swine?

DR. ADAMS: No, these were cattle. These were Holstein cattle.

DR. DUBBIN: I mentioned that study briefly. And that the behavior was
more like that of the dam. She had certain personality characteristics
that were distinguishable and they showed that personality
characteristic. Like, I think, reluctance to enter the barn or something
like that.

DR. McGLONE: Very nice presentations. I thought they were very clear and
well done. I was wondering if there was supporting evidence for some of
the statements. One of the conclusions, which I agree with in terms of
general biology but I was looking for some hard data to support, the
notion that gametogenesis naturally cleared the genome of inappropriate
signals. Do we have any actual data to support that concept?

DR. RUDENKO: I am unaware of any molecular data to support that. The
rather extensive database in mice is what we rely on. And this is one of
those biological assumptions that \-\-- stated as the front part of
reviews that deal with this issue. And for which we would like to have
more data than we do. But at the moment we are relying heavily on the
mouse data.

DR. McGLONE: Right. And, so is it also safe to assume that because there
are differences in the outcome of cloning different species that it
wouldn't be prudent to use the data from one species to draw a
conclusion about another species?

DR. RUDENKO: Interspecies extrapolation is always wrought with danger. I
think what requires good scientific judgment and good corroborating
evidence of an empirical nature is to look carefully at what the results
from the model species tell you and what you observe consistently across
species. But I think all interspecies extrapolation have to be
undertaken with a great deal of caution.

DR. McGLONE: Right. Then on the subject of whether it is safe to eat the
product, a cloned animal or their offspring, but let's just talk about
the cloned animal itself, compositional changes are one piece of
information. But, have there been any studies done where cloned animal
products have been fed to animals in an animal model that might indicate
whether or not there are other or unknown, because you couldn't have
assayed for every biochemical in the animal. So has there been any whole
animal evaluation of products cloned versus convention products?

DR. RUDENKO: I am unaware of any peer review studies of that nature. And
I guess I would ask you, the panel, what the relative merits of such a
study would be. What would you use as a comparison? Toxicological
studies are very hard to do in this kind of mixed medium environment.

And I think one of the reasons \-- there is no etiologic agent. What are
you looking for a difference in? And I think that is one of the reasons
why we have been looking to composition to help provide some of that
information. And as well as to the physiological parameters that we have
evaluated.

DR. McGLONE: Well, it seems to me that if there was a compositional
change, that it wouldn't necessarily indicate there was a problem with
the product. If a cloned animal produced milk with more fat, it would
not necessarily be a problem.

And if it has the same amount of composition, fat let's say, it doesn't
mean there is not a potential problem until you feed it to an animal,
let's say, an animal model. And even if you were just looking for
unexpected findings, you would learn something from doing that, wouldn't
you? That would equate to the safety of the product.

MR. MATHESON: I see Dr. Craigmill writing down notes furiously over
there. I think maybe he has a reply to that.

DR. CRAIGMILL: Well, I wondered if at this time you wanted to address
that or wanted to put it off. As a toxicologist, I don't see any need to
do the long term feeding studies when you are not trying to look at a
toxic affect. We have already assumed that they are not going to be
toxins expressed in this fashion. I believe that was one of the
underlying assumptions at the beginning, is that the genome essentially
of a food animal will not express toxins.

And I think that is a very valid assumption in this regard. Therefore I
don't see any reason for a long term feeding study. Long term feeding
studies are designed to look at toxins and toxicants. They are not
designed to look at nutritional factors, which I believe is the focus of
this. If you were going to do that, then I think you would have to
design something different, which would be a nutritional study.

Personally, I think that the assumption that is being made here is that
a healthy animal will probably produce healthy food as quite good
because if there were a compositional difference that would reflect
dramatically in nutrition, you would probably expect it to affect the
health of the animal. And that is an assumption too.

DR. McGLONE: Doesn't the fact that there are health issues early on
indicate that there might be an issue? I am not saying there is an
issue. I don't think there is an issue. But, the fact that the animals
have certain abnormalities at a higher rate than expected, doesn't that
indicate that there is some change in their metabolism?

DR. CRAIGMILL: I would, again, looking at it as a toxicologist, rather
than a developmental biologist, I would not want to make the assumption
that any developmental problem was a result of a toxin or a toxicant
interaction. I think there are a lot of other factors involved here.

The idea of the epigenetic differences here and expressions, they seem
much more likely. And that would be more a question of quantity than it
would be of difference in the actual proteins being expressed, et
cetera. It could be timing, things like that.

MR. MATHESON: Dr. Kochevar.

DR. KOCHEVAR: One of the materials that we were provided, it was noted
that animals had been created by embryo splitting and blastomere
transfer, for some time has entered the food chains, since the early
80\'s and know there were 1,400 Holsteins that were registered that have
gone through that process. Is there any data at all about the
disposition of those products from those animals? Any evidence that
there were problems with them, or \--?

MR. MATHESON: I don't think there is any evidence that there were
problems. Have you seen any data? Well, there is the blastomere study, I
guess.

DR. RUDENKO: There is one small study looking at back fat thickness in
blastomere derived beef cattle. And there were no noted differences
between those animals and their closely related sibs.

That is mentioned in the National Academy of Sciences report. We did not
include it in ours because we specifically address somatic cell nuclear
transfer animals. The author there is Diles, et al., D-i-l-e-s.

I believe there is also a study on milk quality characteristics from
blastomere clones that comes out of the USDA. But that hasn't been
published yet.

MS. SINDELAR: Do you know if they found anything in that study?

DR. RUDENKO: No differences.

MR. MATHESON: Yes.

DR. PAPPAIOANOU: I would also like to add my congratulations to the
presenters for presenting a lot of information, very detailed
information in a very coherent manner. And I thank you.

I had a question that actually relates to some of the feeding issues,
because in terms as I think about looking to the safety of the food, I
am thinking in terms of people.

DR. RUDENKO: Can you speak closer into the microphone please?

DR. PAPPAIOANOU: Sure. My mind goes to what would happen actually when
you have lots of people eating these products, which has not been part
of the studies. And in some of the background reading material, one of
the potential problems that could occur is there was a change in the
protein, might be allergies.

And so that wasn't really addressed in terms of this data and the
studies that you have presented in terms of the potential for that
occurring. And I wondered if you could, if there were some information
on that that was in the studies that was not presented. Or if, again, if
it's just another area where there is no information.

DR. RUDENKO: There is no specific information alterations and
allergenicity of proteins that come from animal clones. You know, the
FDA along with other regulatory agencies has been actively involved with
various international organizations in determining just how to assay
allergenicity.

And we continue to be very actively involved in that. And as information
comes from those deliberations that might be useful to us in this risk
assessment, we will of course use it. But much of that information, as
you know, looks at comparison of amino acids, primary amino acid
sequences in different kinds of protein to detect whether or not there
is any homology with known allergens.

We know that milk has a known human allergen in it. And we are not
talking about lactose intolerance here. But true milk allergy. And we
have no expectation that the amino acid sequence of that particular
protein will have changed because we are not introducing an exogenous
gene of any sort. So, again, it's a very good point. And we can make a
point of explicitly addressing that. And we do in the last portion of
the risk assessment. Just for limitations of time here we didn't go into
the discussions.

MR. MATHESON: I would like to add though that each of these clones are
one offs. So any epigenetic changes in one clone may not be repeated in
another, even if they are from the same cell line. So how would you
predict allergenicity to appear in a food product derived from clones
collectively?

DR. NOLAN: I really enjoyed the presentations as well. One thing stuck
me as far as the food safety issue is do we have any evidence that the
microbial flora of these animals is different from the norm? If you have
a different expression of protein, some \-\-- of protein in the gut.
Could you have a difference in numbers or types of bacteria? And these
then be passed on to the offspring.

DR. RUDENKO: We have no specific information on the constituents of any
receptor proteins that may be present in the intestines of animals. All
I can tell you is that the information we have regarding the microbial
content of these animals is indirect.

And I would like Dr. Dubbin, who I am going to put on the spot right
now, to address the overall issue of whether or not we see any increase
in bacterial infections in those animals. Because that is the best
source of indirect evidence that we would have.

DR. DUBBIN: We have no evidence of increased bacterial infections. And
we do see evidence that they can respond appropriately. If we were to
talk about, I guess, bacterial load of the gut, which is what you are
essentially talking about, we do see the calves with rotavirus diarrhea.
That is the normal pathogen that all calves have possibilities of
succumbing to that.

But certainly that would be a good case for age and location match
controls because that is so dependent on so many variables. These
animals would have to be essentially raised and identical and next to
each other with all the same variables and environmental variables. But
I don't know that we have any data to show changes in bacterial load or
response to different bacterial pathogens.

MR. MATHESON: Eric is the immune response of these calves relevant
though?

DR. DUBBIN: I think it's the whole point. We are talking about receptor
mediated, colonization of the intestinal tract. And I think that is what
I heard you say, and correct me if I am wrong, could there be some
protein change for allowing certain pathogens to colonize the gut versus
those that didn't.

And all the information we have to date is that their intestinal
response is identical. So we don't have information on changes there.
Did that answer your question, John?

MR. MATHESON: That was one I was concerned. Any more from the Advisory
Committee? Yes, Richard.

MR. WOOD: And then following up on that, I think what the National
Academy of Sciences study report was calling for additional study in
compositional changes. And you asked what our feeling was on that. And I
guess we will have to address that later.

But I want to follow up, go back to the original question I asked, I am
concerned about and would like to hear more about the selection of using
ART's as the base, actually, for a good portion of the study. And in a
way that becomes the norm when yet within that norm there are great
problems.

