GRADUATE SCHOOL
U.S. DEPARTMENT OF AGRICULTURE
* * *
FDA FOOD ADVISORY
COMMITTEE MEETING
* * *
FOOD BIOTECHNOLOGY SUBCOMMITTEE
OF THE FOOD ADVISORY COMMITTEE
MOLECULAR CHARACTERIZATION
CENTER FOR FOOD AND APPLIED NUTRITION
Wednesday, September 24, 2003
J.W. Marriott Hotel
1331 Pennsylvania Avenue, N.W.
Washington, D.C.
The meeting convened,
pursuant to notice
at 8:36 a.m., before Acting Chairman Francis F.
Busta.
MEMBERS PRESENT:
JONATHAN ARIAS, Ph.D.
Associate Research
Scientist
Department of Biological
Sciences
University of Maryland,
Baltimore County
1000 Hilltop Circle
Baltimore, Maryland 21250
Tel: 410-455-3470
Fax: 410-455-3875
Arias@umbi.umd.edu
BOB B. BUCHANAN, Ph.D.
Professor
University of California
Department of Plant and
Microbial Biology
111 Koshland Hall
Berkeley, California 94720
Tel: 510-642-3590
Fax: 510-642-7356
view@nature.berkeley.edu
FRANCIS FREDERICK BUSTA,
Ph.D.
Emeritus Professor
University of Minnesota
Department of Food
Science and Nutrition
1334 Eckles Avenue
St. Paul, Minnesota 55108-6099
Tel: 612-624-3086
Fax: 612-625-5272
DOUGLAS GURIAN-SHERMAN,
Ph.D.
Science Director,
Biotechnology Project
Center for Science in the
Public Interest
1875 Connecticut Avenue,
N.W.
Suite 300
Washington, D.C. 20009
Tel: 202-332-9110 Ext.
377
Fax: 202-265-4954
dgurian-sherman@espinet.org
MEMBERS PRESENT (Continued):
ANNE R. KAPUSCINSKI,
Ph.D.
Professor, University of
Minnesota
Department of Fisheries
& Wildlife
180 McNeal Hall
1985 Buford Avenue
St. Paul, Minnesota 55108
Tel: 612-624-3019
Fax: 612-625-8153
ark@fw.umn.edu
ABIGAIL A. SALYERS, Ph.D.
Professor of Microbiology
Department of
Microbiology
University of Illinois at
Urban-Champaign
B103 CLSL
601 S. Goodwin Avenue
Urbana, Illinois 61801
Tel: 217-333-7378
Fax: 217-244-8485
Temporary Voting Members:
DENNIS GONSALVES, Ph.D.
Center Director
Pacific Basin
Agricultural Research Center
99 Apuni Street, Suite
204
Hilo, Hawaii 96720
Tel: 808-932-2100
Fax: 808-969-6967
Dgonsalkves@pbarc.ars.usda.gov
STEPHEN BENEDICT, Ph.D.
Department of Molecular
Biosciences
University of Kansas
1200 Sunnyside Avenue
Lawrence, Kansas
66045-7534
Tel: 785-864-4007
Fax: 785-864-5294
sbene@ku.edu
MEMBERS PRESENT (Continued):
CALVIN QUALSET, Ph.D.
Genetic Resources
Conservation Program
DANR Building, Hopkins
Road
University of California
Davis, California 95616
Tel: 530-754-8502
Fax: 530-754-8503
coqualset@ucdavis.edu
NINA FEDOROFF, Ph.D.
519 Wartik Laboratory
Huck Institute for Life
Sciences
Penn State University
University Park,
Pennsylvania 16802
Tel: 814-863-5717
Fax: 814-863-1357
Industry Representative:
JAMES ASTWOOD, Ph.D.
Director, Food and Feed
Safety Policy
Monsanto
800 North Lindbergh
Boulevard
St. Louis, Missouri 63167
Tel: 314-694-8396
Fax: 314-694-8562
james.d.astwood@monsanto.com
ALSO PRESENT:
MR. BOB LAKE
MS. JEANETTE GLOVER GLEW,
CFSAN
MR. MICHAEL HANSON
(Public Comment)
DR. JAMES MARYANSKI,
CFSAN
DR. THOMAS CEBULA, CFSAN
C O N T E N T
S
AGENDA ITEM PAGE
Welcome and Introductions 6
Acting FBS Chair
Conflict of Interest Statement 9
Welcome from FDA 13
Charge and Questions 23
Acting FBS Chair
FDA's Biotech Food Safety Assessment 29
Ms. Jeanette Glover Glew, CFSAN
Questions of Clarification 43
FBS Members
Codex Approach 74
Dr. James Maryanski, CFSAN
Questions of Clarification 92
FBS Members
FDA's Discussion Paper — Molecular
Characterization 103
Dr. Thomas Cebula, CFSAN
Questions of Clarification 122
FBS Members
Public Comment 153
Summary and Review of Charge and
Questions 172
FDA
Discussion 179
FBS Members
Response to Questions 194
FBS Members
Concluding Comments 334
Acting FBS Chair
P R O C E E D
I N G S
CHAIRMAN
BUSTA: The meeting is called to
order. And welcome, all of the
committee members, guests, and the members of FDA to the--this Biotechnology
Subcommittee meeting of the Food Advisory Committee.
My
name is Frank Busta. I'm a professor
emeritus at the University of Minnesota.
I'm a member of the, let's see, the term is full committee. I'm--that is not implied that I'm full of
it, but some people would say it. And
I've been asked to chair this meeting as an acting chair.
In
front of you, you have an agenda, and, as you see, in addition to welcoming
you, we'd like to have our introductions so that everybody knows who everyone
is, and we have it on the record.
I
believe that we're asked always to talk into the microphones because it is
being recorded, and that gives us a record, as well as someone taking notes.
So,
if we could start with introductions, telling us basically who you are and
your--the
committee. Douglas, would you start?
DR.
GURIAN-SHERMAN: Doug
Gurian-Sherman. I'm with Center for
Science in the Public Interest.
CHAIRMAN
BUSTA: And you are a member of the--the
regular member?
DR.
GURIAN-SHERMAN: Yes, I'm a member of
the subcommittee.
DR.
QUALSET: I'm Cal Qualset, professor
emeritus, University of California at Davis.
I'm a member--a temporary member of the subcommittee.
DR.
BENEDICT: Steve Benedict, University of
Kansas, and I'm a temporary member.
DR.
ARIAS: Jonathan Arias, University of
Maryland. I'm a subcommittee member.
DR.
FEDOROFF: Nina Fedoroff, Penn State
University. I guess I'm a temporary
member.
CHAIRMAN
BUSTA: Abigail?
DR.
SALYERS: Abigail Salyers, University of
Illinois, and former President of the American Society for Microbiology. And I'm not sure what kind of member I am.
CHAIRMAN
BUSTA: You are a member of the
subcommittee.
DR.
SALYERS: Oh, okay.
DR.
BUCHANAN: Bob Buchanan, University of
California at Berkeley, and I believe I'm member.
DR.
GONSALVES: Dennis Gonsalves. I'm at Pacific Basin and Agriculture
Research Center, and I'm a temporary member.
DR.
ASTWOOD: I'm Jim Astwood. I'm with Monsanto, and, I'm the industry
liaison.
CHAIRMAN
BUSTA: And Mike?
DR.
WATSON: Mike Watson, the Food and Drug
Administration.
CHAIRMAN
BUSTA: And Mike does all the work.
All
right. To get this organized and
straight, I would like you to refer to our agenda. You see estimated times to accomplish what we need to do today on
the agenda.
We
hope that we can stay fairly close to that.
I will try to be as firm a chair as possible so that we do not diminish
our opportunities for discussion and summaries in the afternoon.
Mike,
we're five minutes ahead of time, but I'd like--I don't mind that at all.
DR.
WATSON: That's fine.
CHAIRMAN
BUSTA: I will turn over the conflict of
interest statement, et cetera, to Mike Watson.
DR.
WATSON: Good morning, again. I'm Mike Watson. I'm the Acting Executive Secretary for the Biotechnology
Subcommittee of the FDA Food Advisory Committee.
First,
I would like to read the temporary voting member appointment and conflict of
interest statements into the record.
By
the authority granted under the Food Advisory Charter of July 2002, the
following individuals have been appointed as temporary voting members by Joseph
A. Levitt, Director of the Center for Food Safety and Applied Nutrition:
Dr.
Steven Benedict;
Dr.
Nina Fedoroff;
Dr.
Dennis Gonsalves; and
Dr.
Calvin Qualset.
With
regard to the issue of conflict of interest, committee members, both permanent
and temporary, were screened for interest in bioengineered food
developers. As a result of this review,
in accordance with 18 U.S.C., Section 208 (b)(3), Dr. Robert Buchanan and Dr.
Dennis Gonsalves have been granted a particular matter of general applicability
waiver that permits them to participate fully in matters at issue.
Copies
of their waiver statements may be obtained by submitting a written request to
the Agency's Freedom of Information Office, Room 12A-30 of the Parklawn
Building.
We
would also like to note that Dr. James Astwood is participating in this meeting
as the acting industry representative, and is a non-voting participant.
With
respect to all other participants, we ask that, in the interest of fairness,
that they address any current or previous financial involvement with any firm
that develops or sells bioengineered food crops.
Finally,
FDA received a letter on Monday this week, September 22, 2003, from the Center
for Science in the Public Interest, CSPI, related to the work of this
subcommittee. This letter was signed by
Dr. Gurian-Sherman, a consumer representative on this subcommittee, on behalf
of himself and two other subcommittee members, Drs. Arias and Kapucinski.
The
letter expresses concern about FDA's management of the subcommittee, selection
of agenda topics, and other issues. FDA
has provided copies of this letter to the subcommittee members, and copies are
available to the public.
FDA
appreciates receiving suggestions for enhancing the work of the
subcommittee. Since this letter was
submitted too late for FDA to fully consider its contents and suggestions for
changes for this meeting, we intend to examine the letter carefully and respond
following this meeting.
For
today, we intend to focus on the agenda that we have prepared. Mr. Chairman, we note that one of the issues
raised in the CSPI
letter dealt with future agenda items
for the subcommittee.
We
leave it to your discretion; but, if time permits, FDA will be interested to
hear any suggestions that subcommittee members may have on future agenda items.
I'll
turn it back over to Dr. Busta.
CHAIRMAN
BUSTA: Well, thank you, Mike.
I'm
not sure if we got a copy of that letter by e-mail before this meeting. I'm not sure how many of you are in a
position to see your
e-mail en route. The--we'll have an opportunity to look at
that in case you hadn't seen it earlier; and, as Mike indicated, we will do our
best to get through the agenda. And we
will place that at the end of the agenda for comment, and we can expand that
for other comments beyond the letter as for future agenda items.
All
right. Now, we're going to have a
welcome from FDA. And I assume that's
Bob Lake?
MR.
LAKE: Yes.
CHAIRMAN
BUSTA: They're really neglecting
you this morning, Bob. They didn't give you a name card.
MR.
LAKE: Well, that's all right.
Let
me--well, again, I am Bob Lake. I'm the
Director of Regulations and Policy at the Center for Food Safety and Applied
Nutrition. I report directly to Joe
Levitt, and one of the things in my portfolio is policy issues relating to
bioengineered foods. Jim Maryanski, Dr.
Maryanski, who will be talking to you later, and who I think is--most of you
know very well--has been my technical advisor for probably 15 years.
He
is the biotech coordinator, but we established that position back in the late
'80s; and his title and mine have changed a little bit over the years. But we have worked very closely together
throughout that time.
I
want to officially, on behalf of SISAM management, welcome you here to this
meeting. I know everyone has very busy
schedules, and it's certainly hard to find a time where we can get everyone.
But
we very much appreciate all of you being here.
You are important to us. We very
much appreciate your time, your consideration; and will value whatever advice
we get from you.
I
thought I would take a little bit of a moment to just sort of update you on
sort of what's been going on, or, in some cases, not going on. Just to give you a little bit of a backdrop,
I'm going to try to do this very quickly.
As
you all I think know, FDA is only one of the agencies in the Federal Government
that is involved in issues that relate to bioengineered foods. The Department of Agriculture, most notably. The Animal, Plant, Health and Inspection
Service has responsibility for, you know, the planning of bioengineered
plants. EPA has responsibility for
genetically engineered pesticides that are genetically engineered into new
plant varieties. And then FDA, of
course, has the responsibility for the safety of foods, and, you know, again,
that's--we're talking about what happens to the person who eats the food.
Also,
we have the responsibility for animal feeds, and so we have a concern about
that, as well.
Since
the StarLink episode of a few years ago, there's been a sense across the
agencies that there has been a need for greater interaction. And, indeed, there have been numerous
meetings among the agencies, these agencies, also others, from time to time, to
deal with a couple of sort of cross-cutting issues. These, by the way, have generally been held under the auspices of
the Office of Science and Technology Policy, OSTP.
One
of these issues that we have grappled with in an interagency context has
related to the potential for new plant varieties that are still in the
developmental stage perhaps inadvertently contaminating traditional food
crops. And the OSTP, after numerous
interagency discussions, published a document setting out some tentative
thoughts about that and invited public comment.
Following
that, the--there was a recognition that there's a growing concern about
the use of food crop plants to produce
pharmaceutical, industrial chemicals.
We generally refer to these as pharm plants, spelled P-H-A-R-M, as a
convenient shorthand for talking about these kinds of crops.
As
some of you know, we did have an episode last year. Nothing got into food.
But it sort of heightened the concerns within the government about the
potential for contamination of food with non-food producing crops, such as corn
used to produce pharmaceuticals.
Those
discussions are ongoing. They have not
come to closure yet. When they do, I expect that there will be something
similar coming out of that to the OSTP publication that I mentioned a moment
ago.
Of
course, throughout all of these discussions, FDA is going to the meetings,
participating in the meetings, with the recognition that our primary
responsibility really is about the safety of the food; and we try to stay
focused on that as we go through these discussions,
recognizing there are many other
issues.
But
the one that is primary importance to FDA, and that we like to stay primarily
focused on is the safety of the food itself.
We--as
you all know, we published a proposal to make our current consultation process
mandatory. We have not taken final
action on that. Any of you who read the
proposal will know that we raised in that proposal an issue about whether we
actually had the legal authority to make the process mandatory. That has continued to be an issue.
The
other thing that has come along is the events of September 11th of 2001, and a
need to focus a lot of attention on bioterrorism. I can tell you personally that that issue has largely taken over
my life since I head the office that is responsible for developing FDA's
regulations to implement that new law that was passed by Congress and signed
President Bush June a year ago.
The
other thing, of course, that we always face is that there are a large number of
very
important issues before the agency at
any given time, and we can't deal with all of them all at once.
When
our Center Director, Joe Levitt, came back in 1998, one of the practices he
instituted was a process, a priority-setting process, that results in something
that we normally refer to as the Yellow Book, that articulates the Center's
priorities.
And
the A-list things are things we are going to do within the current, you know,
fiscal year. B-list are things that are
being worked on, and anything that's not on either of those two lists is not
going to be done for a while.
We
have--again, one of the other things that Mr. Levitt instituted was a process
of seeking public input on what these priorities are. And we can't make everybody happy. We can't deal at any instant with anything--with everything that
is deemed by even us to be important; but we do try to have this orderly
process for setting priorities. And one of the things you will note is that the
mandatory proposal is not an A-list
item.
The
other thing that we are continuing to work on, but have not come to completion
on yet, is allergenicity. This
subcommittee considered some of those issues at your first meeting. We still intend to come back to the
subcommittee with allergenicity issues, but we have not, you know, we were not
ready to do that for this meeting.
We
generally are trying to keep up with the science, though, we certainly see this
subcommittee as helping us in that process.
And, as you will hear more about a little later, we have, over the last
four years, participated actively in the Codex Alimentarias effort at the
international level to develop principles and guidelines for the assessment of
bioengineered plants and also bioengineered microorganisms used in food
production. And Dr. Maryanski will talk
about some of that as it relates to the agenda before you today.
In
the meantime, FDA is still following the guidance that we issued in 1992. We--it
continues to be our belief that all of
the foods that are in the marketplace in the United States today have gone
through that process; and, also, so far as we know, none of the foods that have
successfully completed that consultation process is presenting any kind of
public health problems to American citizens.
Nonetheless,
we recognize that science changes. We
want to assure that our guidance remains current. And that is one reason why
this--in fact the primary reason--why
this subcommittee was created.
We
want to use the very best science in all of the work we do, but I think
particularly in this area where there's so much noise that is not about
science. We want to be sure, and we
understand people disagreeing on matters of policy et cetera. But we want to be sure that we are following
the best science possible.
And
with that in mind, we will be seeking your advice at this meeting, and in
future meetings. And today, we're
asking you to look at
some things on molecular biology--I
can't even pronounce it, and I can assure you I know nothing about it, so I'm
not going to say anything more about that other than to return the meeting back
to the Chair, who will explain what it is we are asking for advice on today.
So
with that, I will close.
Thank
you very much. We are looking forward
to your deliberations today, and to the advice you give us at the end of the
day. And, if there's anything we can do
to help, let us know. Thank you.
CHAIRMAN
BUSTA: Thank you, Bob.
I
know there--you have a busy schedule, and you'll be with us for--until the
break at least?
MR.
LAKE: Yes. I'll be here through the break; though, again, the other BT, that
is, bioterrorism, as opposed to biotechnology, it causes to me leave at the
break to go to some other meeting.
CHAIRMAN
BUSTA: Okay. So, if we have
some questions or clarification for Bob
before--
MR.
LAKE: Yeah, and, in fact, I can stay
through the break if anyone has anything they want to ask me privately; though,
I will take any questions other than anybody might have now.
DR.
GURIAN-SHERMAN: Dr.
Gurian-Sherman. Bob, maybe you could
clarify a couple of things: one is I think you mentioned that the mandatory
process is not on the A-list. Is it on
the B-list? You mentioned that things
that are not on the
A-or B-list are probably not going to
get looked at very closely.
The
other is, do you have any kind of timeline, or rough timeline, on your progress
on the allergenicity issue, as well?
MR.
LAKE: Yes. Yeah, I guess I should have clarified. It not only is not on the A-list, but I've been--okay.
DR.
WATSON: It's on the B-list for '03.
MR.
LAKE: Okay. Well, it is still on the B-list.
The '04 is still I think not finalized.
The--but
there's a good chance that simply
because of everything going on, that it
may not even be on the B-list for the next issue, though we have not yet issued
the '04 plan.
With
regard to the allergenicity, I don't know that I can give you a specific time
frame, other than to note that that continues to be something that we consider
to be very important; and we do, indeed, intent to come back to this
subcommittee. But I'm not prepared to
give you a time frame for that. I just
don't know.
CHAIRMAN
BUSTA: Thank you. We'll I'm on line now to talk about our
charge, and questions that we have for today.
You
all should have received in the mail a discussion paper and a draft guidelines
of Codex; and this morning, in front of you, you have the charge and questions.
I'd
like to go through this slowly and try and paraphrase it somewhat, but as
you've heard this is an area that is of interest and activity with FDA.
And,
as it states in the introduction, FDA
believes that it's important to the
developers of products to characterize the genetic modifications introduced in
those food plants.
Developers
using molecular biological data to assess whether these new substances,
intended or unintended, are likely to be expressed as a consequence of the
inserted genetic material. There have
been many advances in the field, as you've heard many times and are well aware. And FDA is seeking to determine whether any
of these new advances would enhance FDA's food--FDA's safety assessment of
bioengineered food plants.
So,
our charge, specific charge for today is to consider the current FDA approach
for the molecular characterization of bioengineered food plants, and to provide
suggestions regarding additional information the FDA subcommittee believes
would enhance the safety assessment.
This is an assessment of the science.
Now,
there's three items, issues that are listed below, and these are some. Our
discussion and questions and issues are not limited to those,
but they are questions that have been
put forth with our charge from FDA.
Number
one: the molecular biology data provide
information that assists in identifying new substances. Techniques like Northern or Western Blot
have been useful in identifying newly expressed substances.
The
question here is: to what extent does sequencing information contribute to the
identification of newly expressed substances?
And if sequencing information is important for the purpose of FDA's
safety assessment, what sequence information should be reviewed? For example, the entire sequence of inserted
genetic material or the sequence of the surrounding region of the plant genome
et cetera.
If
so, how does this information contribute to the safety assessment? The science behind that, and we've got a lot
of experts here that should be able to give us some insight into that after we
hear what FDA is doing.
Number
two: current approaches to safety
assessment recommend certain kinds of
molecular biology data. There are four
that are listed
here--the number of insertion sites,
number of gene copies inserted into each insertion site, the information on the
organization of the DNA within the inserts, and the potential reading frames
that could express unintended proteins.
The
question here is: are there other data that would be useful to safety
assessment? And, if so, what data, and
how would safety assessment be enhanced?
The
third item on the issues is: there have been many advances. Are there new advances that could be used to
enhance the safety assessment? And, if
so, what and how?
I'll
open end, as we said, as I said at the beginning, these are some of the
items. It's not limited to these, but
these are considerations. From my
vantage point, it seems like there's--that could keep us here for a week and a
half. It's plenty open-ended. So, that is our charge.
The
approach that I hope that we'll be
able to do is we will listen to the
presentations on FDA's current food safety assessment and the Codex approach,
and the discussion paper; and we'll have questions for clarification at
the--after each of those presentations, but not significant debate at that
point, or extensive discussion; but questions of clarification.
And
then, we will have an opportunity for public comment. Has any public comment been submitted? One? Okay.
And
then, we will, again, look at this issue and have some real opportunity for
discussion and evaluation, getting into greater depth that need from the
participants of the experts that are here.
And then, in the middle of the afternoon, I would like to see us go
round, one by one, and succinctly--I love that word--succinctly summarize our
thoughts in response to the charge and the issues.
At
that point, and, hopefully, we're on time or even a little ahead of time, we
then--there is a little bit of agenda on the back--concluding
remarks. But then I would like to address the letter and future guidance,
future agenda items, at that point.
But
we will have addressed our charge, and then we can move on to the future.
That's
all right? We'll move on.
Well,
I'm quite proud that we're running about 10 minutes ahead of time, and since no
one else has his timing agenda, no one else is sort of coming 10 minutes late,
so I'm very pleased.
So,
if our next presenter, Jeanette Glover Glew is ready to go, we will--oh, Mike
Watson has a statement.
DR.
WATSON: I'd just like to ask if there's
any questions for Mr. Lake, please do them before the break so they can be part
of the record?
CHAIRMAN
BUSTA: Oh. All right. So we have it
on--
DR.
WATSON: On the public record.
CHAIRMAN
BUSTA: All right. You have copies of the presentation,
PowerPoint, so that you only have to take notes and not write what's on the
slides.
MS.
GLOVER GLEW: I'm going to give a little
caveat up front, as they showed me how to work this device, but I was not very
successful in the rehearsal earlier.
So, we'll see how we do right now.
Good
morning. As I said, I'm Jeanette
Glover-Glew. I work in the Office of
Food Additive Safety in the Center for Food Safety and Applied Nutrition; and
I'm going to be talking to you, in general terms, about our policy for
evaluating bioengineered foods. I will
also touch on parts of our molecular biology review for these types of
foods. However, I'll just do a little
foreshadowing here, and let you know that Dr. Tom Cebula will be going into
some more detail about the type of molecular biology evaluation we do, a little
bit later this morning.
Do
I have to point to that? To give you a
quick outline of what I'm going to cover in my presentation, I'll start out
talking about the Federal Government's regulatory framework, then
talk specifically about FDA's policies
and procedures. And I'll wrap up
talking about some recent initiatives we've made in light of public input we've
received.
In
1986, the Federal Government proposed a coordinated framework for regulating
genetically engineered foods. There
were three primary players: the U.S. Department of Agriculture, the
Environmental Protection Agency, and the Food and Drug Administration.
Two
of the primary principles based on this coordinated framework were that it
would be the product that would be evaluated, not the process of its
development; and that the products would be evaluated under existing
frameworks. The United States
Department of Agriculture evaluates agricultural food safety, doing field
trials; and EPA evaluates the food safety and environmental safety of products
that have, well,
pesticidal--insecticides inserted; in
other words, if BT proteins have been inserted into a crop that is EPA's
responsibility to evaluate.
That
brings us to FDA. Our statutory
authority derives primarily from the Federal Food, Drug, and Cosmetic Act. I'll be calling that the "Act"
through the rest of my talk.
Under
the Act, we're responsible for the food safety and proper labeling of all foods
and food substances, except for meat and poultry products, which are evaluated
by USDA.
That
means that we have oversight over cereals, fruits, vegetables, plant
by-products, such as starch and oil, milk, seafood, and other substances added
to food, such as flavorings and preservatives.
There
are two provisions of the Act that are particularly important in ensuring food
safety. One of them is our post-market
adulteration provision in Section 402.
This is our primary legal tool for regulating the safety of whole
foods. It means that if a food enters
the marketplace, and we find it to be adulterated, for example, if it had a
level of toxicant that was outside of the normal range, or if it had an
unlabeled food allergen, then we could
take action to remove that product from the market using our post-market
adulteration authority.
We
also have the Section 409 authority, which means that an additive that is going
to be added to food must undergo pre-market review and approval by FDA before
it can enter the marketplace, that is, unless the product has been demonstrated
to be generally recognized as safe.
If
we see a product that is not substantially similar to products that have been
consumed in food, then we could ask that it come in under our pre-marked
approval authority.
I'll
next talk to you about FDA's policies and procedures.
In
1992, FDA published a policy stating how we believed the foods derived from new
plant varieties should be regulated. It
was developed for genetically engineered foods, but it described how we would
apply our authority under the Act to ensure the safety of all foods under our
authority.
It
was, as I said, derived primarily for
developers who, at that time, were
using recombinant DNA technology in crop production. And those are primarily the users that have operated under that
policy statement.
Let
me go over some of the basic principles in the policy statement.
First,
we consider the nature of the food, not primarily the method of
development. Any food, including
genetically engineered foods that enter the market place, must meet the same
stringent safety standards as convention foods. And those traditional counterparts are the foods that we compare
the bioengineered food to.
Some
other basic principles in the policy statement. We recommended guidance on particular scientific and regulatory
issues, and we also recommended a voluntary consultation with FDA. The purpose of that consultation was to make
sure that any questions that might arise of a scientific or regulatory nature
would be resolved before the developer went to market.
The
core of the guidance document was a
series of flow charts related to the
safety and the nutritional values of genetically engineered foods. You could see if you were a developer, you
would walk yourself through this flow chart, and you would--could end up
eventually in one of two boxes. The box
at the bottom says no concerns, and the boxes off to the side say consultant
FDA. There is also in the flow charts a
third box that says basically don't even think about going in that direction;
but that's not on this particular slide.
What
happened, practically speaking, is most developers, when they go through the
flow charts, end up in the no concerns box.
However, because of our desire to encourage the voluntary consultation
process, we believe that all of the people have come in to us to demonstrate
what they think are the issues that, once they go through our flow charts, and
to make sure we agree that they fall into the no-concerns box.
The
frequency and level of consultation that we carry on with the developers is
really dependent upon the complexity and the novelty of
the crop and the insert.
We
encourage them to come in early and often.
This is an iterative process. We
believe that, by coming in early, it benefits both the developer and FDA. We're aware of what's being done in terms of
the research, and they're aware of the kinds of issues that we might find of
concern.
We--in
our 1990 policy, we did not publish a suite of testing regimes that people
could go and say, okay, I've got a tomato or I've got this type of insert,
therefore, I need to do these types of testing.
We
wanted this to be done on a
case-by-case basis. And so what happens is the company comes
in. They say, okay, this is the
information we've developed in the lab or in the greenhouse or in our field
trials. And, we say, okay, well, based
upon what you're demonstrating to us, we have these kinds of questions. And the company will use the input FDA gives
them to go back to their lab or the greenhouse or the field trial, and develop
the data to answer those
questions.
So
we have an iterative process, where FDA has credible input about the kind of
testing regime. It's done on a
case-by-case basis.
Prior
to commercialization, the notifier will come in to us with a final data package
that summarizes the information they've developed, and FDA will respond to them
with a letter saying either we have--still have remaining questions or we have
no further questions.
The
approach in these consultations is multidisciplinary. We have teams of individuals who review these submissions. They include molecular biologists, several
of which are here today, microbiologists, chemists, nutritionists, food
scientists of various kinds; and we cover a broad spectrum that's provided,
everything from the agronomic characteristics to the compositional
characteristics of the crop.
In
this next slide, I've just presented the information in this way to emphasize
that we look at both at the intended changes and the
unintended changes to the crop. In the intended changes, of course, we're
going to be looking at information about the trait--desired trait that was
inserted and to the kinds of alterations that might make. And we look at information about the
background of the crop, and the exposure.
However,
we're also looking for unintended changes, because this tells us whether or not
cryptic pathways have been turned on.
We'll look and see whether or not there's been changes in known
toxicants or nutrients to see if there's something that lets us know that a
genetic pathway has been interrupted by the insertion, and that there's
something that we need to be paying special attention to. And another way that we do that is to look
at the genetic stability over time.
I've
added these next four slides just to go over real quickly because it gives you
the elements of the safety evaluation, including what we look at in terms of
the molecular biology evaluation. But
Dr. Cebula is going to be going into some more detail later on; so this is a
just a
skim to prepare your minds for what
we're going to be talking about.
In
the host plant, we'll look at the taxonomy, history of safe use, the presence
of any naturally occurring harmful constituents, and important nutrients. If we were going to be looking at an orange,
we'd expect Vitamin C to be there.
In
the donor organism, we're going to be looking at similar characteristics, but
we're also going to be looking through--whether or not any baggage has been
picked up due to passage through microbial host. And, of course, most importantly for the donor organism, we're
going to want to know about the identity and function of the introduced
material.
For
that introduced material, we're going to look at concentration, so we know what
dietary exposure is.
We're
going to look at the potential for it to be an allergen or a toxin. I already mentioned that we're going to be
looking at
similarity to other substances in the
food supply. Talked about looking for
changes in metabolic pathways.
We're
going to find out if there's
post-relational modification, such as
glycosylation of a protein. And
something that I'll throw out here.
Other countries have been concerned about the presence of antibiotic
resistance marker genes. And we also
evaluate those.
And
this comes to the information that is more the basis of what we're going to be
talking about and getting input from you on today is the inserted genetic
material. And here, we're going to look
at the method of transformation, what the regulatory sequences are, the
promoters, the terminators, how those are working, whether there's the chance
of open reading frames that might read through into the indigenous genome, how
many inserts they are, where they are, if they, you know, flipped or they
inserted into a site that may create problems; and then we're going to be
looking at Mendelian inheritance, so whether or not it's
genetically stable.
I'm
going to switch gears here, and just for a few minutes talk about some of the
recent initiatives that we've taken as a result of a public outreach.
We
know that the biotechnology field is rapidly changing. That's why you're here. That's why we want your advice. But also, in 1999, we decided to hold a
series of three public meetings. And we
said, we're going to look at our 1992 policy to see if it needs to be modified
in any way. And, as a result of soliciting
that input, we received over 50,000 comments.
Excuse me a moment.
We
were pleased to find that, as a result of those comments, that we really hadn't
received new data to question the safety of bioengineered foods that are on the
market today. However, we heard concern
from public, academics, public policy groups about the future, of whether or
not the products that were going to be coming down the research pipeline were
such that we had either the regulatory or scientific framework and background
to address the safety of these
products.
So,
as a result of that solicited input, we have taken several initiatives. One of them is you guys. That's why we're here today. We established the Food Biotech
Subcommittee, and we hope to be using you for this purpose quite a bit in the
near future.
We
have committed to support research on allergenicity, and we have combined with
USDA and EPA to support a study by the National Academy of Science on potential
unintended effects in bioengineered foods.
Before
I wind up, I'm just going to give you a snapshot of the types of products we've
seen. The corn, cotton, and soybean are
the primary commodities that we've seen in.
We've seen other minor crops.
The kinds of traits that have been introduced have been primarily
agronomic traits that are of interest to the farmer, either pest resistance or
herbicide tolerance. Though we expect,
in the second and third generation of crops, to see more complex physical
traits, such as
salinity, tolerance, or drought resistance;
and also traits that would be of interest to the consumer, such as increased
nutritional value.
The
goal of us at CFSAN and here today in talking with you is to make sure that
we're prepared to meet our scientific and regulatory responsibilities in the
future. So we're really looking forward
to you looking at the charge and the questions and advising us as to where we
can to specifically in the arena of molecular biology techniques.