What was the rationale for using ART's as the comparative base in some
of the studies as opposed to using data from the general population in
the experience of birthing and growth in the general population of
animals, food animals?

DR. ADAMS: What we saw as we looked through the information both in
conventionally bred animals and various types of ART's is the more human
intervention in the process, the greater the likelihood of problems
later on.

And certainly there have been a lot of studies on in vitro
fertilization. But those have mostly been laboratory studies. It's not a
widely used practice in agriculture. So in selecting comparators there
was the need to do some comparisons to what generally happens in
agriculture versus these questions concerning the manipulation of the
embryo.

DR. RUDENKO: If I could just add a little bit to that. One of the
questions we were asking was does cloning cause any new kinds of
anomalies that we haven't seen before. And so in order to determine
whether or not you are seeing anything new, you have to try to find, if
you will in terms of technology and nearest neighbor analysis.

And the closest, the nearest neighbor to somatic cell nuclear transfer
might be considered embryo splitting or embryo transfer, something where
you actually have an in vitro culture period prior to reinsertion. And
we thought that that could help normalize across the technologies
somewhat.

So with respect to the identification of the qualitative kinds of
anomalies that might be noted, we thought it was most appropriate to do
our comparison to the assisted reproductive technologies, the outcomes
there.

Now with respect to the actual physiological data that we were
evaluating in the studies that have come through, the reason why we
chose comparator animals that were approximately age and breed matched
and raised on identical farms was because that is how the data came to
us.

And that is a little bit of a facile response to your question. But the
reality is we work with the data sets that we have available and felt
that with respect to understanding the actual physiological responses of
the animals in as consistent an environmental context as possible that
that would give us the most appropriate comparator.

And I think the table that Dr. Dubbin showed you where we were able to
demonstrate that both the comparators and the clones showed about the
same degree of variance to the reference range indicated to us that that
was indeed an appropriate comparator for that set of values.

MR. WOOD: What I was talking about coming to this meeting to the
neighbor who has cattle on his farm, the neatest the thing he raised was
concern about genetic diversity, which is also my concern as well. And I
was wondering why this risk assessment, or is it more of a risk
management question, does not deal with the issue of genetic diversity
and the impact of cloning on that dynamic?

MR. MATHESON: I guess I get to answer that one. It appears that it is a
risk management issue more than a risk assessment because you can use
cloning like these other tools really to either improve genetic
diversity or limit it.

It depends on how you use it. Just like artificial selection or any of
the other assisted reproductive technologies. You can use artificial
insemination to limit diversity as well. It's a tool rather than an
instrument of reducing diversity in and of itself. Dr. Kochevar.

DR. KOCHEVAR: This is just a clarification.

Dr. Dubbin, I think it's for you. In the studies from the cattle you
mention that they had, the clones had greater than 30 percent occurrence
of umbilical problems, or if you calculated it out, it came out to a
pretty high number.

What is the base line for non-clones, or even the comparators from that
same operation? We had some comparative numbers for things like
stillbirth and death within the first year. But I never got much of a
base line for that umbilical problem part of it.

DR. DUBBIN: I don't know the answer to how many comparators had
umbilical problems. But I can tell you from clinical experience that
umbilical problems tend to be somewhat farm specific. Certain dairies or
operations have more umbilical problems than others do. Through
management factors. Through some genetics. There are umbilical problems
that can be genetically influenced.

So, I don't have that answer. I don't know. I could get it for you
probably. But I don't have an answer offhand.

DR. PAPPAIOANOU: This question relates to, again, I think it's largely
going to be an area where there is not much information. But given that
you have reviewed the literature that is out there you may have some
notion of this.

If I sort out where the comparisons and the comparison groups are, if I
think about this, and from a food safety perspective, it would seen that
when you are looking at, given it's the progeny of clones that are for
the most part going to enter the food supply, that the appropriate
comparison for a cloned animal would actually be breeding stock of other
livestock.

And then that their progeny, whether you are talking about clones or
progeny of conventional bred animals, you would be looking for that
comparison. And much of the information that was presented was on cloned
animals presuming they would be into the food supply.

But if you think about long term there actually would be a small
proportion of that. Most of the food would be coming from their progeny.
And it didn't seem that very many studies had been done looking at the
progeny of the cloned animal with these outcomes. Or, that it just
seemed a better comparison for cloned animals would be breeding stock. I
would just like to, as you survey these 500 studies, or just have
thought about these questions a lot what your comments would be on just
the design of the studies that were actually done in terms of being able
to address the questions.

DR. RUDENKO: First, I am going to have to reclarify your question, if
you don't mind. You were saying that you thought the appropriate
comparator group for progeny of animal clones would be the breeding
stock themselves as opposed to the terminal animals.

DR. PAPPAIOANOU: Well, the point that seemed to be made was that cloned
animals, because of the high cost of their production, are themselves in
general not going to be used for food, at least until their purpose,
whether it's age or illness, or whatever, that the vast majority of
food, the quantity of food that is going to enter the food supply would
be from progeny of these animals.

And very few of the studies, it didn't seem like, I can't recall now,
but very few of the studies, if any actually, involved the progeny of
these animals. And then as I started to think about that it was like,
well, okay, so the cloned animal, it's their progeny.

And if you look at conventional bred animals, so clones, to me, equate
more to breeding stock. And progeny to progeny in terms of food entry
into the food market. And, again, you were dealing with the data that is
out there.

So this is not meant to be a criticism at all. I would just appreciate
your thoughts on the studies that you saw whether that approach was even
considered or is this just another area that could benefit from further
study.

DR. RUDENKO: I think you have raised a number of really good, very
provocative points. I think first by way of clarification. We assess
both animal clones and their progeny even though animal clones may not
be entering the food supply in very great numbers.

It was very important to us to make a statement about the suitability of
those animals for entering the food supply. In addition, we also
evaluated the progeny. So, we have tried to take a look at both.

With respect to what the appropriate comparator might be and whether or
not \-- I think the best way I have to answer that is to feed back on
the point that you made. This is a risk assessment. This comes into the
middle of the development of the technology.

As such, as I said at the beginning, the papers, the information on
which we had to draw were all designed to ask various other kinds of
questions that did not directly address either the long term health of
the animals or the safety of food products that come from them.

Most of the papers, and when the risk assessment comes out if you glance
through the bibliography, you will see the highest proportion of those
studies address issues such as use of this cell type versus use of that
cell type. And as the field has evolved and you look at the dates of the
papers as they come along, just as that groups of papers from 1997
through 2000, really tends to address the first developmental node that
we identified.

And there are some papers that address some of the other developmental
nodes as these animals age. But, there are really very few papers that
specifically go after the health of these animals.

And in point of fact once the investigators have determined that there
is no difference between the clones and whatever they are using as a
comparators, sometimes it's AI, sometimes it's IVF, there is a lack of
continuity of the papers. It's not interesting. It's not publishable. It
doesn't go in.

So by saying that we would limit ourselves to publicly available data,
we could only use those data. Now, the overall question of if you had to
design this entire universe, what kinds of studies would you use. What
kinds of animals would you take a look at is a very different answer. We
have what we have to work with. And we are trying to draw the
conclusions that we have based on the available data. But it's a good
point and we will think about it as we go back. Thank you.

MR. MATHESON: I have an explanation for you why there are not progeny
data. It's because we asked that no progeny go into the food supply. So
as a result, folks have not been making progeny from these clones. So in
a way we have created the situation ourselves.

DR. DUBBIN: I would like to make another clarification. Which is it's
been mentioned one of the reasons we don't have data on these adult
clones is because of their cost. But I think that is actually, we need
to reverse our view. It's not their cost, it's their value.

The value of a brood animal is, and how long it can live and produce
it's gametes, not in the quality of it's meat. But in response to your
question, in conventional animals, it's the growth characteristics and
the mothering characteristics. And the weight gain and profitability of
that particular brood animal that it demonstrated, it was measured
through its life. And accordingly, we need that information on those
clones as well before we even find out what the value of their gametes.

MR. : John, perhaps we should move on to public comments.

MR. MATHESON: I think that is a good idea. Aleta, would you take care of
that?

***Open Public Comments***

***by Aleta Sindelar***

MS. SINDELAR: That was a very interesting dialogue here. We have moved
on to the open public comments period. And we have a number of
individuals who have registered on behalf of organizations. And as I
call your name and you come to the mike, will you clearly identify
yourself and who you represent.

Before I start calling those who have registered for the open public
hearing, I would like Dr. Waddell to read into the record an
announcement from the agency.

DR. WADDELL: This is an announcement regarding the open public hearing
for general matters meetings.

> "Both the Food and Drug Administration and the public believe in a
> transparent process for information gathering and decision making. To
> insure such transparency at the open public hearing sessions 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
> the group's payment of your travel, lodging, or other expenses in
> connection with your attendance at this meeting.
>
> Likewise, FDA encourages you at the beginning of your statement to
> advise the Committee if you do not have any 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: Thank you very much, Dr. Waddell. All right. So, the rules
are you have five to seven minutes to speak. At five minutes I will
raise my hand, give you five and please conclude within the following
two minutes.

The first requested speaker is Mike Waner of ViaGen. Is he present?

MR. DAVIS: It won't be Mike.

MS. SINDELAR: Well, you are from ViaGen?

MR. DAVIS: I am.

MS. SINDELAR: Could you please state your name, sir.

MR. DAVIS: I am Scott Davis. And in the interest of full disclosure I am
president of ViaGen.

MS. SINDELAR: So the comments that you are making are on behalf of
ViaGen.

MR. DAVIS: That is correct.

MS. SINDELAR: Great. Okay. Excuse me, hold on.

(Pause.)

MS. SINDELAR: Thank you. A clarification. The floor is yours, sir.