And
I just wanted to let you know that I've given you our website. If you want to look at any of the documents
that I've mentioned today, either our 1992 policy statement or the proposed
rule that Mr. Lake mentioned, or a list of the products we've developed,
including our scientific memos evaluating those products, you can go to the
website and find that information.
But
I think we're running ahead of schedule, so I have time to answer any questions
you might have before we go on to the next speaker
at the break I guess.
DR.
GURIAN-SHERMAN: Jeanette, I had two
questions, clarification. One is
concerning the website. That doesn't
have, as far as I know, any of the more detailed aspects of the consultations,
in other words, the data summaries, which I found very useful to look at to
kind to get a better idea of what is actually submitted and what you're
actually doing with it.
MS.
GLOVER GLEW: That. That's a--
DR.
GURIAN-SHERMAN: So one question is: if
committee members want to see any of those, could they be made available and
how could that be done?
And
the second question is: If you could clarify a little bit kind of the
case-by-case approach. How do you
determine kind of what the baseline minimum assessment should be? And to put that in context, for instance,
when I looked at some of those studies, just as one example, two of the BT
crops, looked at whether phytate levels and known anti-nutrient in the corn had
changed, two
did not. You know, so how do you determine what's enough? Which anti-nutrient should be looked
at? Which allergens, you know, et cetera,
under the current system?
MS.
GLOVER GLEW: Okay. Try and remove the first question before I
get to the second.
The
first question has to do with the fact that I mentioned that at the end of the
consultation process, we receive a data package that summarizes the material,
and this is what we use when we are completing our evaluation.
That
information is not currently available on our website. It is available by Freedom of Information
Act request, which is how Dr. Gurian-Sherman got it.
We--I
did not go into all of the efforts that we have committed to make as a result
of the public meetings. I wanted to
focus primarily on the scientific nature of some of the concerns that were
expressed, particularly the ones that you can address today in the molecular
biology discussion.
However,
we have made some commitments to
try and have increased
transparency. Those are something that
we have to balance with our obligations to protect confidential business
information. But we have--our ongoing discussions. I honestly don't know, Doug, whether or not
the Food Advisory Committee can get copies of those documents outside the FOI
process, and perhaps one of the people on the FAC Committee can help us with
that a little bit later.
The
second question: how do we get a baseline?
That's a good question, and the thing is it's like mini-targets as it
moves. And I'll use your phytate
example; is that when some of the earlier consultations, we would talk about
the areas of concern--the nutrients, or the toxicants, or the
anti-nutrients--and the company would go away; and they would develop that
information. And, this is in addition
to general principles, which we outlined in the 1992 policy, about looking for
allergenicity, examining whether it's a potential for it to be a toxin.
So
we have the general principles, and
then we have some of the more specific
give and take on the case-by-case basis.
And the answer about the phytate is that it does--the target moves.
As
we've been involved with Codex, as we've been involved with our European
counterparts, particularly Dr. William Price, who is in the audience today, has
been participating in committees that are laying out some of the known
important nutrients, anti-nutrients, and toxicants; and we're able to now use
these kinds of materials to give clearer, better, more particular information.
So,
you can look at earlier submissions, and you'll find that they're missing
information that perhaps are in more current submissions. And that's because, as the science advances,
as we are more aware of the types of information that are important for us to
look at, we would be
giving--tailoring our information.
Does
that answer your question?
DR.
GURIAN-SHERMAN: Yeah, I guess the only
follow up I would have is, if you're
developing some of this internal
guidance or guidelines, is there any plan on making them publicly
available? Are they just still in the
development stage?
I
think in 2000, NAS recommended that you do that with, you know, come up with a
database of known toxicants and anti-nutrients. So, you know, is that something that's going to be made public?
MS.
GLOVER GLEW: We're working internally
on guidance. It suffers from the same
resource problems that Mr. Lake referred to earlier, but one of the things
that, if everything works out in terms of our resources, and how productive we
think this would be for industry, we might use the information that we develop
today for a molecular biology guidance.
The
compositional guidance we have held off a little bit on because we're waiting
to see what the NAS says about the unintended effects. So, guidance documents are something that we
constantly have it in the back of our head in order to give guidance to
industry.
But,
as we've just talked about the phytate issue, we weren't--we didn't know that
that was something that we probably be asking for perhaps early in the
process. We know now. So, if we have guidance and it's hard and
fast, that leaves us a little less flexibility in order to look at these on a
case-by-case basis. So there's
advantages and disadvantages to having written guidance.
CHAIRMAN
BUSTA: Abigail.
DR.
SALYERS: I have a question for you, and
for Mr. Lake, both. It has to do with
priorities.
If
I were prioritizing issues on your A-, B-, C-lists, I would put bioengineered
foods on the E-list, and I'd put bioterrorism on the F-list. You know, as in forget it, you know.
And
I would put on the A-list things like probiotics and functional foods that have
been largely un--not looked at; and also just good old early detection of
microbial, unintentional microbial contamination of foods. And so that we don't have to pull things
back after they've
appeared on grocery shelves.
And
so my question is, and I understand why you've had to put bioengineered foods
and bioterrorism on the A-list, but so I'm going to
be--this question is kind of
pessimistic. I know you're stuck with
that because of political considerations, but are you thinking about ways that
you might use whatever money you're pouring into those areas to also address
some of these other issues, the real, which in my opinion, the real public
health issues, the things that sicken and kill people at still somewhat
horrifying level; that there are ways to divert some of this attention and finances
into doing something in those areas.
MS.
GLOVER GLEW: I'm going to let Mr. Lake
answer the part about dealing with substances that might kill people.
DR.
SALYERS: I'm not, I'm not--this is not
a hostile question.
MS.
GLOVER GLEW: I'll answer something that
perhaps is underlying your question, and you
may not have intended this to underlie
your question, is that we have for bioengineered foods a process that is
working, and that we believe is protective of the public health.
So,
there are many ways that we would like to expand our abilities to be responsive
to industry in giving them guidance about molecular biology. That's why we're here. That's why we're interacting with the
National Academy of Science. There are
things that we would like to do to make certain that our regulatory framework
and our scientific background is what we need in order to evaluate these
things. And I think that we have that, and we'll continue to have that in terms
of Center priorities.
DR.
SALYERS: Well, let me just give you an
example. This is one of these things
that happens to me accidentally. It
makes me even more unpopular than I am already.
But
I happen to think probiotics is a good idea, but I found out, sort of
accidentally, that most of the strains of bacteria that are used for
probiotics are resistant to vancomycin,
which is one of our less antibiotics for treatment of certain types of
diseases.
And
so I said to them, to these people, I said, have you--now are you talking about
markered antibiotic resistance genes in transgenic plants, which are for, you
know, effective against antibiotics that basically are not a problem any more;
but here's some vancomycin resistance in these probiotic strains.
And
so I got this storm of anger out of that.
And I said, but you really ought to ask yourself is this just some
metabolic thing or some, you know, could possibly pose a public health
risk. And that, as far as I could tell,
was not under investigation anywhere.
And
I just wonder how many more examples of that kind are out there in the
probiotics, the functional foods area; and then, of course, we have the problem
of is there some way that we could try to detect contamination of foods before
the food actually gets on the grocery shelves.
So that's
the reason I was asking this question.
CHAIRMAN
BUSTA: And I'm being very good on
chairing this, and letting you ask these questions before we lose Bob. But that wasn't a terribly expansive
question on clarification. Bob.
MR.
LAKE: Nonetheless, I think it was a
good question, so let me comment to the extent that I can.
Though
we try to do priorities in a way that we think is rational from our
perspective, you know, there are a lot of forces out there, including
congressional mandates that are, you know, in the case of bioterrorism, very
explicit.
And
one of the things that's driving my life now is that Congress, and the law that
I mentioned earlier, the new bioterrorism law has a couple of regulations, a
couple of requirements, that will go into effect on December 12th of this
year--one on registration and one on prior notification on imported foods--that
will go into effect whether FDA has regulations on the street or not. However, we have been mandated to write
regulations, and it is our strong
belief, and I think the belief of everybody we're hearing from in other
governments and the industry and whatnot, that, if we fail to have regulations
on the street, that there will be chaos; that everybody needs those regulations
in order to implement this law in an orderly way.
So,
whether we or anyone else, you know, necessarily would have chosen those as
being a top priority, it is certainly clear that the events of September 11,
2001 have altered the state of play in a very significant way for FDA and for,
frankly, all of the Federal Government.
But
also, I think aside from the very real issues, which I personally believe need
to be addressed in the area of bioterrorism, I think we're facing a situation
with the registration and prior notice activities, and I will be going
here--from here to a meeting about
those because we really need to publish those by October the 10th if we are to
have an adequate lead time. And we've
had a huge effort ongoing, and hopefully we'll meet
that date.
So
that's one thing that's kind of out of our control. But also, it's just one of the realities that, you know, the
world sometimes gives us things that we didn't expect.
With
regard to--when you talk about probiotics, I assume you're tying that back to
genetic engineering. And I guess my
general comment about that is that we try to keep up with products that are
actually entering the marketplace. And
that, of necessity, I think sometimes means maybe we're lagging a bit on things
that are under development that are not quite close to being marketed.
I
should, however, note a couple of other things with regard to genetic
engineering. We do have, you know, on
the pharmaceutical side of the house, a lot of activity that has been ongoing
for a number of years. And I'm not, you
know, qualified to speak about all of that.
But just keep in mind that bioengineered products are not just about
foods; they're about other things. And
the Agency has people heavily involved
in many of those areas.
The
other thing is, just to comment on your issue of methodology. That is something that is receiving
attention here and internationally, as well.
But, you know, what we are really focusing on here is our job of
evaluating the safety of in particular new plant varieties, and being sure that
we're doing that in the right way. And that's why we're seeking the advice that
we're seeking here.
DR.
SALYERS: Well, the reason I asked that
question, which our esteemed Chairman obviously thinks is not germane to the
issue at hand, and I think you sort of don't either.
But
my point is that, if we're going to talk about technology for evaluating
safety, fortunately because of the new types of technology that are available,
many of the things that we would talk about here today have broader
implications; and maybe we should be aware of those possible broader
implications; that there are broader uses.
And that was the only reason I
raised the issue.
MR.
LAKE: Well, no, I think, you know, I
mean you're raising an important point, and the Chair has added to the agenda,
if I'm understanding it, the issue of what are topics that this subcommittee
perhaps might address in the future; and maybe, at that time, you could, you
know, put some of those thoughts on the table.
And we're certainly anxious to hear from all of you on your thoughts,
and we'll certainly consider them.
By
the way, in my thing earlier, I did fail to mention the one thing that Jeanette
did briefly touch on. And after I'm
gone, if you have any further questions, Dr. Maryanski can address them; and that's
the National Academy of Sciences study on unintended or unexpected
effects. And, as Jeanette pointed out,
that is being co-sponsored by USDA and EPA, as well. And we are certainly looking forward to that input. Thank you.
CHAIRMAN
BUSTA: Anne?
DR.
KAPUSCINSKI: Thank you. Thank you, Jeanette. That was a really nice, clear overview
presentation.
My
question has to do with when you talk about that you are using the language we
look at, for example, when you were showing the slide about intended modifications
and unintended modifications, I'd like to just get a better sense of how the
look at process really works. When--if
you're going into a consultation with a developer, are you primarily going to
look at what that developer on their own has though is necessary to do to look
for both the effects of the intended modifications and possible unintended
modifications? Or, to what extent are
you--and are you going to basically look at what they provide to you as they
think is the information and the issues they should be asking about. Or, to what extent are you going in with a
set of things that you think should be asked about, given their specific case.
And then, I guess, as a follow up to that question, how do you envision that
might change after the National Academy report on unintended modifications
comes out? And I'm sort of focusing
on the unintended modifications,
because that's clearly, I mean, from my perspective, that's sort of the main
bug-a-boo in this area. And,
personally, I'm interested in, you know, helping the agency come up a way that
those unintended modification issues can be addressed in a way that's not going
to completely paralyze the Agency. I
don't think it's realistic for the Agency to be the one that actually carries
out the risk studies and all the assessments.
I think the burden of that has to be on the developers. But I'm interested in helping the Agency
figure out what's a good balance so that, you know, there is some kind of
independent--if it's not a standard checklist, which may not be always useful,
at least some kind of independent process of sort of going through, an
eliciting of, you know, have we thought of this. Have we thought of A, B, C, and D to make sure that the developer
has done an adequately thorough job.
MS.
GLOVER GLEW: Okay. Excellent.
For a while there, I was going, yes, yes, no, yes, to
your various questions. But since I've
lost track of which are yes and nos, I'll try to answer it in a more global
sense.
As
I mentioned earlier, there are specific principles and flow charts in our 1992
guidance document that walk the developer through the types of considerations
they should be evaluating toxicity, allergenicity, is there a marker gene, is
the marker gene expressed for an antibiotic that, you know, is valuable
clinically. So we have principles in
general in our 1992 policy.
Then,
when the company comes in for the early part of their consultation, this
iterative process, we develop collaboratively what they're going to be
doing. They usually will bring us some
early data, and we'll look at it. And
in terms of unintended effects, we may be looking at a Western Blot, and see
that there's a protein that, you know, doesn't belong. It's the wrong shape, size, and it's showing
up on--and then we'll be going, what's that?
And why is it there? And what's
your explanation for that?
And
so, they'll go, okay, well, we, you know, sequenced this little piece, and we
found out that this happened.
So--it--we have--so what
I'm--I guess I'm trying to say, we have
principles that people follow using our 1992 policy, and our 1996 consultation
procedures, which are also on the web.
Then we have an iterative case-by-case discussion; it's a chat that we
have with these people. They tell us
what they're doing. We tell them the
kinds of regulatory and scientific questions we think arise based upon what
they're doing. And they will go out and
develop the data that answer those questions, come back to us with a data
package, and we'll say, okay, these are the questions we asked. Did they address them? Are more questions raised by the information
that they developed? Do we need to go
back again?
And
so it's a collaborative, iterative process based upon established principles,
plus a case-by-case interaction.
And--has
that answered at least a piece of your question?
DR.
KAPUSCINSKI: Yeah, the second piece I
guess is I was just wondering how you envision the, you know, the
recommendations you get from the NAS?
Do you envision that, at this point, changing this process in some ways
and?
MS.
GLOVER GLEW: I just don't have a good
picture in my crystal ball about that.
We're real excited about the potentialities for what we can get, and how
we might use that. We're hoping that
they will do something similar to what you're doing today, and say, okay, the
technology has changed enough that we can recommend that you ask for this type
of information or that they develop this type of data, because this will
provide valuable information. But I'm
not sure what's going to happen with that.
But we're looking forward to it.
CHAIRMAN
BUSTA: Nina?
DR.
FEDOROFF: My question is partly
historical and partly contemporary. It
has always puzzled me that the EPA was approving or not approving StarLink corn
based on the potential for allergenicity of the cryonide seed. That seems to
be your bailiwick, because it's
environmental.
MS.
GLOVER GLEW: Your confusion is
understandable. I didn't spend a lot of
time at the very beginning talking about the regulatory framework because I
wanted to speed through into FDA's part.
EPA is responsible for evaluating both the environmental and the human
food safety for pesticidal proteins, for plant incorporated protectants. And so this is mostly BT products. It's the way the framework of the law is
divided up. We will look at the product
and see if there are any considerations in terms of compositional changes that
might require, like, different labeling.
So we do evaluate the product from FDA's perspective, only we love the
fact that on StarLink, we can do this huge burden shift. It wasn't our responsibility.
DR.
FEDOROFF: Pardon?
MS.
GLOVER GLEW: It wasn't our
responsibility.
DR.
FEDOROFF: Yeah, I noticed, though--on
the other hand.
MS.
GLOVER GLEW: Because of—
DR.
FEDOROFF: On the other hand, is there
any effort to make the criteria uniform?
Is there any effort to reconcile your criteria and theirs?
MS.
GLOVER GLEW: Absolutely. Mr. Lake mentioned the fact that we have
collaborative efforts that are ongoing.