MR. DAVIS: All right. Thank you. So, ViaGen is an \-\-- company that
combines gene mapping, \-\-- assisted breeding and functional genomic
capabilities with advanced reproductive services for agricultural animal
species. ViaGen identifies economic traits in animals and designs
breeding programs that efficiently reproduce those traits in future
generations.

Cloning by somatic cell nuclear transfer is a powerful tool for these
livestock breeding programs because it allows the generation of a large
number of genetically identical animals from donors who have
demonstrated genetic superiority.

The end result is the equivalent of an identical twin and the clones are
not transgenic but genetically modified in any way. Cloning by somatic
cell nuclear transfer offers a way for the animal industry to make rapid
genetic progress in breeding programs for important traits such as
disease resistance and production efficiencies that are difficult and
expensive to measure.

And as a result, this technology has a potential to improve animal
health and reduce waste, important objectives that have proven difficult
to achieve using traditional methods.

As users of cloning technology, we fully support the FDA's assessment of
the safety in food products derived from animal clones and their
offspring. We have provided data to the FDA from cloned cattle, cloned
pigs, and their offspring. And we will continue to do so.

We have complied with the FDA's request to withhold clones and their
offspring from the food chain. And we will continue to do so. And to
echo a comment that was made earlier, that is the reason there are no
offspring of clones to evaluate.

ViaGen's data indicates that adult clones and their offspring are
indistinguishable from animals produced by conventional means. In fact,
the most remarkable thing that we have observed about clones is that
they are totally unremarkable.

In our collective experience with several hundred cloned cattle and
pigs, we have not seen evidence to suggest any food safety concerns. We
agree with the preliminary finding that edible products from normal
healthy clones or their progeny do not pose increased food consumption
risks relative to comparable products in conventional animals. Thank
you.

MS. SINDELAR: Thank you very much. Our next speaker is Michael Hanson,
Consumers Union.

MR. HANSON: Thank you. I do not have any financial conflict of interest
with any of the companies. And I am here on behalf of Consumers Union.
They are the people that publish Consumer Reports magazine and we
welcome the opportunity to comment on the FDA's draft executive summary
of their assessment of the safety of animal cloning.

And I have some written comments which I will hand you. There are just a
few brief things I would like to say. In summary, it is the position of
Consumers Union that while we believe that meat and milk from cloned
animals may be safe, there presently is not enough data to reach this
conclusion.

And we would ask the Agency to require such data and testing of product
of cloned animals before they are placed on the market. We also think
there should be labeling.

But the few comments I want to make that we are particularly concerned
about is first is FDA's continued emphasis on qualitative similarities
between cloned and conventional animals. To say that problems arise but
are not qualitatively different from problems in conventional animals to
us is almost a meaningless statement in the context of food safety.

The problems we are concerned about most in the food safety area are
problems of quantity, frequency, and incidence. Frequency and incidence
of disease, of bacterial infection, of contamination with mercury, of
presence of allergy causing substances, et cetera.

To say that safety problems in clones are qualitatively no different
from conventional animals is therefore not particularly meaningful. It
would be like saying a plant where 95 percent of the chicken is
contaminated with salmonella is no different than on where two percent
of the chicken is contaminated.

The problems are qualitatively the same, but quantity of intense concern
in terms of food safety. And I would just point out that there are a
number of studies in the literature that have found differences between
cloning and both embryo cloning and in vitro fertilization.

Some of these are in a review that Dr. Wilmut and colleagues did last
year. They pointed out that the problem of hydrallantois rarely occurs
in natural cattle pregnancies, but occurs at the rate of some 20 times
higher for pregnancies established with clone embryos compared to in
vitro fertilization. That is 40 percent and two percent respectively.

The rate of stillbirths in a study of pepper cloned cattle by Infragen
that was talked about at the PEW meeting last year was 24 percent, eight
out of 25. This rate is three and a half times the rate of a large study
done in Canada with the Canadian Holstein heifers where two point nine
percent of them were abnormal, looking at thousand of animals.

And then a study that was published by Haymen, et al., on the frequency
and occurrence of late gestation losses from cattle cloned embryos found
that the overall rate of live births from in vitro, from IVF embryos was
seven times the rate for adult somatic clones.

That is 49 percent total success rate versus six point eight percent for
somatic clones. And the figure for embryo clones was 34.3 percent. So
both the success rate for IVF and embryo cloning were statistically
significantly higher.

If they look at the loss of late gestation losses, which is between day
90 of gestation and calving, that was

43 percent loss for the adult somatic clones compared to zero

percent for the IVF group. And four point three percent for embryo
cloning.

So there are differences in quantity is important. So it isn't just
qualitative differences. They are quantitative ones.

Now, if we move, I would also point out that we are also concerned about
this assumption for what you need to look at for food safety. And we
would just point out that the National Academy of Sciences, they
specifically requested that the Agency, as they pointed out,

> "Direct effects of any abnormality in patterns of gene expression on
> food safety are unknown. However, because stress from these
> developmental problems might result in shedding of pathogens and fecal
> material resulting in a higher load of undesirable microbes on the
> carcass, the food
>
> safety of products such as veal from young somatic cell cloned animals
> might indirectly present a food safety concern."

End quote.

And they then further went on to say, quote,

> "There are to date no published comparative analytical data assessing
> the composition of meat and milk products of somatic cell clones,
> their offspring, and conventionally bred animals. Although several
> studies are in progress. However, the Committee found it difficult to
> characterize the level of concern without further supporting evidence
> regarding food product composition."

So they were asking for this data. They even pointed out that for
blastomere and nuclear transfers, which had been on the market and which
were thought to pose a low level of food safety concern, they asked for
data there as well, quote

> "It would seem appropriate that the FDA use available analytical tests
> to evaluate the composition of food products from animals that
> themselves result directly from DNT cloning procedures to verify that
> they fulfill existing standards for animal derived food products."

End quote.

And I note that the specific requests to look at the pathogens and fecal
material, there was no data presented here. And we would hope that that
would be presented.

Finally, with this notion of your critical biological systems, the
hypothesis, that a healthy animal is likely to produce safe food
products. We disagree with that. Because if that were true, we wouldn't
need to have a HACCP system. Because if the animals are safe, if they
appear healthy going into slaughter we wouldn't need to test for any
pathogens. And that is what the HACCP system is about.

So I do think we do need to look at that. And then finally, very
quickly, this is in my notes, this underlying biologicial assumption
that these clones are normal and not any different, I think the work
published in the proceedings from the National Academy of Sciences last
year that found four percent of 10,000 genes were seriously abnormally
expressed.

And Dr. Jaenish said, quote, "There is no reason in the world to assume
that any other mammal including humans would be different from mice."
Jaenish believes that genetic abnormalities will be found even in the
seemingly normal animals. Some of the abnormalities are simply not
fatal, he said. And he calls for, quote,

> "Our results are consistent with the hypothesis that most clones
> independent of their cellular origin may have gene expression
> abnormalities causing subtle phenotypes. Conclusions about the
> normalcy of surviving cloned animals, therefore, should not be based
> on superficial clinical examination, but rather on detailed molecular
> analyses of tissue from adult cloned animals."

To date such data have not been published.

Finally, in January of this year there was one other study that looked
at 15,000 \--.

MS. SINDELAR: Sir. In the interest of other speakers, who need to come.
However, Dr. Waddell, has a question if you could take a moment for him.

MR. HANSON: Who do I leave these with?

MS. SINDELAR: You can leave them at the front desk on your way out.
Thank you. Sir, excuse me. I think,

Dr. Waddell, did you want to ask a question?

DR. WADDELL: Dr. Kochevar has a question.

DR. KOCHEVAR: I actually to clarifications. On the comparison between
the in vitro fertilization studies, was that comparing the industry at a
comparable stage of development to where clones are now? Or is that
comparing IVF some 15 years after it was established to cloning, which
is fairly new? That would be the first question.

Then the second question is, your comment about pathogen load studies.
The previous VMAC meeting, just before this one, there was a great deal
of discussion about what is the value of pathogen load studies.

MR. HANSON: Okay. To answer your first question, the article by Haymen,
et al., is in the [Biology of Reproduction]{.underline}. It's called
"Frequency and Occurrence of Late Gestational Losses from Cattle Cloned
Embryos. And if you look, the IVF clones and they also did adult somatic
cell clones, fetal somatic cell clones, and embryo cloning. And they did
all of them here. So this wasn't data from elsewhere. They talk, if you
look in the paper \--.

DR. KOCHEVAR: Right. But it was data using those technologies as they
exist today.

MR. HANSON: Yes.

DR. KOCHEVAR: Okay. Great. Thank you.

MR. HANSON: Yes. And I will just point out for the other thing, the
National Academy did talk about pathogen loading. There could be some
concern, but I think it should be looked at.

MS. SINDELAR: Thank you very much. Our next speaker is Carol Tucker
Foreman, Consumer Federation of America.

MS. FOREMAN: May I use this one?

MS. SINDELAR: Sure can.

MS. FOREMAN: Thank you. That won't make the Committee too uncomfortable.
I am Carol Tucker Foreman, director of food policy for Consumer
Federation of America. I have no conflict of interest.

We are an organization of 300 other consumer interest organizations,
consumer cooperatives, local state and national organizations. Most of
our members are like most Americans opposed to having milk and meat from
cloned animals enter the food supply.

Some are confident that the perfecting of the technology will lead to
ultimately to human cloning. Some are just concerned about the moral and
social issues involved, ethical issues involved in cloning \-\-- beings.
Others are concerned that it will lead to the further concentration in
animal agriculture. None see any consumer benefit from having meat and
milk from cloned animals in the food supply.

The action last week by the FDA in issuing a press release which
declared these products to be safe will certainly not reassure my
members, even those who are not imposed to cloning. Make no mistake
about it, the FDA's press release went all through the world as the
headline, "U.S. FDA says meat and milk from cloned animals is safe."

This is a process that I ostensibly was just beginning. But the Agency
almost surely has prejudged it. Certainly in the eyes of the public.
Although I think the CVM staff is to be commended for the prodigious
amount of work that they have put into this risk assessment, but you
have seen the possibility of real hard data.

They were completely dependent on companies to give them information.
Why would a company provide negative information if they thought that it
might make FDA hold back from moving ahead in approving these products?

Dr. Hanson raised the issue of the pathogen load in animals. This is of
great concern to us and to the National Academy of Sciences. A healthy
animal can be full of bugs that make human beings sick. And there is
evidence that stressed animals shed more pathogens than others. Did
anybody look to see if the fecal material from these animals have higher
loads of pathogens?

The public needs data that are driven by our needs and not just those
that can be provided to the Agency by the interested parties.

The Bush administration in addition has still not made a commitment to
engage in a discussion of the moral and ethical issues involved in this
technology, as recommended, again, by the National Academy of Sciences.
Nor has anyone suggested that consumers be given the opportunity to
avoid these products by having them clearly labeled in the marketplace.

My members are not sure why FDA has felt the need to move ahead and
bring this issue to you today when you don't have really any more
information about this risk assessment than we do, which is an 11 page
summary of what is clearly an extremely detailed document.

The data are very limited. And as the public becomes aware of the
limitations, and as the debate goes on, I think it is likely that they
will be even less accepting of all food biotechnology than they are now.

FDA could take some steps to reassure the public about food safety at
least in this area by simply prohibiting the passing of milk and meat
from clones into the food supply since we have been told that at least
in the case of meat that is not likely to be essential to the economic
success of the industry. I can't think of any reason why that should not
be done.

And I think, in fact, for the industry's sake, it would probably be
better to keep the milk out too, because I believe that the public's
reaction may be entirely negative and much more burdensome than keeping
it out. Thank you.

MS. SINDELAR: Thank you. Our next speaker is Joe Mendelson, Center for
Food Safety.

MR. MENDELSON: Good afternoon. I appreciate the opportunity to address
the Advisory Committee and the Center for Veterinary Medicine. My name
is Joseph Mendelson. I am the legal director for the Center for Food
Safety. We are a non-profit organization, membership organization made
up of consumers and environmental activists.

I should say I do not have any financial conflict of interest. I come
here representing both our organization and our membership. Similar to
the statement that

Ms. Tucker-Foreman made, our organizations and members do object to the
presence of any cloned meat or milk or products derived from their
progeny entering the food supply at this time.

I must say the risk assessment creates significant questions for me
about how this administration deals with science. And if I can digress a
moment, it's a very warm day outside. A beautiful day in November. Maybe
a symptom of climate change.

In the climate change arena, we have a process called the
inter-governmental panel on climate change.

2,500 scientists from around the world have gathered to develop data
over 15 years. Consensus documents were released every five years. And
this administration still says we don't have the adequate science to
judge whether we can address climate change.

And we come here today on an 11 page draft risk assessment with
ostensibly one study and one new data set. And as Ms. Foreman mentioned,
we have the FDA putting forward some type of draft determination on
safety. Clearly that is premature. And I don't know if this
administration can have it both ways. 2,500 scientists and we don't
know. You know, a couple, and we do.

The issues may be different and certainly different in degrees. But it
goes to the heart of what is rigorous science.

My colleagues have also mentioned that there are a number of issues that
haven't been looked at. We talked about the pathogen load. It was
mentioned the question of genetic erosion. That is another issue that
the National Academy of Science did raise, page 50.

On the compositional data, I would say if it's a question of whether
there is costs involved in slaughtering an animal, that burden shouldn't
fall on consumers. That is a cost of doing business to make sure that
that product is safe. So that should not be an excuse for not having
that data.

I also think the Agency should start engaging in what it is calling risk
management now. Our organization thinks that there should be a, the
moratorium should be made mandatory. Consumers have no reassurance that
this product is not entering the market right now under a voluntary
system. I am not suggesting that it is. But there is no assurance right
now.

It also raises the issue with FDA should be engaged in an
inter-governmental process with USDA to determine what exactly it's
legal authority is to regulate this issue. Is it the animal drug
application process? Is it the Animal Health Protection Act? Is it the
federal meat inspection and Poultry products inspection? What is the
authority to regulate this?

Because if you don't have authority to do it, or the Agency determines
it doesn't have the authority to do it, then this risk assessment
becomes somewhat academic.

So I would ask right now that the Agency engage in that inter-government
process and release a formal opinion from the general counsel's office
of FDA and USDA about what its authority is.

Lastly, I do want to get to the transparency issue. I appreciate
statements made about transparency. But we have had a Freedom of
Information Act request before the Agency for over a year on any data
that the FDA has on this topic. And we have not gotten anything.

Consumers want labeling issues obviously addressed. We talked about
animal welfare issues need to be addressed in this process. One way in
which the Agency can increase transparency is through some public field
hearings, akin to the year 2000 biotechnology field hearings you had
across the country.

That way you could possibly vet some of the consumer issues. I think as
Ms. Foreman mentioned, you will find out what consumers' opinion really
is about this issue. Thank you.

MS. SINDELAR: Thank you very much. Our next speaker is Bob Welper from
Alta Genetics. Why don't you come up here and you can manage your power
point.

MR. WELPER: My name is Bob Welper, and I will be presenting, as you can
see on behalf of Alta Genetics. And the financial implications will be
come clear through all my presentation.

Again, thanks to the CVM for allowing me to speak. And I would like to
commend them for the work that they have done with the limited data that
they have had to work with at this point in time.

Just to give a background on Alta Genetics, we are a marketer of bovine
semen for primarily dairy. We have worked with different ART's before.
As far as artificial insemination we are a developer, marketer and user.

We have been involved in the process of developing IVF, embryos from
clones. At this point in time as far as somatic cell nuclear transfer,
we are a user, hopeful marketer. And have worked primarily through
Cyagra for our technology partner. And we have been very happy with the
service we have gotten from them.

(Slide)

I want to talk a little bit about the experience that we have had with
our clones.

(Slide)

We have 23 Holstein male clones at this point in time from five donor
animals. The ages range from six to 23 months. And they have been under
our care from ages one to six months. And they are housed in U.S. and
Canada.

(Slide)

At this point in time we have had no deaths from these animals. No
serious health problems. There have been a few minor health problems.
One case is seminal vesiculitis which we do see in traditional animals.
And one case of naval infection that ties into the umbilical challenges
that they have had with the clones. At this point in time they are all
healthy and growing well.

(Slide)

This is a picture of the original, or the donor of five animals. As you
can see they are all quite health and different color markings. But
other than that, fairly close.

(Slide)

These are two additional clones that are housed in a different area.

(Slide)

As far as semen production, staring the precursor to reproduction, we
have 15 of these animals that have been in production. All 15 have
produced quality semen. Average age at first freeze is 13.7 months,
which is just slightly behind the average for traditional animals.

85 percent of the production has passed quality certification. So that
is above normal. Right now we produce a total of over 160,000 units that
have passed quality control, so from a precursor to reproduction or
fertility in the field, they do appear quite productive and higher than
normal.

At this point in time, the field trial challenges, as we have talked
about before with a request not to put this semen out in the field,
which really challenges to generate any data at this point in time. It
just sits there.

(Slide)

This is a picture of another line. Three animals housed in one location.
All quite healthy, growing well.

(Slide)

Two additional ones housed at a different area.

(Slide)

As far as comparison of clones to their donors, they are very close in
confirmation. Very close in semen production differences. Very close in
temperament. It's amazing to talk to the people that work with them. We
have one of these lines where the bull is a bit of a teddy bear, so are
their clones. The other bull is not quite so nice and neither are his
clones.

Small variation within the clone groups. I mean, you are going to see
that due to different environments or different daily management. Les
stressful lifetime production from our standpoint that these bulls are
actually in production at a time when it's less stressful on them. Since
we know their genetics they can be produced at a young age as opposed to
an older age when they are not quite as healthy. Longevity, that is yet
to be seen.

(Slide)

Example of another group of animals that we have. Again all healthy. You
are seeing all the animals that we have. None of them held back.

(Slide)

Clones versus contemporaries, there really is no differences in the care
that they are getting. We have really seen no differences in the health
incidence or health problems.

Very little differences in growth. Really no differences in semen
production. They are producing at or above what their contemporaries
are. And, again, longevity, we are gathering data as we speak.

(Slide)

Another example of clones. And just a disclaimer here. That is a camera
error, they are not mutants with blue eyes.

(Laughter.)

(Slide)

Customer acceptance. I mean looking at the people that buy our product
as far as buying the semen in the field. The survey results that we did
a year ago were very clone friendly. That certainly there are some
religious differences that people do not want to use it. But there are
few that have no interest in the semen from the clones.

The main concern seems to be with genetic value of the clones versus
donors that they are actually a genetic identical duplicate. And we do
have continuous requests for semen from the clones.

(Slide)

Regulatory process concerns. Certainly at this point in time it's been
slow in development and behind schedule. Seeing what has been done in
the last couple of months and over the past year and see what was
reported today certainly is encouraging.

It's limited, of course, by the available data that we have especially
from progeny clones. Right now the rest of the world is watching as was
stated as to what FDA and what the U.S. does. I think what the main
interest, what the main impact in the food system is going to be progeny
of clones, or cloned progeny.