We are right in the middle of discussions with EPA and USDA about what
our requirements--I say requirements loosely since it's a voluntary
program--but what types of information we look at in the data packages that we
get. Mr. Watson, Dr. Watson is working
on that right. He developed this table,
and we pay very close attention to the kinds of information that EPA developed
in terms of allergenicity detection for the StarLink, because that's something
that's real pertinent to us. Those of
you who were on the previous meetings, subcommittee meeting, you know, heard
about what we're doing about allergenicity, and the kinds of considerations
we're taking. A lot of that came from
our interaction with our counterparts at EPA and their experience with
StarLink.
CHAIRMAN
BUSTA: Bob?
DR.
BUCHANAN: A general question: how many
new conventional foods and genetically engineered foods do you approve per year
approximately?
MS.
GLOVER GLEW: I'm sorry. I didn't.
DR.
BUCHANAN: How many new conventional
foods, for example, a new type of nut that existed somewhere, and it's sought
to have approval in the U.S., and how many genetically engineered foods do you
approve per year?
MS.
GLOVER GLEW: Per year. Okay.
We have since 1994, when we first started receiving these biotech
notification files, or BNFs, evaluate a little over than 50. If you're talking about do we have some
brand new novel, never-before-seen food on the marketplace, I don't think that
you could characterize it that way.
It's mostly people who have taken maize, soybean, cotton, and they have
added an herbicide tolerant, or a pest-resistant chain to it. So it's something that, if
you drove by the field at 55 miles an
hour, you'd look out there and say, that's cotton.
So--just--an entirely novel crop isn't
something that we see. We see mostly
modifications to existing commodity crops.
DR.
BUCHANAN: So there's no new macadamia
nut or something like that?
MS.
GLOVER GLEW: No, not at this point in
time.
DR.
BUCHANAN: Thanks.
MS.
GLOVER GLEW: That could be coming down
the research pipeline. Who knows?
DR.
FEDOROFF: I think your question was
whether your approve, when someone brings in a new whole food from a different
part of the world that has not been marketed here before, wasn't that the
nature of your question?
DR.
BUCHANAN: Right. Yes, right.
MS.
GLOVER GLEW: Okay, so it's like--
DR.
FEDOROFF: I misunderstood your
question. Do a kiwi fruit--
MS.
GLOVER GLEW: --If I showed up from
New Zealand.
DR.
BUCHANAN: Yeah, kiwi is a great
example.
MS.
GLOVER GLEW: Okay. If--I mentioned that our post-market
adulteration provisions were the primary legal tool for evaluating whole
foods. If something came on the market
today, and we didn't have any information indicating that it
was--had toxicant, or wasn't allergic,
we probably would have no need to take action; and so we would not utilize our
post-market authority to take action against that crop. However, if something came on the marketplace
that was just totally novel for the American food supply, we have our authority
under the Act, totally aside from the bioengineered food process.
DR.
BUCHANAN: Yeah, that was the--
CHAIRMAN
BUSTA: That's separate from the
biotechnology activity. So I'm not sure
that--
MS.
GLOVER GLEW: Yes.
CHAIRMAN
BUSTA: I'm trying to keep us obviously
focused--
MS.
GLOVER GLEW: Well, I'm trying to
explain is that we still use our authority under the Act for bioengineered
foods. If we needed to see something
that was adulterated or, you know, if we saw that something needed to come
through the petition process, we would do that for a bioengineered food. So the Act applies uniformly. We have the same safety standards for all
foods the FDA evaluates.
CHAIRMAN
BUSTA: First of all, before I call on
Doug again, are there others who have not asked a question that want
to--clarification questions?
Or,
last call for Bob Lake.
Doug?
DR.
GURIAN-SHERMAN: Yeah, I want to make
two points of clarification. They're
not actually questions, but they're both points of clarification. In terms of new foods, I know of at least
one that's come on the market in the last few years in the U.S. It's called Kworn. It's made with fusarium finatum.
It's a soil fusarium. It
was never the food supply before; was
marked in Europe, and did go through the grasp process at FDA that did have
some toxicity studies, animal studies, et cetera that that was subjected
to. That was, again, grasp studies,
voluntary.
To
Anne' question, I would just like to venture, and I know the committee isn't
really privy to this, but when we did our study looking at FDA, we FOIAed not
only the actual data packages that FDA looks at, but also the communications
between the developers and FDA. And I
won't say that it's impossible that I missed anything, but only found about six
examples where FDA, on record, asked the company, let's say for more data or
for clarifications. And three of those
went unanswered or were not, we felt, adequately answered. So, there certainly is give and take. Maybe some of it isn't on the record. It should be. But there's not, from our perspective of what we saw, a lot of
information to indicate that FDA is pushing the companies for more data.
CHAIRMAN
BUSTA: Doug, to keep us--
DR.
GURIAN-SHERMAN: So that's—
CHAIRMAN
BUSTA: On line that's good discussion
comment, but not in the presentations.
We have this afternoon to get into discussion. We're still in the clarification--questions for
clarification. Dennis?
DR.
GONSALVES: Well, I just was going to
add, you know, the question on the whether FDA asked questions that had an
impact. Well, when we were deregulating
the transgenic papaya, we actually were moving two lines through the
process. And when we hit the FDA,
another line had some other inserts in it, and because of the questioning that
we needed more data, basically we withdrew that line, because we did not have
enough information. So the point here
is that--the experience that I had was that the questions that FDA did ask had
an impact on our actions to withdraw one of the papaya lines.
MS.
GLOVER GLEW: Just a quick remark. I'm sorry to interrupt. I just want to say that FDA, along with all
the other regulatory agencies,
occasionally struggles with the do we
want to know this or do we need to know this.
And occasionally, we do err on the want to know, but primarily believe
that when we ask questions, it's in the need to know area. And if a company or developer did not
provide us with the information that we needed to know to evaluate the safety
of that product, we would not give them a letter saying that we had no more
questions.
CHAIRMAN
BUSTA: Any more clarification. James?
DR.
ASTWOOD: Thank you. I have one question, and it kind of relates
to Dr. Fedoroff's earlier question.
Would you agree that, although it appears complex that both the EPA and
the FDA share jurisdiction over plant incorporate protectants, or BTs in
particular, that when you look at the history of the regulation of pesticides
and the experience that the EPA has with food-feed environmental safety of
chemical pesticides, and then the subsequent history that they have had
regulating and evaluating the safety of microbial
pesticides, including BTs, that it
makes sense, in fact, for the FDA and the EPA to collaborate and share
responsibility for the evaluation of those kinds of products.
MS.
GLOVER GLEW: Yes, I think the way the
roles are laid out right now has been working very successfully.
CHAIRMAN
BUSTA: I have one last question. If the use of biotechnology has developed
to, let's say, double a specific nutrient--
MS.
GLOVER GLEW: I'm sorry. I'm not hearing
you.
CHAIRMAN
BUSTA: If one uses a biotechnology to
double a nutrient, a given vitamin or whatever, this is arbitrary, would that
be in the same consideration?
MS.
GLOVER GLEW: As I just mentioned
briefly is we believe that some of the products that are going to be coming
down the research pipeline are going to be products that are targeted to
consumers who want to have increased levels of, you know, a fancy nutrient or
something. And
certainly a product that was
bioengineered and had an alteration in its nutrients would--we would request
that they come to FDA during our--are part of our consultation process. And if there was a substantial change in
nutrients, we would probably have to consider whether or not the product would
need different labeling or a different common unusual name.
CHAIRMAN
BUSTA: We're at break time. I just would like to--before we come back
say that what I'm trying to do is keep us on focus. Our charge is to consider the current FDA approach to the
molecular characterization of bioengineered foods and make suggestions for
additional information that will be needed.
We'll try to stay with questions of clarification for the next three
presenters. And then we can get, and
after public comment, get into depth of discussion and where we want to--what
we want to tear apart and put together.
Let's take 15 minutes. Let's
start promptly at 10:14 on my watch.
[Whereupon,
the meeting went back on the
record at 10:15 a.m.]
CHAIRMAN
BUSTA: May we reconvene, please. The next presentation is on the Codex
Approach, by Dr. James Maryanski. I
have been negligent in my chairing to remind you all--I've just been calling
you by your first name, and it's appropriate that individuals give their name
before you make your comments or you ask your questions so that it's in the
official record. I think the
stenographer, being that no one has the same first name, we're all right. But if would be appropriate that everyone
give their name as they speak. And with
my voice, I rarely have to do that.
Most people, whenever I talk, people know who I am. I'm--I guess I've stalled long enough. We're about ready to--
DR.
FEDOROFF: Almost everyone's back.
CHAIRMAN
BUSTA: Almost everybody's back.
DR.
FEDOROFF: Not quite. She's still getting coffee.
CHAIRMAN
BUSTA: Yeah, and we will have Dr. Anne
Kapuscinski read her name into the record
when she returns, because she wasn't
here on our initial round. But she is
here for the record.
Dr.
Maryanski?
DR.
MARYANSKI: Okay. Thank you, Mr. Chairman. Good morning, ladies and gentlemen.
I
have the pleasure to tell you a real success story in biotechnology this
morning. You know, we hear so much
discussion that's often seems either difficult or even contentious; and you
often hear of differences between our country and other countries around the
world on biotechnology.
I
want to tell you a really different story, a story where everybody actually
came to agreement at the end of the day.
So this is really a pleasure to be able to tell you about the new
guidelines that have been developed on the--in the international community for
assessing the safety of foods developed by biotechnology, and one which we at
the Food and Drug Administration have participated in.
But
let me first tell you who Codex is.
Many of you, I'm sure, know, but, in case you don't
know, the Codex Alimentarias Commission
is the body that has been established under the U.N. system by the parent
organizations--the World Health Organization, the Food and Agriculture
Organization. Codex Alimentarias is
Latin. It means food code. And, as such, it is a collection of
internationally adopted food standards and guidelines, and those are intended
to ensure consumers' health, as well as to facilitate free trade. And, so, this is a body that has been in
existence since 1962. There are about
169 member countries, so this organization has global representation around the
world in both developed and developing countries, as well as NGO
representatives that include public interest groups, as well as industry. And so it's a very broad organization.
Woops. Wrong way.
Sorry. In 1999, the Codex
decided that it would take on some work in the area of food biotechnology, and
it established a temporary committee.
Codex has lots of committees that work on various things. But it
also occasionally establishes temporary
committees for specific purposes; and these are often called ad hoc task
forces; and, in this case, with the long title of the Ad Hoc Intergovernmental
Task Forces on Foods Derived from Modern Biotechnology was established by the
Commission in 1999. It was given a
four-year charter, and Japan was selected as the host country to facilitate
this committee. And the Japanese Ministry of Health, Labor, and Welfare was the
part of the Japanese government that ran the secretariat, essentially helped
organize the meetings for this.
The
task force was chaired by Dr. Ushikora, who is world renowned virologist, and
is fluent in both English and French, and Japanese, of course; and did a superb
job of negotiating through various complex issues during discussions. And I think everyone involved recognized
that the Government of Japan deserves a great deal of credit for the success of
this work.
Japan
did host four meetings of the Task Force that just concluded this past March in
Yokohama. And the recommendations that came out of that work then were
presented to the Commission at its meeting this summer.
The
Task Force was given, in terms of reference by the Commission, which you see
here, very general terms, consideration for the elaboration of standards,
guidelines, or other principles for foods from biotechnology. So a very broad mandate. The Task Force, at its first meeting, in
looking at this mandate, felt that there are many things in the word of food
biotechnology, and it would have to somehow identify work that it could
accomplish within four years so that it would have something finished at the
end of that time; and do that in a way--on a priority basis. And they felt that since foods derived from
crops were already in the marketplace that that should be the top priority; and
that they would focus their work on developing guidelines for assessing the
safety of those foods for human consumption.
They
also felt that foods developed using
organisms modified using recombinant
DNA, using microorganisms modified with recombinant DNA techniques, would also
be on the frontier and of a priority.
Animals,
of course, were well understood to be in research, but they felt they were not
quite ready to discuss animals yet at this time.
So
that was the order of work that was set out by the Task Force.
And
the work that was accomplished I'm really showing you here the final product,
and then I'll tell you what it means.
But the Task Force, within its four years of work, developed three
documents.
One
was a--the principles for risk analysis you see here. That's really an umbrella document that talks about how risk
assessment and risk analysis can be carried out within the existing framework
of the Codex. And it's thought to be
sort of an umbrella for the guideline documents, but the real crux of the
matter, the important work, are the two guideline documents.
The guideline on foods derived from
plants, and the guideline on foods derived from microorganisms. Both of these guidelines have an appendix to
them as well that deals with assessing the possibility for allergenicity for
new proteins that would be in the foods derived from the plants or
microorganisms. And so those also are
important documents that go with and are part of these guidelines documents.
These
documents were presented to the Codex full body at its meeting this summer, and
were adopted unchanged. And they are
available, at least in their draft form, on the Codex website. They will be published simply taking off the
draft. So they are the texts that--I
believe we have given you the texts for the guidelines for foods derived from
plants, because that's the one we'll be focusing on for the discussion today.
Now,
I want to talk about one of the principles that the Codex felt was
important. The Codex system has a
number of defined terms--risk analysis, risk assessment, risk management, and
so
forth--that are all well understood
withing the food safety system and Codex to deal with things like pesticides
and food additives and contaminants in food, essentially single chemical
substances. And often times, certain of
those substances will have some hazard associated with them and how to manage
that in terms of tolerance setting, for example, for pesticides. But it was recognized early in the
discussion that we're dealing with food crops when we're talking about foods
derived from crops, and trying to establish guidelines for safety
assessment. But these are crops we're
well familiar with--corn, potatoes, soybeans, and so forth--that are modified
in some way, using recombinant DNA techniques; and that often when we go
through the process of evaluating these, we don't find a hazard. In fact, that has been in the case in the
50-some varieties has looked at.
And
so we felt that there really was a new term that was important here. And so we established the term "safety
assessment" as a way of having something to focus on that really takes
the emphasis on making sure that this
food is as safe as other foods, but doesn't necessarily find a hazard or a
risk. So, if a hazard is identified,
and, of course, there's always the possibility that that could be the case,
then that hazard, then, would be treated as it is in the Codex system. You wold have to decide does this food have
to be removed from the marketplace, or are there conditions by which the food
can be marketed, recognizing the nature of the hazard; for example,
establishing a tolerance for a pesticide as a way to manage a risk. And so, if there's a hazard identified, then
the system would work just the Codex systems normally operates. But the focus that we're going to talk about
is really on safety assessment.
So
safety assessment, then, is something that the Task Force felt was important,
recognizing that it does fit within the Codex framework. But it's--this safety assessment process is
really a comparative process. It is one
we recognize that the standard that we have are the crops that are
already out there. The foods that we have accepted in the
marketplace are the gold standard.
That's what we consider to be safe, recognizing that no food is
perfectly safe or necessarily safe for all individuals all of the time. But, in fact, the process, then, is to
compare the new food with what has gone before, with its counterpart. And the purpose of that is to try to
identify whether there are any differences in the new food derived from this
newly modified plant that would have any effect on health; and where those
differences are identified, to make sure that those differences are also safe
for the consumer.
So
the idea is to look at what's new; make sure that that's safe for the consumer;
make sure that the food is still what it's expected to be, because this is food
that we have consumed and have a history of consuming. And this comparison should take into account
both the intended changes that have been made in the plant, as well as, to the
best that one can, to look for any unintended changes that may have occurred;
and make sure that
if they have occurred and can be
identified, that they are also safe.
This
is what we call substantial equivalence, a big, long term that is often
confusing, but a very simple concept.
We don't decide at the end of the day that the food is substantially
equivalent. That's not the
decision. This is the tool at the
beginning of comparing what's new; what's different about this new product, if
anything, and making sure those differences are safe. That's what we mean by substantial equivalence.
The
Codex has adopted a number of definitions so that they would have terms to use
in the documents that would be understood by all the countries. Modern biotechnology was adopted as the
general term, and that was adopted because it had already been defined in the
Cartagena Biosafety Protocol, so there was a large agreement on the definition
by many countries, and so it was felt that there was no need to create a
different definition and that would work for the purpose of
this work of elaborating food safety
guidelines.
The
Codex also did something that I think was very useful. They avoided all the terms that cause
everybody a great deal of angst, such as genetic engineering, genetic modification,
GMOs, and other kinds of terms that would be difficult to get consensus. And, so, they simply referred to recombinant
DNA plant or recombinant DNA microorganism where they needed to refer to the
modified plant.