I guess our question is how can we help to expedite the process? We have
talked about limited data. And certainly there is a limitation when we
can't \-\-- progeny of clones.

So certainly we are willing to work with the government or people to
develop any targeted research that we can because we are confident, if
we get the data that we will show that there are very little
differences.

(Slide)

And, again, I would just like to caution. We did make a lot of
references to qualitative differences. We haven't made some on
quantitative. But we have to realize too, that we also have said that
same rules apply to normal animals and cloned animals.

You have to realize that genetically there are differences across lines
for fitness traits. So if you look at abortions, if you look at
stillbirths, that there are differences in normal animals across genetic
lines. So if we are going to apply the same rules, then we are going to
have to start differentiating among genetic lines on normal animals.
Thank you.

MS. SINDELAR: Thank you very much. Our next speaker is Karen Davis from
United Poultry Concerns.

(No response.)

MS. SINDELAR: Is Karen Davis here?

(No response.)

MS. SINDELAR: We will proceed on. If she happens to show. The next
speaker is Richard Nelson from the Holstein Association. You can come
right to the mike.

MR. NELSON: I am Dick Nelson. I have been affiliated with the Holstein
Association of America for quite a few years. Holstein Association is a
non-profit organization, but we would like to break even.

(Laughter.)

It is a membership organization and so I work for the members and have
no financial involvement in anything that I might say. In fact, I'm old
enough that I could retire if something happened that prompted such a
move.

(Laughter.)

The Holstein Association has maintained the identification of
registration slash identification records of the seed stock segment of
the Holstein dairy cattle population in the United States in which over
90 percent are Holsteins.

The record organization is the largest of it's kind in the world and
works to promote harmonization of animal and embryo identification and
record procedures throughout the world.

This organization has maintained the records of those Holsteins
resulting from embryo transfer since the first one and registered in
1974. Through 2003 nearly 359,000 animals, male/female, that resulted
from embryo transfer technology have been registered.

Throughout the life of this technology there have been constant
upgrading and amending of record and identification procedures to
accommodate improved and advanced technology with U.S. Holstein
Association staff providing leadership on an international basis. And
including in that is cloning and sexing and through semen and biopsy, in
vitro fertilization.

When a technician pulls a cane out of a land nitrogen tank, it likes to
know what exactly what is in the straws that contain that cane.

The impact of the embryo transfer was increased early on by dividing
embryos with one-half of the cytoplasm transferred to a zona pellucida
from which all cytoplasm had been removed. This was an early enhancement
of embryo transfer technology.

While citing records from only 1982 through 1997, there were 1,280
females and 680 bulls registered during this time resulting from this
technology, with 974 females having genetic evaluation and 189 out of
680 bulls having genetic evaluations.

While this time span is limited, this technology has been used
continually from the beginning until the present with this example
inserted to report there was nothing unnatural about the animals
resulting from the divided embryos.

While this might be considered the earliest type of cloning, we have not
regularly thought of the dividing of embryos as being a cloning
procedure. The livestock industry has traditionally accepted events
technology that improves efficiency or increases animal value as a
matter of course when producers feel there is opportunity for improving
the breed or for further financial reward.

Naturally, the acceptance of some of advancements have been met with
varying degrees of apprehension. The Holstein Association began
registering animals born early in 1989 resulting from transferring
blastomeres of each individual cells from within a parent embryo to an
enucleated oocyte.

As you know, an embryo grows from one cell through natural cell division
to 16 cells in five days. But embryos for cloning may require another
day or two. From March 1989 through '96, a total of 106 females and 64
bulls have been registered resulting from this technology with 70 of the
females having genetic evaluations.

Therefore we have records that prove they produced successfully and
created records of milk with its components as developed through regular
dairy heard improvement association procedures for genetic evaluation.

This must not be interpreted to mean only 70 females matured to \-\--
age and reproduced. As many may not have been housed with access to data
collection procedure. There were no reports that these animals produced
meat and milk that was not normal.

While 64 bulls were registered resulting from this technology, 11 had
genetic evaluations which suggest they sired several female offspring
from many different side dams, with all steps in the process appearing
normal. This does not in any way suggest that there were not a
substantial greater number of bulls that were raised to breeding age and
sired one or more offspring, but not a sufficient number to produce a
genetic evaluation or were within a system where data was collected.

On the other hand, one must conclude that some of these animals were not
raised to breeding age and were therefore slaughtered for human food. By
now most of these animals resulting from this technology have gone into
the food chain.

More detailed information showing dam, offspring combinations and other
detail identifying animals resulting from this technology was assembled
from the Association's filed by \-\-- Robertson early in 2002, and
provided to a member of the committee on defining science based concerns
associated with the products of animal biotechnology appointed by the
National Academy.

However, the commercial application of this technology was virtually
abandoned in 1992 for a variety of reasons, though embryos continued to
come out of storage until 1996. While there were apparently cases of
abnormally large birth weights, there were not other abnormalities
reported.

The Holstein Association has solicited and collected reports on abnormal
animals since 1958. It has recognized that certain infirmities may not
have been reported. During this time the animals resulting from this
early technology of cloning embryos were in the general population.

Though this technology involved interaction between the nuclear material
and the cellular plasm into which it was inserted, as is the case with
transferring somatic cells, there were not reports of any kind to
indicate any animal or person was adversely affected by the meat or milk
from those animals.

Given early indications that cloning procedures using somatic cell
nuclear transfer would not be considered differently, inventors and
breeders of registered Holsteins implemented use of this technology on a
limited basis. To date 63 females and 17 males have been registered.

MS. SINDELAR: Mr. Nelson.

MR. NELSON: Particularly in \-- just a minute. Were not registered in
lightening capacity for market meat. And many animals were destroyed.

MS. SINDELAR: Sir, we have your comments. That will be available on the
web this evening.

MR. NELSON: All right. Thank you.

MS. SINDELAR: Thank you very much. If there is more time after everyone
has had a chance to speak,

Mr. Nelson, we would like you to come back up and finish if that is
suitable for everyone. Our next speaker is Michael Appleby. He is the
vice president, farm animals and sustainable agriculture, the Humane
Society of the United States.

DR. APPLEBY: Good day. Dr. Michael Appleby from the Humane Society of
the United States. I have no financial involvement with biotechnology
companies. And I have to say I think it's unlikely that situation will
change.

I had many years at the University of Edinburgh where I worked on animal
welfare and animal ethics. And in that position I knew Dr. Welmer well,
who was the man who created Dolly. And indeed I met Dolly. Anybody who
would like that photograph taken with me, you can form a line at the
door afterwards.

(Laughter)

On food safety, we do not challenge the Committee's conclusions with one
exception. That the assumption you made that sick animals do not get
into the food chain is simply wrong. There are many examples, many major
problems of sick animals. Downer cows, for example, getting into the
food chain. And insofar as that affected your conclusions, it's one you
should reassess.

But our main point is that food safety is not the major question that
should be emphasized. We are well aware and we commend you for the fact
that there are other assessments that proceeded parallel and
subsequently. And as has already been emphasized the fact that the
headlines are given to food safety is a dangerous emphasis given the
number of other ethical questions which are obviously important.

On risk assessment, I would like to put to you the suggestion that this
discussion should in fact be happening ten years hence or possibly not
happening at all. The technology is clearly still an extremely
experimental stage. There are very few papers to report. And there are
major gaps in the data.

The conclusions are still potentially altered by a single paper. And I
notice that you did not take into account the paper that is prepared in
[Nature]{.underline} in August on cloned pigs. Four pigs, one died
shortly after birth. The other three died before six months old from
heart attacks that would excel. It may be too recent for you to take
into account. That itself would alter the conclusions of this draft
summary.

Being experimental work requires review by institutional animal care
committees. And the basis those committees work on is potential costs
and benefits from the work.

So let me concentrate on the potential costs to the animals. You asked
have we adequately identified the risks to animal health. Well, the
costs you have outlined are graphic, if occasionally considerably
understated. For example, when you say the proportion of live normal
births appears to be increasing. Yes, it's increasing from very, very
bad to very bad.

One issue you have not covered is the unspoken assumption that there is
a neutral status quo in the absence of cloning. And as has already been
emphasized, the fact the costs to animals are similar to those of other
technologies does not, of course, justify those costs.

And on the contrary, an area which you have not picked up is the fact
that the animals being cloned are those with particular problems, such
as cows with udders so large that these produce major leg problems and
lameness. Very high producing animals frequently have major welfare
problems from growth rates or milk production or whatever it should be.

And one reason this is not being recognized is another unspoken
assumption in this case, which is heavily value laden. Use of phrases
like superior genetic merit, improved milk production, better growth
rate, are value laden and assuming that production from individual
animals should always be increased. And increased is the right word
rather than improved.

So that is potential costs. What about potential benefit. I suggest to
you that the potential benefits of this technology are none. We are
already producing far more meat than we can eat in this country to the
extent that the agriculture industry has to export it in order to make a
profit.

We are already producing milk so cheap that it is in the supermarkets
cheaper than water. Society, consumers, do not need this technology. The
only benefit that would accrue from this technology is to biotechnology
companies.

And it could well be that the people who will benefit from this
technology number less than three figures. We could be talking about
this being introduced for a handful food benefit of a handful of people.

The conclusion of any reasonable cost benefit analysis is this work
should not be proceeding and that is why I say that this discussion
should at least taking place in some years in the future and maybe not
taken place at all.

We commend the precautionary approach being taken by the FDA. But we
would warn against the expectation that this moratorium will soon or
indeed ever be lifted. And in view of the major problems to animal
health, we are very concerned that the lack of appropriate mechanisms
for control other than a voluntary moratorium.

There is a strong feeling here that we are on a down escalator which has
no break. We would urge the FDA in parallel with its other assessments
to look urgently into mechanism for installing a break on progress on
this technology. Thank you.

MS. SINDELAR: Thank you very much. We only have a few minutes here. Are
there any others who are interested in providing a brief statement from
the public?

MS. FINELLI: My name is Mary Finelli. I am here as a concerned citizen.
I have no conflict of interest with cloning technology. And no interest
in it either. Except to oppose it. It's known to cause pain and
suffering.

In an October 31st article in the [Washington Post]{.underline} entitled
"FDA says cloned animals are safe food" states

> "The technology is plagued by high failure rates, spontaneous
> abortions, and severe health problems in many clones and their
> mothers."

It goes on to state,

> "Cloning problems are worse in some species than others. They are
> notably severe in cows, the prime targets for firms working on
> commercial cloning."

In the FDA's own press release, it states, "The adverse outcomes may
occur at a higher frequency with cloning than with other assisted
reproductive technologies."

For the same reason it is immoral to clone humans in that it entails
unnecessary pain and suffering, it is wrong to clone other animals. They
too experience pain and suffering. The public is opposed to animal
cruelty, which cloning involves. And the government should in no way
support or promote it.

In its report on cloning last year, the National Academy of Science
panel also pointed out that animal welfare is a serious concern. The
government is on one hand urging the public to eat less animal products,
it is contradictory to endorse a process that will make animal products
more readily available.

I ask that any public outreach effort that the FDA undertakes regarding
cloning should make it very clear to the public that cloning causes
animal pain and suffering. Thank you.

MS. SINDELAR: Thank you. Are there any other comments?

(No response.)

MS. SINDELAR: Is Karen Davis here?

(No response.)

MS. SINDELAR: Okay. I think this closes our open public comment process.
And we will take a break and return at 3:15.

(Whereupon, a brief recess was taken.)

MS. SINDELAR: \-\-- and begin with the VMAC deliberations. If everyone
can have a seat please. I would like to thank Dr. Sundlof and his
speakers for staying up here for the rest of the deliberation process
here such that the VMAC members will be free to address them with any
questions. So at this time I would like to hand the baton to Dr.
Waddell, the chairperson.

DR. WADDELL: Oh, yes. If I may, we had just finished up public comment
prior to the break. And to be fair to all the speakers, we cut one off.
And I would like for him to come to the microphone and finish his
statement before we begin deliberations.

MR. NELSON: I am sorry. I apologize for taking more time that was
allotted. And I sincerely appreciate this opportunity. All I would like
to say is that we have many, a few entrepreneurial breeders or
registered dairy cattle that want to be on the cutting edge of leading
technology, who have invested five figure dollars from 40, to 50, to 60,
to 80 and \$100,000 in animals that are clones. And who are anxious that
these animals and their offspring are such that the meat and milk from
them and their offspring can enter the food chain and that it not be
labeled. Thank you.

MS. SINDELAR: Thank you, Mr. Nelson. Thank you, Dr. Waddell.

***VMAC Deliberations***

***by Dr. John Waddell***

DR. WADDELL: Okay. We will begin our deliberations. And the questions
are posted on the screen. And what we will do is I will read the first
question, and we will go around the Committee and if each Committee
member could give their comments and how they will address each
question.

So the first question to VMAC is,

> "Based on what we have been presented, has the risk assessment
> adequately identified the hazards and characterized the risks relating
> to animal health?"

So, Dr. Craigmill, would you begin?

DR. CRAIGMILL: As a toxicologist, as I was explaining early to Dr.
Sundlof, I have little difficulty using the term risk in this regard
because when I look at risk I look at quantitative information. I am not
sure we have real good quantitative information in this regard to
actually come up with a risk.

I do appreciate very much the fact that we are talking about a
qualitative risk assessment here and looking at the differences and
trying to identify unique problems. There are some data in terms of the
risks to the animals. I believe the FDA has done an excellent job in
characterizing what information is available.

In that regard, as to whether it answers the question definitively, I
can't really say that it does. But I think it answers it definitively to
the point that it's not an area where a whole lot of additional study
needs to be done other than to collect information on the ongoing
process and what is currently underway.

So I think current, if we collect more data on what is actually going on
now, I think we can elucidate this question a little bit later.

DR. WADDELL: Richard.

MR. WOOD: I don't think we do have the data that is needed. Where there
is data, it's identified clear health problems, particularly in the
earlier nodes of development. I think we also, the risk assessment needs
to reassess the tension that has been identified between qualitative and
quantitative issues in the risk assessment.

For example, if the number of calves that die on a post-natal period is
doubled, is that a qualitative difference, and questions of that nature
that were also raised in some of the public testimony.

I mean, overall I think that would be my general comment about the risk
assessment as was noted and said very forthrightly by all the presenters
today, is the lack of data. And it would be helpful I think to learn
what the strategy is for accomplishing the wish list that was alluded to
in one of the presentations.

So my view of what we have is an interim risk assessment and that is
okay. The technology is developing so the assessment perhaps needs also
to get underway and to review the studies that do address the questions
at hand as they are apparent.

A separate track that goes beyond both of these that I feel a need to
mention, even though it was referred to earlier as perhaps a risk
management strategy, but I think it needs to be addressed because
perhaps the motivation for moving ahead on the risk assessment is to in
some ways be out in front of the developing technology on cloning.

And that is the need to define regulatory authority. And as a consumer
representative, I thank the industry for voluntarily withholding the
marketing of their products even at some loss, I am sure, to them, while
there is regulatory action.

But I do think that attention and time needs to be addressed in defining
that authority and taking, or taking the legislative steps necessary to
achieve that authority. I also think as was mentioned earlier by one of
the commentators from the public that a larger forum should be called
together.

Perhaps as a risk management step and maybe risk management at this
time, if that is that step, needs to happen at the same time as risk
assessment that would involve the USDA, FDA, and perhaps others. A model
could be, and not a clone, because it's certainly had it's failures. But
the administration's task force on food safety that was a larger
gathering of interested parties and stakeholders around this question.
Or perhaps even the ethical and religious questions that underpin some
of the questions that we are dealing with today could also be addressed.

So my answer to the first question is that the data is not there to
provide a sufficient risk assessment. I do thank the FDA for
acknowledging that and taking the data sets available to begin the
process of a risk assessment. But that is yet to come.

DR. WADDELL: Dr. Pappaioanou.

DR. PAPPAIOANOU: Thank you. My answer to the first question also is that
with what was presented that there is not sufficient data to be able to
answer the question. There are very few studies at best. Most had
incredibly small sample sizes. If one even \--.

Many of the statements that were made was there were no differences
noted. You just wonder if they calculated the power of that what was the
probability of finding a difference if one existed. I don't know. You
know, five, ten, 15, 20 percent. It's just hard without a power
calculation there.

I understand the difficulty of the endpoints that they were trying to
contend with. But nonetheless I think the data with that regard makes it
almost impossible to be able to answer the question.

New studies are needed. I take heart and absolutely believe in a risk
assessment or a research synthesis effort. That one of the big values
from doing that is to identify the data gaps and to guide the research
that is needed to answer the questions.

And I would think too that with what we have heard too with considerable
money going into the development of this technology that some resources
could be found to do those studies and to get that data. That would
allow a clearer picture as to be able to be able to answer the first
question. Thank you.

DR. WADDELL: Dr. Wages.

DR. WAGES: Thank you. Clearly the cloning issue is a powerful technology
that at least personally I see the potential benefits far outweigh the
risks. However, if you look at the answer to the first question as it is
proposed to us, it's difficult to answer that question, yes, with the
data that we have been given.

If you look at it qualitatively in clone versus uncloned, if you will,
animals, I think there was a decent job in the information presented
that anything happening in the cloned animals also happened at least in
some percentages or some aspect in the uncloned, or the partners, if you
will.

However, the majority of the data is in cattle. And you have a lot of
other species in question that are just not there to make a decision on.
I think when you have information that was presented today with limited
data \-- and I want to interject. If you are an anti-cloner, you are
never going to get enough data. There is never going to be data to
support cloning. So I think to go to that aspect, it's never going to
happen.

There is always going to be a gap in the data if you don't like what is
being presented. However, I think you can look at trends even in small
numbers. And I would think even with the breeding that was done in the
cloned animals, you at least got some impression that there were
different hazards that would be coming apparent versus, you know, the
uncloned animals. And it just wasn't done.

Everything that occurs, even though there is an increased quantitatively
in some of these, like hydrops, \-\--, those clearly do occur in the
normal population. However, to straight answer the question, I think
there is still enough lacking information to where I don't think I can
assess where all of the hazards have been adequately identified.

DR. WADDELL: Dr. Parkhurst.

DR. PARKHURST: Thank you. I think you are trying to tackle a very, very
difficult issue and clearly, as everybody said, and as you, yourself,
said the data set is very, very small. But you have to start somewhere.

And in that spirit, I would say that you looked at what you have and you
started to make categories. And you said that as age became, as they
became older well then they started to even out. The problems that were
there started to even out.

And so that is a beginning. In my view you also looked at it and you
didn't identify any catastrophic events. I mean you can at least say so
far we haven't come across anything that is catastrophic.

And you are starting to build a data base, which is no small thing. In
looking at the summary of values that you have here both in the
chemistry and the hematology, you have different parameters. And looking
at those parameters I think you gave a nice picture of the numbers and
where they are going.

I do think a power assessment would be nice, you know, given the numbers
that you have. And what you think a meaningful difference would actually
be. That would need to be specified.

And you started. You have looked at it in a

uni-variate case. You are looking at it a one variable at a time which
is the way you begin. But then we all know that these variables are
correlated. And the more they are correlated, then we have to take that
into account when you talk about the picture as a whole.