And
then they did, of course, design--or define conventional counterpart because we
have a comparator, they wanted to make clear what we mean by the
comparator. The comparator is a food or
a component of food for which there is a safe history of use. And the Task Force recognized that, in some
case, there might have to be more than comparator used in a particular
assessment.
But
those are the definitions. I don't want
to spend much time on those, just to make you aware of them.
And
I'll quickly just go through some of
the elements of food safety assessment
that are laid out in the Codex guidelines.
These will be no surprise to you, but it is, of course, asking what the
plant is. What's known about the plant
in terms of its use for producing food?
How has it been modified? What
are the new techniques that have been used?
The
Codex guidelines use a method of first describing what the developer intends to
do, and then going on to characterize what was actually done. So you will see paragraphs that start
description of molecular characterization, for example, or genetic modification
rather; and then characterization of the same thing. That's the reason for the difference. The idea is, well, they intended to do this. This is what they started to do. Now, what did they actually do? What do you find actually occurred. So that's how the document is set up.
In
terms of safety assessment, of course, use for substances that would be in the
food are really one of the major keys to safety assessment,
and are those substances likely to have
any impact on public health, including toxicity or allergenicity. As I've said, there is a separate guidance
that deals with allergenicity. I think
that today that annex represents the best consensus that there is
internationally on how to approach the question, is a new protein likely to be
an allergen.
The
compositional analyses are part of addressing unintended effects, a part of
answering the question, is the food still what we expect it to be?
Evaluation
of metabolites: if there are new substances of food that break down into other
metabolites, obviously one wants to be sure that any other substances are also
safe.
Effects
on food processing may be taken into account.
In some cases, of course, such as a refined oil, there may be no protein
in the food. Or there may be other
cases where the processing may concentrate things in the processing of the
food.
Nutritional
modifications. Obviously, if the food
is modified in a nutritional sense, it has to be looked at in terms of the
overall diet of what people eat, not necessarily just the modification of this
particular food, but how does that affect the diet and what are its
implications; and other considerations, such as the use of selectable marker
genes and so forth.
Now,
to get more to the topic of today, the guidelines do set out, in a number of
paragraphs, first, as I said, describing what the developer has done in terms
of a genetic modification, what is the host plant that's being modified, what
are all the materials that are contributing to that modification, in terms of
the source of the organism; the genetic material that's obtained from those
organisms and how that's combined and introduced into the plant; what is
introduced; what its size is; what its function is and so forth; and then going
to what actually happened in the plant, characterizing the plant in terms
of--at the molecular level, what are the
genes that have been inserted; how many
sites; how many copies.
Using
sequence data to identify open reading frames, for example, so that one can get
a sense of what likely substances are--can be expected, and will those be
present in the food.
The
Codex discuss the sequencing of the inserted region and the border sequences,
as well. And they also recognize that
there are other ways to get at the question of expressed substances, looking at
transcripts and expression products as a way of keying in to what might be new
substances that would be present in the food.
So
I think in terms of looking at new substances, the molecular data being used to
both establish what is the function of this substance; what's the phenotype of
the plant; what is the level of expression.
In other words, one of the common food safety questions is always how
much do we eat. So are these metabolic
enzymes or are these substances that are seed-storage proteins. What will this mean in terms of actual
consumption.
In
some cases, we can think back to the old flavor saver tomato. We may be actually not adding genes, but
modifying the genes.
[Reporter notes that main tape deck stopped
here due to a sticky tape.]
inclined to modification. So that is here in the guidelines, as
well. And there are other things that
are taken into account when this genetic material has been inserted. Have there been rearrangements in the DNA,
and is there any consequence of those in terms of safety for health.
Post-translational
modifications of the proteins that may have occurred as a result of changes in
protein sequencing and so forth. And is
this material inserted in a way that it will be heritable, stable, over several
generations.
So
I think that these are things that are not of any surprise to you.
So
what is the goal of these guidelines?
First of all, that the food should be safe; that it should not, when
it's used as it's intended to use, it should be as safe as other foods on the
market.
And that's important. We're not trying to show that this food is
absolutely safe or guarantee that the food is safe. We're comparing it to foods that are already on the market. We're not accepting foods that would be of a
lower standard with respect to safety, so they should be as safe as their
conventional counterparts, taking into account any changes in dietary patterns
that may occur, if there have been nutritional modifications. And the idea of these safety standards within
the Codex system is then to allow risk managers to have information that if
there are hazards identified or other considerations that have to be taken into
account, that they have this information that is based on sound science that
they can use then to make their decisions about allowing these products to
enter the marketplace.
So
this is--these are the new guidelines that have been adopted in the Codex
system, and represent an international guideline and, basically, yardstick for
countries to look at to see whether a food has been evaluated in a manner
that has been accepted in the
international community. One of the
things that these guidelines do note is that while this is all focused on
recombinant DNA and was designed to answer questions about recombinant DNA, no
one knows any other way to evaluate the safety of a whole food if we were asked
to do so. So if someone came to FDA and
said, well, we didn't use recombinant DNA, we used some other method, how should
we go about evaluating the safety of this food.
We
would point to similar guidelines. Our
own or these guidelines, because we don't know any different way. Some of the questions might be different,
just as some of the questions might be different for recombinant DNA product
that might present different characteristics than have been laid out in this
general framework. But while this focus
is on our DNA, you should really think of this as way to evaluate the safety of
a whole food using a scientific approach.
Thank
you very much.
CHAIRMAN
BUSTA: Thank you. Abigail?
Abigail Salyers. Say your name, and then we'll have it in the
record.
DR.
SALYERS: Abigail Salyers. Okay.
So my question is I don't know if any industries are getting ready to do
this, but, in theory at least, one could produce foods that are safer. Take the peanut, for example, if you could
produce a peanut that didn't make peanut allergic people sick, and you used
recombinant DNA to do that, would proving that that is a--I mean, how would you
evaluate something like that?
DR.
MARYANSKI: I would actually--
DR.
SALYERS: Casava also has been brought
up as a possible case--
DR.
MARYANSKI: Right.
DR.
SALYERS: Where they might use
recombinant DNA to--
DR.
MARYANSKI: No, and actually, of course,
the Japanese did some early work using antiscents, trying to suppress the
allergenic proteins in rice, and, you know, it was partially successful. The problem with allergenicity is that
there are a number of proteins within
any given food that are allergens, and some are more allergenic to some
individuals than others. Dr. Astwood is
much more of an expert in this, and Dr. Jones, who works with me, is also much
more knowledgeable about this. But I
think the potential is there for--
DR.
SALYERS: I'm just asking in terms of
the Codex, do you think that the basic principles there would apply to cases--
DR.
MARYANSKI: Well, I think that one of
the things that Codex recognized is that these guidelines were set up to assess
the safety of food. They--we--they
can't really address that question in the sense that you would have to look at
clinically, probably, whether the food still can cause clinical reactions. In other words, have you eliminated all of
the allergenic potential, or at least sufficient allergenic potential that that
food is going to be safe for consumers. That's going to be a difficult standard
to meet, at least as far as we know technically now. No reason not
to try, of course.
CHAIRMAN
BUSTA: Dr. Benedict?
DR.
BENEDICT: Steve Benedict. The previous question actually raised
another thing. Isn't it true,
though--this isn't my question. Isn't
it true, though, that if someone did attempt to eliminate an allergen, it would
still have to go, the product would still have to go through the Codex for
changes in safety and unintended effects and other sorts of things? Exclusive of what you talk about proving no
longer allergenicity, you still have to take it through all the recombinant
questions; would you not?
DR.
MARYANSKI: Yes. I think if you're asking would--for the
product to be acceptable in various countries, and it's, you know, modified
using these techniques, I think that today at least most countries would expect
that it would also
be--you know, these other issues would
also be taken into account.
DR.
BENEDICT: Yes. So actually my question is fairly trivial;
and that is at the
meeting, did anyone discuss the range
of sequence, border sequences up and downstream? How many KB that people thought should be sequenced in order to
determine that you're really not near an opening reading frame you could
influence?
DR.
MARYANSKI: I think that certainly one
of the questions that was raised was whether there could be any fusion
proteins. In other words, is the insert
done in a way that there's not
read-through into the plant DNA; and if
there is, then can you identify that.
But there certainly wasn't any boundaries given in terms of how far out
one should look. And, quite honestly,
some countries were interested in that more for methods of detection than
actual, you know, safety considerations.
So there were various reasons why people are interested in border
sequences. So, but our focus here, of
course, is on the safety assessments.
So, but the issue of whether that insert leads to any fusion proteins or
read-through into the plant genome that would express different proteins than
what the plant normally expresses, I
think is the sort of fundamental
question about the region surrounding the insert.
DR.
BENEDICT: Yeah, one of the things I
recall that we sort of discussed in 1994 was insertion into a gene, which you
would pick up with just a short distance, inactivation of a host gene. But the other possibility is that if you're
bringing in regulatory sequences, the possibility of some sort of downstream
promotion, having not so much to do with fusion, but just is there an opening
reading frame nearby that, for some esoteric and maybe unpredicted reason, you
can, in fact, activate or inactivate an adjacent gene. And so that was why I asking how many KB
downstream you should go to say, well, there's a low probability we're going to
influence a host gene in its expression.
DR.
MARYANSKI: Well, I think that's a very
good question for you to come back with after Dr. Cebula gives his talk.
CHAIRMAN
BUSTA: Other questions of
clarification?
DR.
ARIAS: Jonathan Arias. James, I'm--
CHAIRMAN
BUSTA: Could you? Why don't you pull the mike in front of you?
DR.
ARIAS: Is that better? Okay.
I'm concerned about the issue of substantial equivalence in regard to
characterizing the meat food as being no more unsafe perhaps than conventional
derivatives. Does this include
long-term studies, or just acute, sort
of toxicology biochemistry?
DR.
MARYANSKI: No, we have taken
long-term effects into account at FDA,
and in the Codex, because long-term effects are, of course, a question and a
difficult one. But we know a lot about
the foods that we eat. There are also a
lot of things about foods we don't know.
I don't know what consuming carrots over my life time does for me, other
than my mother told me it was good for my eyesight. But whether it has any other effect on my health over consuming
that, or any food does, we know very little about long-term effects of most of
the foods that we consume beyond the nutritional
kinds of things that are, you know, we
know about saturated fat and so forth.
But we don't really know much about consuming foods to begin with.
What
we do know about foods is that they do contain certain nutrients, certain
toxicants, and so forth, and that we have accepted the foods that we have in
spite of the toxicants that certain crops have; that at the levels those occur,
we've accepted those as safe. What we
believe about the foods that we've seen so far with bioengineering is that the
modifications that we see are fairly small modifications of the genome. And
most of these, of course, produce metabolic proteins in the case of the
proteins that FDA looks at or the BT proteins or viral proteins that EPA has
been seeing. And we know a lot about
protein toxicity, and we know that the proteins that we're seeing do not lead
to
long-term effects. So we know at least the introduced proteins
do not lead to long-term effects. And we're not aware of any reason why these
foods would produce long-term effects any differently than foods developed by
other methods
of plant breeding.
DR.
ARIAS: Thank you.
CHAIRMAN
BUSTA: Are there other questions. Dr. Benedict?
DR.
BENEDICT: Since there's open air--
CHAIRMAN
BUSTA: It's Steven Benedict.
DR.
BENEDICT: Steve Benedict, again. One of the things that, as I read through
this, clearly, you're dealing heavily with allergenicity, and the thing that
came to mind, and I'm an immunologist, and I'm not sure I have the definition
correct, even though I am an immunologist; but, as we all know, there are
billions of epitopes going through the system daily, and their toleringenized
[ph]. And so we've been tolerant,
immunologically speaking, to all of those.
And the lack of tolerance may lead to an allergenic response. But lack of tolerance might not necessarily
be allergenic, but it might, in fact, lead to something that was immunogenic,
and I'm not sure that there--this is where I'm not sure that there's a
distinction between the two, because
I haven't thought it through for more
than five minutes. But the possibility
seems to me that that checking for immunogenicity exclusive of allerogenicity
[sic] might be something that someone should think about other than me. And I'm wondering whether that came up at
the Codex discussions.
DR.
MARYANSKI: Yeah. I would say yes that it did in the sense
that there was certainly a recognition that there is more to allergenicity and
immunogenicity than IGE responses. I
think that what was felt to be important is that we do our best to address the
issue of the IGE kind of response because we know that certain proteins are
allergens through that mechanism, and that the idea of transferring genes from
one source to another, and obviously the expression of those proteins, raises
the question of whether there could be an IGE-type response.
I
think that your question is one that's much more appropriate when we get to the
issue of allergenicity as opposed to the molecular subject
today.
But I just want to recognize that, yes, there is--we don't just simply
put blinders on; that we only look at IGE.
But these guidelines are focused on IGE because of the need to address
the safety of the new proteins.
DR.
SALYERS: Just a brief question. Abigail Salyers. The--we have people who are today who are living a lot longer
than in the past, and we also have people who are alive today, like cystic
fibrosis patients, who were not alive in the past, and so did the Codex
consider the fact that we've got these new populations of people, especially
I'm thinking especially about the geriatric population, where our previous
experience may not be as good a guide as we tend to think it is as to effects
that foods, even conventionally used foods, might have.
DR.
MARYANSKI: Yeah. I'm becoming much more interested in the
geriatric population.
[Laughter.]
DR.
SALYERS: So am I.
DR.
MARYANSKI: Actually, the Codex didn't
address the geriatric population
specifically, but it did discuss the fact that there are basically subgroups
within the population that one needs to take into account, including the
elderly, pregnant women, infants and so forth.
And so, yes, while not addressing that in detail, the guidelines do
generally recognize that in thinking about the safety of a new product, you do
have to think about subgroups in the population as well as the population as a
whole.
CHAIRMAN
BUSTA: Thank you very much.
DR.
MARYANSKI: Thank you.
CHAIRMAN
BUSTA: We'll continue on. Dr. Thomas Cebula on FDA's approach.
DR.
CEBULA: Thank you. I'm Tom Cebula. I'm the director of the Office of Applied Research and Safety
Assessment. I'm also the lead scientist
for molecular biology for the Center, and those that know me in the room know
that I never give a scripted talk. I'm
taking out a crib sheet because I was taking notes.
The
first thing I'd really like to say
about the process that FDA uses is that
it's an evolutionary one. And, since
joining the Center, I've interacted with Jim Maryanski, Bob Lake, others in
this room since about 1987, so, like Jim, I'm also worried about the geriatric
population.
In
that process, we saw a number of people come to us with a lot of ideas about
what they were going to do, and I think Dennis made a very valuable point when,
early in a consult, some advice might be given, the company goes back, and we
don't hear anything more about it. So
there is a lot of oral history perhaps that should have been captured, and
I--the point that you make earlier about how do we see those numbers. Early in the process, it was an evolutionary
one. I think Jeanette made a very good
point about after a series of discussions, clearly, we're trying to make that a
very much more transparent process to really capture how many times the sort of
advice that's given from this side out has influenced.
The
other point I'd like to make before going into my talk: I think Abigail Salyers
made a
very credible point about connecting
dots in the scientific community. All
science is interconnected and interwoven.
Jim Maryanski talked about R-DNA and the subject for transgenic
plants. Clearly, we've taken cues from
R-DNA in microorganisms. I serve as one
of the experts for WHO for the microorganisms in R-DNA. But Abigail's point
about probiotics. I'd just like to
extend probiotics, counter terrorism, and our budgetary process called
OMB. I do believe that what we have
heard is that there is a real need to really take some of the counter terrorism
dollars and move them into other areas of food safety.
I
believe something that FDA is doing, and our laboratories within CFSAN are
actively engaged in. My office, for
example, has the mission to ensure, to do research that ensures food
safety--microbiological food
safety--and we also have a team of toxicologists.
Post
9-11, that mission changed somewhat, and it became food security and food
safety. It's a very valuable point,
because the research that
we're doing for food safety could be
immediately applied to food security.
And, of course, those dollars that are coming in, we're using as a
twofer. So if we're developing methods
for the intentional contamination, those serve for methodologies for
accidental. So, again, we're trying to
be very proactive, recognizing that it's a zero-sum game. There's only a certain number of budgetary
dollars out there; and if it's applied to counter terrorism, we have to get the
most bang for the buck.
The
point about Vancomycin is a very important one. And I'm just going to say that probiotics in the genomic era, as
people have looked to sequence total genomes, people have looked at probiotic
organisms; FDA, in contributing to the genomics project, has often emphasized
it is nice to know that a bacillus cereus that is being used a probiotic, we
can know the entire genome. But isn't
it more important to know about a bacillus cereus that causes disease. So, again, FDA is trying to move in the
direction of saying if
we're going to use those dollars, let's
get some information about food safety from that.
I
just want to make sure that I've covered some of those points.
The
final thing I would say is that since 1987, we have served in a way as internal
consultants for some of the process that you've been hearing. We are primarily the laboratory portion of
the Center, and since our hands are the wettest on the techniques, we're often
called in to say how would you evaluate this.
So there's a very responsible team, and we interact with that
responsible team to offer some advice and also do the consult--also do a
review, as well. So there is, if you
might say, there is some partial duplication, but it's a very important
duplication, I believe.
With
that said, I'm really going to take some of the slides that Jeanette gave and
Jim gave and kind of put our wrinkle on it.
Jeanette
pointed out that really we're asking for companies to come in to provide the
documentation that assures us that
there's a reasonable certainty of no harm.
But I think the important caveat is this is the real opportunity to find
out what's in the pipeline and what's coming down in the future so that we can
be proactive rather than reactive.
We
neither prescribe or proscribe specific tests up front. We're there to hear what industry has to
offer, and somebody said, well, how much input do we have. Clearly, the input is we are going to offer
advice, but we're going to be focused on the characteristics of the food
product, as you heard Jim say, as you heard Jeanette say.
We
are there for scientific evaluation.
Our intent is really obviously the food safety question. But, as scientists in this room, as you
heard around the room, often we get off on a tangent. We talk about the strengths, and that should say limits of a
particular technique that might be used, because this helps us in future
deliberations. But our primary focus is
food safety, and that's the important thing to remember
for our evaluation here.
Again,
borrowed from Jeanette, we do take a multidisciplinary approach, but I want to
point out that the duplication is very important, because we're going to be
really focused on the molecular analysis and really talking about the genetics
of a particular manipulation or a particular plant.
We
often get clues from the chemical and nutritional analysis about stability and
genetic stability, so we're looking at pretty much the same thing that a
chemist might be looking at, a nutritionist, but perhaps from a different
slant.
Clearly,
as you've heard, we want to know about the identity and source of introduced
genetic materials because that will tell us a lot about what are the potential
food safety concerns. For example, in a
sidebar during the break, we were talking about transferring genetic material
from one microorganism to another. I
point out that the nomenclature has changed over the years, and something that
is streptococcus a few years ago and may have been considered commensal is now
enterococcus and is a pathogen. So we definitely ask people to identify the
organism, but to trace the nomenclature of that organism to ensure that we have
taken into consideration that nomenclature changes haven't affected our
assessment.
And,
again, the intended changes of the composition of the food--clearly, we're
always concerned about the intended effect, but, as you heard from all of the
discussions, clearly, in evaluating food safety, it is often the unintended
effects--allergenicity, toxins, and I should add the toxicants that Jeanette
mentioned--because in a manipulation, as you heard, if you happen to insert and
get downstream expression, you might get the expression of a toxicant. We want to know that.
The
allergenicity, as you've heard, will be a separate discussion, but I would
point out in our evaluation, since we are seeing sequenced data, the
bioinformatics tools are there to say what sites could be potentially
glycosylated; and these days, with the glycosylation kits, we're often seeing
the data for whether those sites are,
indeed, glycosylated.
The
nutrient levels. Again, you've heard
why we look at that, but I would just like to take a digression, and say when
we talk about natural foods, and we're looking at a nutritional status of
anything be it a nutrient and this is also true for a toxicant, you would
expect a normal distribution from the natural varieties over time. When you're looking at a R-DNA plant, since
the manipulations are among one variety, we would expect that distribution to
be much tighter, and the sort of data that we see says that. And so, if we're looking for toxicant
values, which might also be this value, where this is low to high, clearly the
data that we have been seeing up until now is that can fall on the low side of
the toxicant. So, when we're
considering an R-DNA plant versus a natural variety, we find that all of the
data, thus far, seems to follow the strength; that you're getting nutrients
that you expect, with a narrow distribution, and lower toxicant values. And I would say that's a fairly general way
of stating
the sort of data that we have been
looking at.
And
finally, something I neglected to say that our laboratories are very interested
in DNA repair and effects on the emergence of antibiotic resistance, and the
penetrants of virulent straits. We are
very interested in evaluating antibiotic resistance. And, again, from an evolutionary perspective of the process, as
you are all aware, the primary marker that was used early was antibiotic
resistance, and we now see a drift away from antibiotic resistance.
Now
stealing some of Jim Maryanski's slides and the Codex slides, I would really
like to emphasize some points, but I'm not going to reiterate all the
points. When we're describing the
genetic modification, the sort of data that we have been seeing is people are
showing you the nucleotide sequence of the material that they're starting with.
They're
telling you about the promoter set they're using. They're telling you about the terminator set they're using. That's a very
important piece of data, because that's
direct information, and now you can use indirect methods; and there's a host of
indirect methods that could be used to evaluate the construct once it's inside
the plant. And that's a very important
point as we consider do we need sequence data and how much sequence data do we
need.
What
I'm establishing here--if you know the sequence, you then can do a restriction
map and ask does--is the restriction map consistent with the sequence that was
delivered to the plant. You can look at
restriction maps. You can look at expression. Northerns.
We actually--or expressions of the protein, Westerns. Now, clearly, there's a distinguishing
factor here. If you look at expression,
Western analysis of the protein, you're usually looking at the intended
effect. The Northerns, however, give
you a lot of information, because, if there are other transcripts made, that's
something that we would be looking for as an unintended effect. So unless it is stated that the intended
effect is, any Northern
expression that would be aberrant, we
would be questioning what is the significance of this RNA, this extra RNA.
Again,
I've already made the point about marker genes and the nutritional
modification, so I'm just going to skip this slide and talk about the
transformation process that Jim alluded to.
Again,
when you are talking about a ballistic method of random insertion, we might
have a number of things that we're looking at.
You know, how many sites does this randomly insert. If we're talking about site-specific
recombination, if it is a site-specific recombination, it's a more tailored
type of mechanism. So, again, in making
the point that it is a case-by-case analysis, it's important that if you
prescribe the tests too soon, scientifically some of those tests would not make
sense or some of the questions would not make sense. So we're very interested in the DNA to be introduced--the genes,
the markers, the regulatory sequences.
But Steve Benedict mentioned a point about regulatory sequences and
sequencing, and I
really would like to make the following
points right here.
We
are consistent, I think, with Codex, we're talking about size, identity, and
location. If we're saying we know that
there is material inserted into a genome, say, the tomato genome. We are also consistent in saying we would
like to know orientation of that insert.
However, the location down to the nucleotide is something that we
personally don't ask for. And the
reason is, and I should state it up front: all of the effects that we're
looking at are SIS proximal because you can sequence 10 KB, 20 KB versus a
trans effect from another chromosome, you're going to miss it anyway. So I would really view them as a--up until
now, we have said that we are looking at SIS proximal effects and the integrity
of the genome in the intended and unintended effects the researcher has
inserted into a gene.
As
far as the data that we've been seeing, basically, there have been times over
the years, I can remember where people have provided inside-out
PCRs as to tell us some
conference. Okay so I will leave it at
that to say that the location to us is that it is inserted and that it is
stably inserted.
The
number of sites and organization.
Clearly, we all know that when the material goes in, that you have
duplication. Okay, so at the same site,
you can have many inserts lined up or you can have many inserts lined up at
different sites in the chromosome. One
is more important in our evaluation than another. If you have multiple copies at different locations, the chance
for recombination, reassortment, rearrangement, and ultimately effects on
genetic stability are much more of a concern than if you have a single
insert. So that's why talk about
wanting to know how many inserts and how are they located. And, of course, as Jim emphasized, we are
definitely interested in any open reading frame and insertions the possibility
of fusion proteins.
The
important thing here I wanted to emphasize un-translated RNA. Jim mentioned one possibility. If the intent is to make antiscents
RNA, it's not going be translated. We want to know about that. But there's another--it seems every journal
you pick up at least there are two articles in each of the journals talking
about un-translated small RNAs. That is
not our intent. We're not asking for
people to tell us about every small RNA that's produced in the plant, because I
don't know what those data would tell us.
But I leave that to you. That is
a very burgeoning field right now, the un-translated small RNAs that act as
regulatory molecules.
And,
again, the intended effect and heritable stability. I've mentioned a couple of ways we measure genetic stability or
we assess genetic stability. One of
them is the Mendelian inheritance.
Clearly, if the insert is unstable and is hopping, the mosaicism rather
than the Mendelian inheritance pattern would be seen. So that's a very important thing. But some of the other data that we've been talking about, the
expression data et cetera, are also measures of stability also.
And,
again, these should read strengths and limits rather than limitations, because
from the perspective of an R-DNA, it's important to realize that one or only a
few genes are being incorporated into the plant. There's a limited number of manipulations. One can talk about unintended effects, and
we'll get to that in a moment.
But
it's also important to remember that, as genes have been introduced by R-DNA
techniques, those genes will become the docking points for traditional
breeding, and those sites, then, will be now the conventional traditional
breeding that we're all used to. So,
again, as people talk about propagation of R-DNA, the R-DNA will be propagated
by traditional breeding also.
So
the questions that I took from this were what tests are necessary and are there
tests that should be required. I think
those are all the questions in your minds, and you will be discussing this
afternoon.
I'd
really like to point out that Mendel
did a nice experiment many, many years
ago, talking about round and wrinkled peas.
And that experiment was reproduced in the molecular era about a decade
ago or so. And basically, if you do
traditional breeding, and you get round or wrinkled peas, and then subject it
to some proteomics, you find that 62 of the 636 protein spots are qualitatively
different. The R-locus, of course, now
we know affects sugar content, lipid content, storage protein composition. But the round pea is safe to eat, and so is
the wrinkled pea. Okay.
The
way I would like to look at this is as we were musing about this in Paris at a
meeting, I went off to the Monet exhibit at the Musee Marmite, and there's some
wonderful water lilies, canvases that just dominate. For those that have seen, this is definitely Monet. Everybody knows the blues, the greens, the
purples. This one happens to be the
blues and the greens and the whites, but this is also Monet. It looks more like a Jackson Pollard. And this is about 1917. The other one was 1880. Okay.
But they're Monet, and I submit
to you that they're safe to consume.
[Laughter.]
It's
also important that Gottlieb and de Vienne in '88 did an experiment also that
found that if you take the AF mutants, you'll see that tendrils can replace the
leaflets. So it's something that you
wouldn't want to see in a plant. Weeding this is not a good characteristic,
but, basically, the protein profiles were absolutely identical. So, again, the tests would not reveal a
difference, whether it was a food safety issue or not. I'd leave that for
discussion.
I
said I'd return to unintended effects, because, again, I think we have to
recognize that, as the techniques get better and better, pleiotropy will be a
universal trait of any mutation. We
know how much cross-talk is going on in the cell, and within an organ, and
within an organism so that there will be always cross-talk anytime a mutation
is introduced; and now I'm talking about a point mutation, be it an insert of a
couple of genes or a point mutation, a base substitution.
So,
again, not to argue that pattern recognition can't work, okay. We are believers and users of technologies
like genomics, like DNA arrays, like proteomics. But, again, I'll borrow from the impressionists and say that
pattern recognition works Seurat proved that points of paint on a canvas can be
recognized. It can look like a
lighthouse, or it can look like an afternoon on the island of the Grand Jatte.
However,
in a regulatory setting, I want you to concentrate on the dog, because that dog
is very docile, at least captured at this moment. So when we are doing expression profiles, if that dog changes to
green, red, polka dot but remains docile, it is not a food safety
question. If that dog happens to bit
that individual in front, it becomes a food safety question.
I
submit to you that we're at a stage to recognize that expression arrays do,
indeed, work, but it's not at a point where we can find and isolate the genes
that define safety. And so, as people
are talking, I would suggest that we talk
about the new technologies as they
relate to food safety. And with that,
I'll stop.
CHAIRMAN
BUSTA: I just want to make a
comment. You didn't need your entire 55
minutes.
DR.
CEBULA: That was intentional. I really wanted this to be a conversation,
and, as I had pointed out, I would--
CHAIRMAN
BUSTA: Dr. Salyers.
DR.
SALYERS: I have a question.
CHAIRMAN
BUSTA: Please identify yourself.
DR.
SALYERS: Oh, Abigail--Abigail
Salyers. I have a question about the
extent to which or how you see your group's position vis a vis advising
industry about what it should do. I'm
struck, as I talk to various, especially the small biotech companies, but even
the bigger--people at the bigger companies like Monsanto is the extent to which
they have a very narrow range of expertise.
And even in the big companies, where they might have a broader range of
expertise, the components don't necessarily communicate freely with each other.
You're
a world renowned scientist with a lot of contacts, and I'm sure that you've--so
you're the sort of person I wish we had more of in industry, but we don't. And I'm sure you've assembled a group that
is--has outstanding representation of the various sciences; and that you are
probably more like to the many people in industry to become aware of changes in
the basic science technology. So my
question is one would hope that the FDA somehow could serve in an advisory capacity
to industry; and yet, of course, you see the other side of it, which is the
conflict of interest side I guess. But
how do you see your role as an advisor of people in industry?
DR.
CEBULA: I believe the--when I said that
we were serving a consulting role, I meant within the context of FDA.
DR.
SALYERS: No, I understand that.
DR.
CEBULA: Oh, okay.
DR.
SALYERS: So I'm just asking you to
expand on the outreach part of it.
DR.
CEBULA: In the outreach, I believe,
as I said since '87 or thereabouts,
everybody time somebody has decided to talk to Jim or Bob Lake, Jim Maryanski
has graciously said, well, why don't we get Tom involved. He may have some ideas. When we're out at meetings, we are
scientists; and, clearly, if there's a technique out there, you know, we're
doing that right with pyrosequencing.
Pyrosequencing is a very valuable technique. Some people haven't heard about it. We're using it. We're
saying how about this. So it is scientist
to scientist. We're trying to exchange
information and the technologies as we see it, and we're welcoming the input
the opposite way. We're getting
fantastic input from academia and from industry; and we're working collegially
I think--is the important thing. And if
I might say something about the whole process, again, over time, let's start
when we first consulted, if we said, do you have data. The first response was why. I believe now it is, you know, developed to
a point where people are saying, well, these are the sort of data, and this
is--there's scientific reasons for
the data. So, I believe there is a trust in its finest sense of the word, a
mutual trust, that questions aren't being asked for it would be nice to know,
but as was stressed in the two talks here, there is a need to know because it
may impact a safety decision.
And
so I think there's been a good rapport built up over time.
DR.
FEDOROFF: Nina Fedoroff. I was very struck by your cogently pointing
out that you can have many differences, and the foods are still safe. I think if people had suggested that we
would knock out starch genes and get sweet corn, somebody would haven't
objected to the religious grounds or ideologically grounds.
In
any event, the other point that you made that I'm struck by, and that leads to
my question, is that, so far, your assessments have indicated that the
distributions are narrower and that none of these unintended effects have
surfaced. My question is: how many
instances do you have to assess before you can evolve your
guidelines to say, okay, this is not a
major problem, we don't have to collect all of these data.
DR.
CEBULA: Well, I think one thing you've
heard from the two speakers before me, we are clearly waiting to hear what the
National Academy has to say. We're
awaiting what the input of your group will say. But, clearly, I wanted to point out there will be unintended
effects. The question is, will those unintended effects affect the quality or
food safety of--
DR.
FEDOROFF: Sure.
DR.
CEBULA: Okay.
DR.
FEDOROFF: But the other thing is that
there are--in--in-those of us who work on little experimental plants have been
making insertions left, right, sideways, hundreds of thousands of them. And the information that comes back is that
plenty few of them make a huge difference.
In fact, people struggle to identify insertions that change how the
plant grows, flowers, reproduces. It's
a very small fraction of them. And the
ability of insertion--even when people
set out to activate genes by pointing a promoter out, that doesn't even work
much of the time. It does work
occasionally, but not--certainly not as frequently as you'd expect. And it seems to me that there's a large
volume of information, not just new techniques, but accumulating information
from actually insertions done for mutagenic purposes that one could bring to
bear to increase the amount of information that you have available to you in
making judgments about how frequently there are unintended consequences.