And looking at whether these are all part of the same population would
be, you could take this to your statistician and talk about influence
points and whether they truly are part of the same picture. It's just
much harder to see as you get into multi-dimensions that are going on.

So I think you have made a start. And you just keep having to say over
and over again the way you did that this is just the beginning. It's a
very small data set and we have to be very, very careful about making
any conclusions whatsoever.

DR. WADDELL: Dr. Jack.

DR. JACK: Ditto is probably too easy an answer to give. But, I tend to
agree with most of what my colleagues have said. As you described
yourselves, this is an iterative process and not to belabor the point,
but it's a good first step.

I think many of the hazards have been identified. I think the
characterizations of the risks of the data is just lacking at this
point. So it's hard to say. Based on what we have been presented, yes to
both of those questions. I would say at best, it's a start. The answer
can't be given at this point.

DR. WADDELL: Dr. Nolan.

DR. NOLAN: Thank you. Ditto, again. Well, I am a bacteriologist. And
what strikes by what you have been doing is, you know, I can study a
million sub organisms in a single mill. And you are studying a very
complex organism and its very, very difficult to do. I never lack for
data. You have to struggle with the other problem.

So I guess where I am is I feel like we could use some more data to be
able to answer this question. At the same time I recognize how very
difficult it is. Thanks.

DR. WADDELL: Dr. McGlone.

DR. McGLONE: I would like to commend the FDA again for putting together
a complex set of data in a qualitative manner. I think the answer to the
first question is clearly no. That we don't understand enough about the
risks to animal health.

And I would encourage the FDA to think about the issue of cloning as
they might think about a drug and cloned animals are not a drug. But in
that they ought to develop a plan for what information might be needed
and then execute that plan in an expeditious manner.

And include in the animal health evaluation animal safety and something
that might be termed animal welfare. I know you don't like that mandate.
But I think there is not a lot of difference between animal safety and
animal welfare.

And what I would be looking for as a scientific reviewer is some data
that already exists, but more data on behavioral comparisons of cloned
animals, their relatives, and non-relatives, on physiology,
endocrinology, and immunology of the three set of animals.

Of diseased challenged animals whether they would be differently,
whether their clones, and their relatives and non-relatives would be
different in response to disease challenge, which would include food
safety studies.

And, finally, with all of those data in hand, then you could and you
should and you could even begin a quantitative risk assessment to animal
health that would indicate the increased risk to morbidity and
mortality, behavioral changes, physiological changes and so on based on
comparisons.

And it's not to say that if there is a two fold increase in mortality,
for example, that that would necessarily mean that it wouldn't be a
reasonable technology that would be acceptable under some circumstances.

So, the last challenge, I think, is that for the country, is that there
are a lot of apparent critics of cloning. And there are advocates of
cloning. And perhaps the two groups should get together and fund the
studies. Because the studies that are needed are in the general interest
of the country and the world and not only unique to individual
corporations.

So I think a little cooperative planning and execution of the studies
that I described would give comfort to the consumer that the animal
health is being protected. Thank you.

DR. WADDELL: Dr. Kochevar.

DR. KOCHEVAR: I would start by saying that I think the FDA had done a
very good job of creating a system in which more data can be added and
rationally assessed. And the two components to that are the care with
which you look for comparators to your clones that are meaningful. And
the creation of the five node system whereby you are not comparing for
the most part apples and oranges. You are comparing animals within a
group.

I think with that system in place and the wish list that you have
provided, the track to getting the data you need will be faster than
what you have had to date. That as you said there are inherent problems
with publishing some of this data, so some of it has just not been done.

That said, I think when you look at the data that you have looked at for
cattle that I think you are approaching the point where you have
adequately evaluated the risk to animal health. I think that you have an
end that if you did the power analysis on, you would probably be close
to being where you need to be.

In addition, I think it's very hard to know where the base line is on
this stuff. That if you took 500 completely normal animals and looked at
the incidence of the things you are trying to quantitate in these
clones, there would be as much variability there as there is in the
clones. And so I mean you might just collect data forever and not really
ever have a compelling conclusion to it.

So, at some point I think you have created the framework to be able to
make a rationale analysis. I personally am compelled by the bovine data
because there are much higher numbers represented there.

And I guess the final piece is that this intuitive sense that if you
have done embryo splitting, you have done other assisted reproductive
technologies, we obviously have natural occurrence of 20, that none of
those represent apparently risks to \-- well, now I am on question to
two. Risks to the consumer.

But, overtime have also not presented compelling risks to animal health.
Then I would suggest that you are approaching at least with cattle the
point where you can say, yes, you have adequately assessed that risk.

DR. WADDELL: I too believe that it's a very good first step. And I mean,
this technology is in such a infancy stage that we have to start
someplace. And I think if you really look at question one, on just it's
own merits that a risk assessment has identified the hazards. And
characterized the risks.

And compared to some of the other ART's, that were mentioned today and
even were developed prior to that, we have already gone off a lot
further with this issue and this technology than what we did with those.
And so I think it is a good first step. And I realize there are tons of
data to come yet. So I think the answer to number one is yes.

Okay. We will move on to question two.

> "Based on what we have presented, has the risk assessment adequately
> identified the hazards and characterized the risks relating to food
> consumption?"

And we will start again with Dr. Craigmill.

DR. CRAIGMILL: Just briefly. I think the answer is yes. And then I will
fill in why. Again, it's very difficult to do an actual risk assessment
on this other than a qualitative look at the possible hazards that might
exist. And when I talk about a hazard, again, it's a possibility, it's
not a probability.

I think if you looked at this scientifically, there is really little
reason to expect that there could be a problem from this. Seeing as how
you are taking a nucleus from one cow cell, or sheep cell, and putting
it into the cell body of another cow or sheep cell and you are just
transferring genetic information, it's all epigenetic.

There is nothing new added there which would add any new toxins or
potential proteins which would add new allergenicity problems.

In terms of the expression of proteins, that is a difficult question to
answer. That is certainly something that could likely occur in the
clone. It seems very unlikely in their offspring.

So in brief, I would just say that I think they have done an excellent
job on this and support the recommendations that have come out.

DR. WADDELL: Mr. Wood.

MR. WOOD: In response to this question, in one of the first pieces that
came out anticipating this event, somebody from the industry said, I
think it was Mayor Times, quote "Is there a strong and impressive body
of scientific evidence that will convince consumers that this food is
safe?"

And that is a general question. Not a specific question that is before
VMAC, but to that, I think the answer is still no. And looking more
specifically at the second question and looking at what has been
provided, there still is insufficient data in our view, my view, that
regarding the composition of cloned bovine meat or milk, although a
great stride has been taken in the direction regarding bovine meat with
the Cyagra data.

And it would be great to validate that with other data. I said in a
break to somebody, I said, how many studies does it take to say that we
now have something this scientifically valid? And I am sure that is a
question that is open for debate.

But there is still insufficient data as far as I am concerned. Because
not enough of the data on milk from clones, as was identified in the
risk analysis in its executive summary. There is not enough data on the
safety of pork, swine meat. There is no data on sheep clones.

So, that to me says that there still is not sufficient data upon which
to take this step. And to respond to one of my colleagues here, it's not
as if there never will be enough data on this question. I think that we
are moving in the right direction.

And you have been encouraged by others to look at pathogen load. I think
that is an important focus as well. And you asked whether or not the
composition of food should be further examined. Then I think you ought
to continue that focus as was called for by the National Academy of
Science report.

So I don't believe that meat or milk should be approved from clones at
this time as a result of this risk assessment. Nor should the meat or
milk of progeny until there is further review.

Also, the issue of labeling has been raised by one of the comments. And
that certainly is a risk management step that, if there was approval,
would allow consumer choice.

DR. WADDELL: Dr. Pappaioanou.

DR. PAPPAIOANOU: As before, I really do commend the group in terms of
the risk assessment that was done and very much appreciate the
constraints that they faced on

the limited data. You can only do so much with what you have. And it was
a very fair look.

However, again, some of the issues in terms of lack of information on
several of the species. The desire to lurch into the expression of
proteins and potential outcomes from that, or possible impacts on the
intestinal flora in terms of overall as animals would go into the food
supply, which is really where the rubber would meet the road, that is
definitely deserving of more investigation.

Many of the assumptions and the biological hypotheses put forward are
very believable. They make all kinds of sense. But, as I kept asking
myself as I was actually looking at the data that was being presented, I
didn't see where the data began to lead me to a confident answer.

And I am not one, I work in public health. We are used to making lots of
decisions based on incomplete data. But it's easy to say well we will
never have enough data to basically, with 100 percent confidence, be
able to say that this is safe.

And that is true. There is nothing that is

100 percent. But one can generate data, studies that give more
confidence and that does relate to the design of the study, the quality
of the study, how the studies were conducted. How many animals were in
the study.

And one can then come to a conclusion that if you come up with a quote,
unquote "negative finding" of there is no difference, that you are at
least 80/85/90 percent confident that you can believe the negative
results.

So, again, my overall conclusion is that, no. Based on the posture of
data, clearly not the model that was set forth or the process. But a
good beginning as others have said, with hopefully the research agenda
that comes out of this that can begin to be addressed to fill those gaps
and to answer the question affirmatively. Thanks.

DR. WADDELL: Dr. Wages.

DR. WAGES: I am a little more comfortable with this question than I was
with the first. Even though there may be some data lacking in both of
these questions.

When I look at potential for food safety, there was a variety of blood
chemistries and blood values that were given in comparing the cloned
versus uncloned animals. Or the comparators, if you will. Up into the 99
percent comparable to the comparative counterparts.