DR.
CEBULA: Those data, indeed, would be
very helpful. I think when we were
talking about CalGene, I think that you were on the committee then, and I was
giving a talk. And I--you said the
problem is that the negative experiments are seldom, or can't be published, and
we're saying that we need that database, whether that database is in the
published literature or available, we would like to see the number of cases so
that that can really help us.
DR.
FEDOROFF: That's a real challenge
because people frequently don't--you know, they put a lot of effort into
identifying mutants. They don't put a
lot of effort into quantifying the frequency of those mutants.
CHAIRMAN
BUSTA: Doug.
DR.
GURIAN-SHERMAN: Doug
Gurian-Sherman. I think that whole
issue brings up a discussion that we should, you know, probably take up at some
point. But, with time limited, I wanted
to focus on a whole other issue.
You
mentioned several instances of types of data that you look for, so you--you
know, you talked about stability, and, you know, differences in nutrient
levels, and all that kind of stuff. One
concern that I have that maybe you could address is, what the level or type of
analysis that you consider to be acceptable, because, again, and I have to put
this in context of the studies that I looked at that you folks looked at, and
often found there was limited methodology described, limited statistical
analysis. You know, stability is one
thing brought up. Half the cases we looked at--a lot of them
did look at Mendelian analysis.
Probably half of them didn't do any statistical, like the chi square
analysis to tell you--I mean, you're not going to get a perfect four to one
ratio in most cases, so you have to have some kind of analysis that tells you
how much of a deviation you get, and then try to figure out what that means.
So,
I mean, I think a whole other issue the quality of the data, and the expected
level of analysis, and how--I mean, you know, one standard could be comparable
to what goes into a peer review journal.
To be frank, I don't think that, on average, that was the case. So how do you decide what the quality is
that's acceptable?
DR.
CEBULA: I think it's very important to
recognize that I said several times that one way of measuring genetic stability
is Mendelian inheritance. As I said, if
it weren't Mendelian inheritance, there would be a large deviation. However, if those were the sole data that we
were looking at, I would say yes, you would have to do a
very sophisticated statistical
treatment to unequivocally say it's Mendelian inheritance. But there's a body of other evidence that
says, the material is still where it is because on the second generation, we've
done, you know, a map that has provided us other data that supports it's
sitting in the same site that it started out with. It's also being inherited at almost, or, I mean, I'm taking your
word. You know, I don't know which data
you are speaking to. But if it's almost
Mendelian, and it's sitting at the same place, it's likely to be Mendelian
rather than some runaway jumping gene.
And that's so--you use the different techniques. I would rather see the company offer three
different techniques to verify it rather than working on the statistics to come
up unequivocally to come up with a Mendelian inheritance.
DR.
GURIAN-SHERMAN: I think that's a good
point, but, again, you know, addressing that issue: you know, when we looked at
this, some companies did do things like expression analysis for a bunch of
plants that, you know, the F-3 generation or F-4
generation, but many of them
didn't. And similarly, you know, some
companies did bioassays, but at levels of expression that might be, you know,
20 times over the lethal dose, so variations that could be fairly substantial
wouldn't even necessarily show up.
So,
I think, you know, what it comes down to often is a lot of times the devil is
in the details, as we'd all expect, you know, in empirical science. And I'll just raise it and leave it as a
concern that there need to be sufficient analytic standards, redundancy if you
want in tests, but then they need to be there.
And I didn't find that that kind of redundancy was there in many cases.
CHAIRMAN
BUSTA: Jim.
DR.
ASTWOOD: This is Jim Astwood. Dr. Cebula, thank you for the thoughtful
presentation and interesting art. In
thinking about it, I was wondering if you could comment on, what seems to be in
this presentation, an analysis at the genotype level, you know, fundamentally,
if you think about it as a geneticist.
What importance should be
placed on the phenotype, the agronomic
evaluations, the compositional analyses, which can be thought of as biochemical
sampling--these other factors. How do
you, as a molecular biologist, how do you sort of think about the weight of
those different aspects?
DR.
CEBULA: Well, the agronomic issue I
believe is away from my bailiwick. I'm
expecting a company to make a decision if there's, I hate to say it, but
there's a different bottom line. If
it's going to be developed and marketed, there has to be one bottom line.
The
molecular analysis, by the time somebody has made the decision that they're
going to bring something forward, I believe they've already done some of the
routine analysis that impinges upon molecular biology; and that is the genetic
stability, the ease of manipulation, and when I say stability, I mean it on two
different levels: the internal rearrangements that could occur, the possibility
of methylation and silencing--all of those have been done by the time
they came in. So, in that sense, by the agronomic consideration that a company
might do, I feel that a lot of experiments have been done that we haven't seen
the data for. But, again, the data that
we're analyzing supports the notion that you have a stable insert; and it
supports the notion that it is constantly being expressed.
I
presume, again as Nina Fedoroff said, those data are to come by, but within the
notebooks, they are probably a lot of failures to come forth simply because a
methylation pattern decided to silence a gene or something. But those are the data that we don't see, so
we can't give statistics on those. But,
by the time we're seeing the data--
DR.
KAPUSCINSKI: Thank you, Dr. Cebula.
CHAIRMAN
BUSTA: Identify yourself.
DR.
KAPUSCINSKI: Anne Kapuscinski. I also appreciate your presentation, and, by
the way, I'm a lover of that art, and I was born in Paris, so it kind of got
under my skin a little bit.
But
I have a question. It seems to me
that the question about these genomic and proteomic methods for
the committee should really be, and I assume, therefore, for the FDA, should
really be how could using those help to improve sort of strategic searching for
the few cases where something unanticipated might cause a real food safety
problem, rather than asking about those techniques alone.
So,
I would like to get your feedback on that.
What I'm really getting at is I think I want to ask sort of what Dr.
Astwood asked but a little bit differently.
Isn't it better for us to think about how can we direct the use of these
techniques in combination with information at the level of biochemistry, and
then at the level of the whole plant, phenotype, et cetera, rather than ask to
only look at those techniques alone. I
think if we just look at those techniques alone, we're kind of barking up the wrong
tree. And I fully appreciate, you know,
your concern that the status of the technology right now is you could generate
tons of data about transcripts and expressed proteins and
not really know what it means. But I think it seems to me what we need to
do is figure out how can we, knowing that there's that limit, how can we direct
the Agency, and maybe even direct recommendations for research, to improve the
use of that technology in a very strategic, focused way so that it could add to
the toolbox that you have right now.
Because it seems like the bottom line challenge in this area is that,
yes, the large majority of the time, there isn't going to be a problem. We just want to make sure that that doesn't
make us complacent so that it becomes hard to proactively detect the few cases
where there will be problem. And we all know that coming down in the future,
this technology is becoming more and more powerful, and there's going to be
chances to make much larger scale changes as we get into gene stacking and
genes that we know will have major effects on composition because you actually
want them to have major effects. So,
that definitely raises the question that they might also have some major
unanticipated effects. So, we have to
be
looking at the future. So, what's your reaction to what I'm saying?
DR.
CEBULA: I think these technologies are
wonderful technologies to do just what you said, search and discovery. If I could read into your question and say,
what could you do to help, the first message that I would do--ask you to send
is to ensure that any of the technologies being used have been validated,
because there are a number of these expression chips out there, and you read
the same literature that I do.
Recently, one of the major manufacturers of a particular chip, there was
an article in Nature, called "When the Chips are Down." The company in their quality control missed
the fact that they put the wrong strand, and, even then, 30 percent of their
sequences were aberrant sequences. And
this was sent out, and people are using them, and flooding the literature with
array papers.
DR.
KAPUSCINSKI: Trash.
DR.
CEBULA: The rush to public a new
technique has often showed us that there are lot of
holes in the technique. So, I would say that what you could do is
make sure that we don't damn a technology because we got started with the
technology prematurely.
So,
for expression, there are some very good examples. David Bottstein teamed up with Stanford to come up with a
lymphoma chip, very predictive. But to
get to using a lymphoma chip, they had to go back and show that the repository
for the sequences were cluttered with about 24 percent of the sequences that
had the wrong sequence.
So,
everybody's using these chips, and it takes a couple of scientists to say,
well, let's not rush to publish. We'll
just go ahead and find out what's going on first.
So,
my first message would be could you carry back and say, let's go slowly but
very together on making sure that the chips we're going to use to evaluate
biotechnology, natural foods, or any other is the best chip to make sure that
it's right. We don't repeat
mistakes. I mean, we saw
the same thing with the emerging PCR
technology. Everything gets exponential
the first few years, and that's where the mistakes are buried. I'm sorry.
CHAIRMAN
BUSTA: Dr. Fedoroff.
DR.
FEDOROFF: But I think that's missing
the point. In order to make a lymphoma,
and you've made the point earlier, in order to make a lymphomas chip, it's not
only important to have accurate sequences, but it's important to have the
lymphomas.
DR.
CEBULA: That's right.
DR.
FEDOROFF: Okay. And that's really the whole point--is that
we're--we need to avoid focusing on the technology when we don't know what
we're measuring. There is a huge range
of permissible compositions that are perfectly good foods, okay? We seem to slip off that over and over and
over again. And I think it's extremely
important because some of the notorious incidents that have hit the press
worldwide have been based on the lack of recognition that the very processes
of transformation, the culturing of
cells, which has been used to generate variation, does generate variation. And, so, people attribute variation to
somehow this terrible recombinant DNA when it has to do with tissue culture.
But
it's not an unexplored territory. And
so the question is one of connecting the limits of variation with
permissible--and I think that we're going about it the wrong way. Instead of saying what is--characterizing
the entire range of variation for every component of foods, we need to collect
the information on what has proven to be problematic health
wise--glycoalkaloids in potatoes, sugar binding proteins, which are lectins,
which are under characterized as yet in both plants and animals.
But
it's not an infinite variety. One
doesn't have to look at everything.
DR.
KAPUSCINSKI: That was why I was asking
about, to kind to get your input, on how your thinking about potentially
directing the use of these new technologies for strategic searching
for the things that might go wrong,
sort of playing off of what Nina is saying.
So, I just wanted to get a sense of whether you, as a molecular
biologist, are thinking in those terms and whether you realize that or to what
extent you're thinking on drawing on information from the biochemistry and
other levels of the phenotype to guide, then, how you would use, for example, a
DNA chip.
CHAIRMAN
BUSTA: That the first comment there was
Dr. Fedoroff. The second one was Dr.
Kapuscinski.
DR.
KAPUSCINSKI: Sorry.
CHAIRMAN
BUSTA: We'll let you respond, and then
we've got two more over here.
DR.
CEBULA: I apologize. Nina, thank you for bringing me back. You're absolutely right. That is the major point.
The
one thing that I think would be very helpful, and this is something that we've
discussed internally, is that narrow distribution versus the broad distribution
is, in a way, comparing apples and oranges, because that is the gamut of
varieties
versus one variety.
DR.
FEDOROFF: But only for one component.
DR.
CEBULA: No, I know. And no, no.
And what I meant to imply is if we are going to use the new
technologies, it might be important to really do counterpart, the natural
counterpart to, the variety from whence it came compared to the transgenic and
then ask, because I've looked at some data where clearly there are differences
in expression, but I don't know what it means; because I don't know what the
variety used, how that compared to the manipulated variety.
So
I think first of all we have to do some fundamental genetics. If you're going to approach it, approach the
new technology, take the new technology and combine it with some good genetics. That's all I'm saying. And, there, I would say that we would like
to see, you know, again,
data--if you're doing it strategically,
as you're suggestion, I would say that any gene that you see from an array
would be verified by another technique, a more sensitive technique.
To
say, if you have a knockout, do you get the expression that you expect or the
non-expression. It's what's going on in the field right now
in array technology everywhere else.
So, if it's going to be applied, and I'm not saying I'm recommending it,
I'm saying if it's going to be applied, it should be applied in a very
structured way to follow the sound scientific principles.
CHAIRMAN
BUSTA: First Jonathan, then Calvin.
DR.
ARIAS: Jonathan Arias. Thank you for the very interesting and
informative presentation. I had two
points, or questions, actually, to address.
One is in regards to the overall view of risk assessment and safety.
And
it seems to me that one of the difficulties intrinsic in these more
computational biological approaches of genomics and such is ultimately how to
interpret all of this data. Genes will
go up. Genes will go down. And are those changes in ways--or confer
changes in the plant that would be significant in terms of health.
And I think that's a real challenge,
that maybe the answer isn't quite known at present.
The
second point is related to more global issues, and that is, the input of safety
analysis. You mentioned that, and I
commend, that the FDA has a consultative process with developers, and, as part
of that, wants to get heads up about new products in the pipeline. Likewise, does the FDA also communicate what
they would perceive as recommendations to minimize risk intrinsic in the
state-of-the-art technologies, for example, the use of strong viral promoters
that can activate genes at distances might be, for instance, less preferred
than using more tissue of targeted promoter systems. Obviously, if a product is expressed in non-food components, it
may be less of a concern than if it's generically expressed in the plant,
including in the food component. So, is
that dialogue also two ways?
DR.
CEBULA: I'll answer the second
first. I believe it is. I think over the years, there have been a
number of times when, in a very
interactive discussion, FDA scientists
have made some suggestions, and that has led to a shift in the thinking of what
was going to be used. There have been
cases where we suggested an experiment, and I keep on saying it was an
evolutionary process; so these are earlier times, where the very technique,
there was a concern that there may be read-through through a border sequence,
and we suggested some experiments that ultimately turned out to be a very nice
publication for the company. I noticed
that in the acknowledgment that FDA scientists weren't acknowledged.
[Laughter.]
You
know those things happen, but it was a good experiment. It was a nice experiment. So, I mean, I think it happens, but again
it's part of that consultative nature: that somebody comes forward and shows
you the data. I think I said in the
sidebar, I almost treated it as an academic, you know, show me what you've done
in the lab lately. And over the first
few consultations, it was why do you want to know this. And, over time,
people said, I did this experiment
but. And, you know, that's how you find
how people are thinking. You know, we
really--it was more collegial, and people were opening up to say we were trying
this. It didn't work. We were trying this. It did work. That's the process that I'm trying to define, and I'm probably
not doing a good job of it. But it is a
learning process on both parts.
DR.
ARIAS: I think we recognize that in
very few cases are we going to find clearly demonstrable risks associated with
a particular transgenic plant. I mean,
those would be probably be quite evident in the range of studies that are done
to date. And it's the more subtle ones
that we would obviously be--considered as problematic. Thus, using new to change the overall level
of risk or probability of risk would seem to be also intrinsic in this
process. And I gather that's what I'm
hearing, as well.
DR.
CEBULA: I would just like to return to
your first question of combinatorial. I
actually should have put a slide in here, because I
usually keep the yeast genetics--the
yeast array up there. Brown, out at
Stanford, now has looked at 20 different strains of yeast, using a chip that
has about 2,000 pieces of DNA down there, so 2,000 reporting groups for each
experiment. And he's done it under
seven different environmental conditions.
So, you have 2,000 to the 20 times 7, 2,000 to the 140th power, bits of
information coming in. And so that's
why I'm saying, let's be careful what we ask for because that information
cannot be sorted through. And we will
always see genes go up and genes go down, but the question, again, remains is
it a food safety concern.
CHAIRMAN
BUSTA: Dr. Qualset. You've been very patient. I appreciate that.
DR.
QUALSET: This is Cal Qualset. I've sort of forgotten what I was going to
talk about--
[Laughter.]
Because
I'm intrigued with this discussion. I'm
a old-fashioned plant breeder. And I
see us drifting quite a ways from the 1992 policy; that is, product versus
process issue.
What
I understand is that FDA will receive a product--is that not on?
DR.
FEDOROFF: I think it's not close enough
to you.
DR.
QUALSET: Okay. Anyway, I think that we are drifting away
from the discussion of approval of a product versus discussion of all the
academic issues of process. So, I think
we need to, as a committee or a group, needs to slow down on this and decide
what is important to know about a product.
And it's a--the developer is already obligated to product a product that
is stable; that demonstrates the functionality of a gene or segments being
introduced; and to show how they established the stability, the genetic
stability as well as the performance stability, over environments in which a
plant will be grown.