And I think if you look at, especially in the cattle data, if you will,
I think if you look at, again, trends, I think with the numbers that we
at least observed in cattle, I think if there was something that would
come up from a nitrogen retention, some type of physiological problem
that has the potential of affecting quality of meat or milk. I think it
would have come out.

One think I would have like to have seen in the milk studies at least is
butter fat content, even though that varies. Depending on diet it does
give us a sense of the electrolyte or at least the acid based balance of
the dairy cow. And if there are any changes there.

I am reasonably comfortable that the food consumption portion of the
cloning issue, I think we have identified the potential hazards and the
answer to that question would be yes.

I think one thing that would solidify even things more for me would be I
think there is a lot of universities that would just be tickled to death
to get these cloned progeny, food science departments, and pick these
guys apart. And actually provide some of that final data in carcass
quality and even analysis of meat or milk.

And that might be something that could be very, very useful to put more
of an end to some of the questions or speculations on the quality of
meat. So, yes.

DR. WADDELL: Dr. Parkhurst.

DR. PARKHURST: Thank you. Again, I would have to say I don't know. I
don't see that there really is enough data. But I do think that in your
presentation you have presented a well constructed design as to how you
could get more data.

And, in fact, I thought that that was some of the things that you were
asking for. You said in general there is just so much variation in the
whole population that we consider normal. How can we go about and get
something on cloning animals that would be any different.

And one thing I would suggest is to look at the analysis of variants
components. That is a study in which you would be able to see if they
came from the same population or if there was something different along
those lines. That is the biggest thing I have to say right now.

DR. WADDELL: Dr. Jack.

DR. JACK: Thank you. Again, I think I am going to fall in line with most
of my colleagues. I believe that a lot of the \-- I tend to fill that
the evidence or my sense of what is going on with the risk assessment
for food, I feel a little bit better about that than the risk to the
animal health.

So that is if these animals are living to maturity or getting to a point
where they enter the food chain that a cow is a cow is a cow. That you
are taking the nucleus of a normal healthy animal and sticking in
another cell.

I guess my concern though is that we don't have much data on the
progeny. And if those are the animals that are really going to enter the
food chain, we really need to take a look at those.

And, again, my intellectually, it would seem a fair assumption that the
progeny shouldn't be changed at all. But we don't have any evidence to
show that one way or the other. We just don't know.

So, you know, based on the assumption that the offspring are like the
parent, we are in good shape. But it's still an assumption.

DR. WADDELL: Dr. Nolan.

DR. NOLAN: Thank you. Well, based on the data presented and on the
rationale assumptions on which their interpretation were based, I don't
think there is any reason to assume that the milk or the meat from these
clones or their progeny will be unsafe.

But I do feel uncomfortable, often and unqualified, yes. Again, like
many of my colleagues here, I think it would be good to see more data.
And I would especially like to see data on the progeny since they are
the ones likely to enter the food supply.

I think it's an interest, something we may want to see addressed is the
microbial flora of the clones and their progeny. Thanks.

DR. WADDELL: Dr. McGlone.

DR. McGLONE: On this question, I think based on composition data, that
the answer to the question is yes. That the cloned animal is
functionally similar in composition. But I think, qualifying my yes,
that in this case the consumer wants more.

The public wants more. And in fact in this case science at the moment
cannot deliver that. The consumer has the fear of the unknown of things
that might be in the meat that are not yet described, perhaps.

And the only way to confront that from a science point of view and move
on is to actually do the studies where when products are fed. And not
only where they are fed to normal animals, but also to animals at risk
and to young animals, neonatal animals, because people have a fear of
what goes in the mouth of their children. And any other member of the
population that might be at risk, perhaps people that are sick or
elderly.

So to go an extra step in this case, I believe, is required. More so
than if it were normal food stuff that doesn't have any consumer hot
button attached to it. So in this case I think we need some data that go
one step beyond what would normally be required under these
circumstances in order to develop the confidence. So that we don't lose
the confidence that the consumer has in our food supply. And we can in
fact culture it and nurture it and help the animal industry satisfy this
consumer desire for animal products.

DR. WADDELL: Dr. Kochevar.

DR. KOCHEVAR: I think that one of the slides that was shown pointed out
that until this fall no, zero peer review publications relevant to SCNT
on \-\-- were available. And then the Walsh study was then looked in
some detail.

I think those studies are the direct evidence that you need to be able
to answer yes to number two. I think you have abundant indirect
evidence. And that evidence is, again, back to the bovine data set.

You had such high percentages of sort of concordance between the clones
and the normal animals.

90 percent, 99 percent in that. That the reasonable expectation is that
these animals have those parameters that similar and obviously function
normally in terms of being able to emulate and reproduce and various
things. Then it is a reasonable assumption to say that they are not
going to be a danger in terms of the food supply. That is all indirect
evidence, though.

And so truly if you had to have direct evidence, you really would have
to do some of the studies that you mentioned on your wish list. I don't
think those should. I mean those kind of studies seems to me would not
take an overwhelmingly long period of time to do. Those are basically
meat composition and milk.

They are confounded by the variability in normal milk and the meat. But,
except for that caveat than those studies seemingly should be fairly
direct. And I do think that data would be very useful to support the
argument.

DR. WADDELL: Again, taking the question in its face value, and what we
were presented earlier today, I would have to answer yes to question
number two also. And echo many of the comments from the rest of the
Committee as far as the data. But, I think that it is coming. The thing
is coming. But we, you know, have to make the first step somewhere along
the line.

Are there any other comments from the Committee?

(No response.)

DR. WADDELL: Hearing none, that concludes our deliberations.

MS. SINDELAR: Dr. Matheson will take over for the concluding remarks and
next steps.

***Concluding Remarks and Next Steps***

***by Mr. John Matheson, Moderator***

MR. MATHESON: For those of you that have been patient enough to stay all
day and are victims of the Advisory Committee who have had to stay all
day, we thought we would treat you with about ten or 15 minutes about
where the next steps are in reaching a decision.

Again, not being specific about particular risk management options, but
to explain the difference in how we look at them.

(Slide)

This is a repeat of what you saw this morning. It's our goals. We are
still trying to reach a science based decision. And I think we are
accomplishing some education about cloning. And we are still reaching
for a risk management process that is proportionate to the level of
risk.

(Slide)

You saw the spin diagram in Dr. Rudenko's presentation. But if you
imagine these tubes as a three D structure and turn it on it's side.

(Slide)

The point being that a risk assessment does not automatically lead to
just one risk management option. Many risk management options can be
perfectly consistent with the data you have in the risk assessment.

That is the next stage in this process after we get past the risk
assessment. So many options are possible. I think you heard some
suggested during the afternoon.

(Slide)

Does the risk assessment or what we have discussed today change CVM's
position on food derived from clones or their progeny? The answer is no.
This is just the science portion of the process. So only through risk
management would we change the policy.

Would there be any change in the position? Some of the risk management
actions that are available to FDA include things as simple as guidances
for industry. Policy statements. Regulations. Even compliance policy
guides which are instructions to the field for how to inspect.

(Slide)

A few words about the risk management process itself. This is the stage
where burden comes into place versus the benefits. And the tolerance for
uncertainty from the risk manager's point of view. What level of
uncertainty are you willing to live with?

Enforcement issues become important. Can you enforce any policy? How can
you enforce it efficiently? How about in international trade? What are
the consequences for noncompliance?

These are all non-science issues really. These are things that come in
when you start talking about risk management options, and the role of
other public and private groups. It has been mentioned there is USDA at
the slaughterhouse to consider and we have been coordinating with them;
by the way; and also private groups like Dick Nelson's group; and other
breed registries for example. What is their role in tracing, following
clones and their progeny?

(Slide)

No policy is ever final. Final guidance are always open for comment,
continuously. And they are monitored for effectiveness, especially where
there is concern that there may not be something working or that there
may be some changes in the technology that will change the effectiveness
of the guidance.

(Slide)

And then there is also communicating. So a word or two about risk
communication. Not only to our stakeholders here in this meeting in the
U.S., but you may have noticed there are a number of people in the
audience from Canada. And we have also met with folks from Australia,
Japan, the U.K., Italy, France. They are trying to reach the same
decision that we are trying to reach. We are all faced with this
technology and trying to make a rationale decision about it.

There is also an OECD project underway to look at cloning, and the food
safety. And we will be participating in that later this month.

(Slide)

And the place where we will be updating folks on a regular basis is our
website. We encourage you to keep checking there. And we have a special
biotechnology page, which now has a cloning sub-page so to make it
easier for you to find.

With that we have a few final words from

Dr. Sundlof, who would like to wish you well. Thank you.

DR. SUNDLOF: Thank you, John. And I would just like to thank all of the
folks who came and participated in this. This is an extremely important
issue not just for FDA and the Center for Veterinary Medicine, but
obviously, it has much broader ramifications. And your input is very
valuable to us in making those difficult decisions.

I especially want to thank the Committee. To kind of step into FDA's
shoes for a day and try to make some of the difficult judgment calls
that we are required to make every day.

And just as we do, you see that there is not a unanimous consensus among
the members. And that is very representative, I think, of population as
a whole. So I think we have impaneled our Committee very well to
represent those diversiti4es of opinions.

Again, your recommendations and your counsel will be very valuable to us
as we proceed forward. As John has indicated there will be additional
information coming out. We are right in the middle of the process. And
it's good to have everybody along with us for the journey because it's
a, as you have seen, it's not an easy path to walk.

But, again, I want to thank John Waddell serving as a very able Chair
again. John, thank you. And thank you to the members of the Committee.
And all have a safe trip home. Good night.

(Applause.)

(Whereupon, the meeting was adjourned at

4:10 p.m.)