So
I think it will be nice to know about these various kinds of molecular things
that can happen with genes jumping around and all that. But the issue is, is the product produced
and is it stable. We cannot understand
every genetic thing
that could happen. But if the product is as advertised, and it
does not have any risks with human food safety as a whole food or as a
processed food, I think that we are thinking steps further than are necessary
for the evaluation process. So that's
just my comment. I'm throwing that out
as a point for detailed discussion I think by the people who understand both
product marketing, development; and they understand whether they're on the
right track.
So,
I like the idea that there's consultative process with FDA, so they can kind of
get a clue of where the product--what the targets are for a new product. But the developers really have to provide
the information to support the claims.
So, I hope we can discuss that further.
CHAIRMAN
BUSTA: Bob. Identify yourself.
DR.
BUCHANAN: Bob Buchanan. I was intrigued by your discussion of Mendel
and the proteomic analysis. Of the 62
proteins that differ, did any, would any raise eyebrows as to whether the
product might be a problem? We know
the peas are safe. Do any of the
protein changes look suspicious?
DR.
CEBULA: Well, I gave you some
classes. Some affected sugar
content. Some affected sugar
storage. But none of those changes
said, you know, there's an unknown toxicant, cryptic toxicant peas that came
up. That answer is--yeah.
DR.
BUCHANAN: That's good to know.
DR.
CEBULA: Right.
DR.
GURIAN-SHERMAN: Just--did they actually
look for--
CHAIRMAN
BUSTA: Ah, yeah—
DR.
GURIAN-SHERMAN: Doug Gurian
Sherman. I'm sorry. Just for
clarification in that study, did they look for those kinds of changes? I mean, we assume they're safe, and they're
probably safe, you know. But in terms
of specific new anti-nutrients, you know, toxicants, were those looked at in
that study or they looked at just general classes, like protein, starches, et
cetera?
DR.
CEBULA: What they did was they
resolved over 600 proteins on a two-D
gel, found approximately 10 percent changed, and then went about to
characterize all 10 percent qualitative changes, and showed that, you know, it
was sugar storage. It was lipid
storage. So, they would have--if there
were a toxicant, they would have had an unknown protein, but it didn't show up
in their analysis. Sixty-two of them
were fully characterized. So.
DR.
GURIAN-SHERMAN: Well that's--just again
to follow up. Doug Gurian-Sherman. I mean, most--many products, especially
legumes do have toxicants and anti-nutrients, and they're often removed through
the process, and through cooking, they're not--for instance, they're not heat
stable. So, you know, if there's a
change in levels, some of them could theoretically have been, you know,
toxicants and anti-nutrients. I guess
what I was getting at was were they trying to identify whether those proteins
were, you know, trypsin-inhibitors, or amylase-inhibitors, or, you know,
whatever things that--maybe it wouldn't be problematic
anyway, because they may be removed
through processing; but others that if the level was increased--I mean, some
allergens are also, you know, some of these types of proteins that might have
an effect, and that's what I was getting at.
DR.
CEBULA: I really don't know if the
wrinkled peas in that experiment were consumed by the investigators. I am sure they went a lot of blood, sweat,
and tears to get it published in Genetics, but that was the standard.
DR.
FEDOROFF: What does conventional
alleles work? That wasn't recombinant
DNA anything.
DR.
CEBULA: It wasn't. No, no.
DR.
FEDOROFF: It was just round peas and
wrinkled peas.
DR.
CEBULA: It was a natural. Right.
CHAIRMAN
BUSTA: You know the conversation is
rolling toward lunch. Any other
questions for clarification? The
speakers will be around this afternoon, correct, as we go to discussion for
additional expansion if we need it?
DR.
CEBULA: I will be on a conference call,
but I said I would be available.
CHAIRMAN
BUSTA: Okay.
DR.
CEBULA: I will be on a conference--
CHAIRMAN
BUSTA: But, if we have to, we can drag
you in; right?
DR.
CEBULA: Okay.
CHAIRMAN
BUSTA: Any--immediately after lunch, we
will have the public comment. Is that
one? Is that correct? And we will have that public comment--it's
generally set for 10 minutes, and then we will go directly into the summary and
discussion. Anne?
DR.
KAPUSCINSKI: I was reminded that you
need to read my name.
CHAIRMAN
BUSTA: I was going to do that right
after lunch, but do it right now. We
have the time.
DR.
KAPUSCINSKI: Okay. So, my name is Anne Kapuscinski, and I'm
from the University of Minnesota; and I'm on the subcommittee, and I'm really
here.
CHAIRMAN
BUSTA: And she showed up immediately
after we went through that activity this morning.
DR.
KAPUSCINSKI: Twice.
CHAIRMAN
BUSTA: Twice.
DR.
KAPUSCINSKI: That's because I have to
get some good coffee. It's my one
weakness. One of my weaknesses.
CHAIRMAN
BUSTA: Thank you all. I'd like to thank all the speakers this
morning--and for your tenacity and the group.
I look forward to an exciting discussion after the public comment this
afternoon.
[Whereupon,
the meeting went back on the record at 1:05 p.m.]
CHAIRMAN
BUSTA: We have one public comment, and
Mike Watson will introduce it.
UNIDENTIFIED
SPEAKER: We have one public comment from Dr. Michael Hanson, from Consumers'
Union, and he asked for 10 minutes to present to the committee.
CHAIRMAN
BUSTA: Yes, please. Use the
microphone, so it's recorded.
DR.
HANSON: Thank you. My name is Dr. Michael Hanson. I work for Consumers' Union. They're the people that publish Consumer
Reports magazine. And we've been very
interested in genetic engineering issues; have actually been commenting on all
the--ever since 1992, on the FDA's various bio tech proposals. And I should also point out that Consumers'
Union is part of the international network called Consumers International,
which is composed of 270 consumer organizations in 117 countries. And we have observer status at the U.N., and
we've also been very actively involved in the whole Codex process. We went to all the meetings of the Task
Force on Biotechnology. And we would
actually agree with Dr. Maryanski that that was a very positive process.
What
I'd like to do here today is very quickly just make a few comments about
molecular characterization. And these
are the few points that I want to make.
First,
we think that it's a very good idea that the FDA is now talking about requiring
a lot of molecular characterization data, as is laid in these Codex
documents. But we have a basic
question, and that is, whether this will be mandatory and not voluntary, and
also to what extent data is going to be required post transformation. Because, in what you were told earlier
today, it made it seem like the FDA has sort of been requiring this data all
along. But that's not really true. That was a new requirement that came in with
this 2001 policy. And I'll tell you
about three years ago, I was on a State Department Committee, this Trans
Atlantic Policy Project, and it was focusing on biotechnology; and the idea was
to try to get the U.S. and Canada and the European Union to work toward
harmonization. There was a lot of
debate within the subcommittee, because, first, they wanted to look at full
biotechnology, like a--and they argued about should we require, should we look
at a human data package or environmental issues. And they couldn't decide
on anything, so the one thing that they
decided on in this working group was to focus just on molecular
characterization. And what happened, this was I think in 2000, late '99, early
2000; when we finally met, data had come in from both the U.S. and Canada
saying here is the molecular characterization data that's required. And the European Union, because I guess the
data is different in different countries, they actually never submitted
anything. So, this subcommittee has
only met twice. We still haven't gotten
any data from the European Union. But
it should be pointed out that the data that was submitted by the U.S. and
Canada, the molecular characterization that they said they were requiring, was
functionally complete maps of the vectors and plasmids and what you were going
to insert. But post insertion, it was
just information to show that the transformation had been complete; that is,
that the gene was in there and was active.
But there was no requirement in terms of the data that they were showing
us to do this--these nice maps of
how many insertion sites, what the
structure is at each insertion site.
So, that's what caused us some concern, and we really think that all
that information needs to be in there.
I would also point out that, in the 2001 pre-market biotech notification
proposed rule, it says in this paper that was handed out today that it's just
an extension of the 1992 policy. But it
really isn't because there's, in the Federal Register Notice, they said for the
first time they will be requiring data, and the data that they--part of the
reason that they said that they were going to be requiring data is they said
that the unintended effects that come from the random insertion, they called it
insertional mutagenesis, because that can differ between different
transformation events, the Agency said that they would require data on each
separate transformation event, even if the vectors and plasmids used were the
same, and the genetic background used was the same; that they would require
separate data.
We
think this is a very positive thing,
but we wonder whether the FDA is
actually going to move forward with those rules, because I should point out
that the molecular characterization data, for example, for the BT crops that
EPA used in their safety assessment, they actually bridged, they allowed
companies to use data from separate transformation events and have it go
collectively.
And--so,
we think that the data that should be required is that there should be complete
molecular characterization of each line with respect to identity, stability,
and unintended positional and pleiotropic effects. And the agency--the components of a complete molecular
characterization should, for molecular identity, would include for each
transgenic or transformed line the total number of inserts; the location of
each insert, whether organelle, chloroplast, mitochondria, et cetera, or
chromosomal; the exact chromosomal position of each insert; the structure of
each insert, whether duplicated, deleted, rearranged, et cetera; the complete
genetic map of each insert, including all the elements--the coding
region, non-coding regions, marker
gene, promoters, enhancers, enterons, leader sequences, terminators, T-DNA
borders, plasmid sequences, linkers, et cetera, including any truncated
incomplete sequences; also the complete nucleotide base sequence of each
insert. And we also suggested that the
base sequence of at least 10 kilobase pairs of flanking post-genomic DNA on
either side o the insert, including changes in methylation patterns. The reason for this is because the prominent
use of hyper-promoters, such as the CAMV-35S promoter.
And
the other main point I wanted to make is for determining molecular stability,
we think there needs to be data on both functional and structural
stability. And the functional stability
should be the level of expression remains constant over time and over
successive generations. And I would
point out that just requiring Mendelian data is not good enough. For example, with the BT crops, there's a
high dose strategy, and the high dose is defined as 25 times the LD-99. And so, if all you're doing, in some of the
data that was submitted to the EPA, they would just say to show that
something's stable, you just had to show that the trait still worked; that is,
that it still had activity against these insects. Well, if you're talking about a high does being 25 times the
LD-99, you could have variability, and one trait could be 20 times lower and
only have 5 times the LD-99 of the cryoprotein in there. But if you did a simple bioassay with
caterpillars, you would find that 99 percent of them still die. That is, you couldn't see the variability
there.
So,
that's why we think that for structural stability that the FDA would need data
on the physical location of the insert in the genome, as well as on the
structure of the insert throughout the lifetime of the plant and over
successive generations, say, three to five generations. And, particularly, to look at that
structural stability, we think there needs to be data on the flanking
sequences, so you can see whether it's moving around inside the plant or not,
because we noticed that those kind of
data were not submitted for the majority of crops that have gone through this
process. Of the 54 crops that--54
things that have gone through the FDA's process, I believe only two of them
have gone through since 2001.
And
finally, for the other form of stability, we think that the FDA--I'm sorry--to
look at the tests for unintended positional effects, we believe the FDA could
carefully look at methylation patterns of genes in the flanking host genome
DNA. And that's, again, 10,000 or 10
kilobase pairs upstream and downstream of the insertion site.
So,
in sum, we think this is a very positive movement that the FDA is proposing,
but we do have the question of whether these data, which they say are going to
be required through the PBN, since we hear that that's going to fall off the
radar screen, not be on category list A or B, whether the FDA will be requiring
all these data that they said they will in the future. Thank you.
CHAIRMAN
BUSTA: Thank you. Any burning questions? Just one.
DR.
SALYERS: I just want to make a comment
about this. Monsanto must love you,
because if that grocery list is actually enacted as obligatory, it's going to
make it even harder for small companies to get into the biotech; and for
developing countries who follow our lead, even though they're not bound by our
requirements to develop their own products.
So,
I just think that we need to be careful about--it's always appealing to add on
another item to the long list of existing ones. But the question is, is there a reason to do it? And are we doing anything but further
increasing the power of the big companies in this area?
DR.
HANSON: Well, my response to that is I
think that all we're asking for is the kind of data that has now been agreed
upon internationally; that are actually--it's in paragraphs 30 to 33 of this
Codex document that was agreed upon.
And the reason that this is important is, written into the
GAT agreement, which set up the World
Trade Organizations, if there is disputes between countries, they'll look,
written into the GAT agreement is, indeed, Codex Alimentarias is considered the
neutral, scientific standard. So the
concern we have is that some other countries could pass laws saying that they
require all the data that is mentioned in here, and then they could turn
around, and since this data is not required in the U.S., they could exclude
products coming from the U.S., saying that they don't meet this standard.
So,
we're not suggesting that further data should be added. We're asking that the FDA require the level
of data that has now been agreed upon internationally so that there is not a
problem with trade, potential trade impacts with products that come from the
U.S. Because you should know, most of
the world did agree that these safety assessments should be required. The U.S. does not require that at this
point. So, that's why--we're not asking
for extra data that will overly burden
developing countries. It's just the data that has been agreed upon
globally.
CHAIRMAN
BUSTA: Now, it's Dr. Salyers.
DR.
SALYERS: Abigail Salyers. Sorry, I didn't hear--
CHAIRMAN
BUSTA: Dr. Qualset. Go ahead.
DR.
QUALSET: Okay, it's Cal Qualset
speaking. It seems that if the
developers are developing a product for U.S. markets, then why would they be
required to get data that isn't essential to the evaluation of the efficacy of
the product in terms of food safety? If
the developers want to go to international markets, they can follow the
international standards. But why make
everybody fall into this, whether it's a small university, a small company, or
large company? I think it should be
clear that we have to evaluate for the product safety, and not necessarily all
the ins and outs of its development.
DR.
HANSON: Well, but I think a response to
that is the main crops are engineered right now, corn and soybeans and cotton,
are actually used a
lot in international commerce and are
submitted--if this is only something used within the U.S., then that could be a
different story.
DR.
QUALSET: What I'm thinking is that
there are people considering doing modifications to minor crops that may not
ever get into the export stream, and they can't afford to go through all of
this for a crop that will be sold to small farmers, for example.
CHAIRMAN
BUSTA: Dr. Fedoroff.
DR.
FEDOROFF: Nina Fedoroff. I guess my question is, could you say
there's data from the literature that would suggest that this information that
you think should be made mandatory is predictive of--is useful in predicting
unintended consequences that affect food quality?
DR.
HANSON: I can get back to you on
that. There is--all I can say is that
there was a lot of data that was talked about at these Codex meetings, and part
of the problem is you have to know what you're dealing with before you can
start to figure out what the safety implications are,
right?
And so, with the unintended effects, since that's actually a new field,
and there was a huge discussion at Codex.
There's quite a number of paragraphs on that. They're talking about these metabolomics and the use of genome
arrays. And I think that's useful, but
I agree with the other scientists here.
The basic problem is how do you take, once you've identified all those
differences, how do you then figure out what the safety implications of them
are. But before you can figure them
out, you have to know what they are.
CHAIRMAN
BUSTA: Dr.
DR.
FEDOROFF: Yeah, but my question to you
was how does accumulating all of these sequences and methylation patterns help
you identify what the safety--that the food quality implications are?
DR.
HANSON: Well, I can point to studies in
the scientific literature with yeast and actually with tobacco where there have
been unexpected effects that have led to toxins that were not previously
present in the plants or to
things that have an--would have an
adverse effect on DNA or other things, I mean.
DR.
FEDOROFF: That's what I'm asking
for. Could you cite those references?
DR.
HANSON: Yeah, I can get those. One of them is Enos and Eurata. I mean, we can talk afterwards. I mean, I do have a list of those various
studies that I can get to you--
DR.
FEDOROFF: Please do.
DR.
HANSON: And I will submit them.
CHAIRMAN
BUSTA: Dr. Gurian?
DR.
GURIAN-SHERMAN: Yeah, I guess one issue
in terms of--
CHAIRMAN
BUSTA: Introduce yourself. No, introduce yourself.
DR.
GURIAN-SHERMAN: Oh, I'm sorry. Doug Gurian-Sherman. I think the economic issues kind of go
beyond, you know, what we're supposed to be talking about here, and I don't
think we're qualified to really even talk about them, because there's--you
know, we could get into all kinds of sidetracking to discuss those. For instance, you
know, for pesticides, where there's a
minor crop issue to getting pesticides for minor crops comparable to this with
biotech, there's a set-up system that is not as effective as it could be but
could be stronger called IO4 that probably a lot of your are familiar with to
help small companies and minor crops get through the system. So I think we're just getting into areas
that are way beyond what we need to be talking about here, which is the safety
issue.