1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR FOOD SAFETY AND APPLIED NUTRITION
FOOD ADVISORY COMMITTEE MEETING
Advice on CFSAN'S Draft Report:
Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food
Wednesday, July 13, 2005
8:30 A.M. to 5:50 P.M.
Greenbelt Marriott
6400 Ivy Lane
Grand Ballroom
Greenbelt, Maryland 20770
2
P A R T I C I P A N T S
FOOD ADVISORY COMMITTEE STANDING MEMBERS:
Richard A. Durst, Ph.D. - Acting Chairman
Jeffrey A. Barach, Ph.D. (Industry Representative)
Patrick S. Callery, Ph.D.
Dennis Gonsalves, Ph.D., M.S.
Jean M. Halloran (Consumer Representative)
Douglas C. Heimburger, M.D., M.S.
Margaret C. McBride, M.D.
Mark Nelson, Ph.D. (Industry Representative)
Carol I. Waslien Ghazaii, Ph.D., R.D.
TEMPORARY VOTING MEMBERS:
Petr Bocek, M.D., Ph.D.
Margaret Briley, Ph.D., R.D.
Erica Brittain, Ph.D.
Ciaran P. Kelly, M.D.
Soheila June Maleki, Ph.D.
David O. Oryang
Marc D. Silverstein, M.D.
Suzanne Teuber, M.D.
FOOD AND DRUG ADMINISTRATION:
Catherine Copp, J.D. - Senior Policy Advisor
Food and Drug Administration, CFSAN
Steven M. Gendel, Ph.D. - Senior Scientist
Food and Drug Administration
National Center for Food Safety and Technology
Rhonda Kane, M.S., R.D. - Consumer Officer
Food and Drug Administration, CFSAN
Michael M. Landa, J.D. - Deputy Director for Regulatory Affairs
Food and Drug Administration, CFSAN
Stefano Luccioli, M.D. - Senior Medical Advisor
Food and Drug Administration, CFSAN
Marcia Moore, Food Advisory Committee, Executive Secretary
Jenny Slaughter - Director
Food and Drug Administration Integrity and Ethics
Staff
3
P A R T I C I P A N T S (Continued)
GUEST SPEAKERS:
Rene Crevel, Ph.D. - Senior Scientist
Unilever, Safety and Environmental Assurance Centre, United Kingdom
Susan Hefle, Ph.D. - Associate Professor and Co-Director
Food Allergy Research and Resource Program, University of Nebraska
Stefano Luccioli, M.D., - Senior Medical Advisor
CFSAN, FDA Assistant Professor, Georgetown University
Anne Munoz-Furlong
Director, Food Allergy & Anaphylaxis Network
Steve Taylor, Ph.D. - Maxcy Distinguished Professor & Director
Food Allergy Research and Resource Program, University of Nebraska
Robert Wood, M.D. - Professor
Johns Hopkins University School of Medicine
4
C O N T E N T S
PAGE
Call to Order, Welcome and Introductions
Charge to the Food Advisory Committee
Richard Durst, Ph.D., Acting Chairman 6
Conflict of Interest Statement & Other
Instructions
Jenny Slaughter, FDA 10
Welcome and Opening Statement
Michael M. Landa, Esq., CSAN, FDA 14
Use of Food allergen Thresholds
Catherine L. Copp, Esq., CFSAN, FDA 18
Introduction to Food Allergens
Robert Wood, M.D. 23
Patient Perspectives on Food Allergies
Anne Munoz-Furlong 72
Allergenicity: Analytical Methods
Susan Hefle, Ph.D. 99
Question and Answer Session 126
Oral Challenge Studies: Purpose, Design,
and Evaluation
Stefano Luccioli, M.D.
Senior Medical Advisor, CFSAN, FDA 133
Question and Answer Session 161
Threshold Modeling Approach
Rene Crevel, Ph.D. 170
Food Allergen Thresholds
Steve Taylor, Ph.D. 189
Overview of Approaches to Establishing
Thresholds: Allergens
Steven M. Gendel, Ph.D., FDA 218
5
C O N T E N T S (Continued)
PAGE
Public Comments:
Tracy Atagi 228
John Carroll 232
Diane Castiglione 242
Will Duensing 247
Martin J. Hahn, Esq. 250
Peggy Mockett 254
Kim Mudd 257
Kim Mulherin 260
Linda Webb 264
Jupiter Yeung 268
Committee Discussion:
Panel Discussion with Guest Speakers
Thresholds for Food Allergens - Questions 272
Adjournment
Richard Durst, Ph.D., Acting Chairman 414
6
P R O C E E D I N G S
CALL TO ORDER, WELCOME, AND INTRODUCTIONS
CHARGE TO THE FOOD ADVISORY COMMITTEE
CHAIRMAN DURST: I would like to call the
meeting to order.
Good morning. I am Dick Durst, professor
of chemistry in the Food Science and Technology
Department at Cornell University. I was asked to
chair this meeting over the next two and a half
days. I would like to make a few announcements
before we begin our meeting this morning.
I would appreciate it if everyone would
turn off their cell phones, unless they are
expecting a call of a super emergency nature. I
would also like to ask if the guest speakers could
make themselves available for the discussion this
afternoon, I would really appreciate it. We may
have some additional questions.
We have received a charge from the FDA to
give our evaluation of the draft report prepared by
the Threshold Working Group. I assume all of the
members
have read that thoroughly. In my
opinion,
7
I it was fascinating.
It was an excellent article and I commend
the Committee for coming up with it. It was very
educational. Not being an expert on food allergens
myself, it was extremely educational, and I was
able to follow it quite clearly.
Our charge is to evaluate this report to
determine whether the approaches that are presented
in there are the only ones or the better ones,
which of the ones that are in there might be the
most appropriate. This is the focus of our meeting
today, both on the food allergens and on gluten.
Let me also begin by asking the committee
members to introduce themselves. We will start
with Dr. Silverstein.
Marc, would you start it off?
DR. SILVERSTEIN: Good morning. My name
is Marc Silverstein, and I'm a general internist
and geriatrician at Baylor Health Care System in
Dallas.
DR. TEUBER: Good morning. My name is
Suzanne
Teuber, I am an allergist at UC-Davis.
8
MR. ORYANG: Good morning. I am
David Oryang. I am a risk analyst and agricultural
engineer at the United States Department of
Agriculture, Animal and Plant Health Inspection
Service.
DR. KELLY: I am Ciaran Kelly, and I am a
gastroenterologist at the Harvard Medical School in
Boston.
DR. MALEKI: I am Soheila Maleki. I am a
scientist with the USDA.
DR. BRITTAIN: Erica Brittain, I am a
statistician at the National Institute of Allergy
and Infectious Disease.
DR. BRILEY: Margaret Briley, University
of Texas at Austin, nutritionist.
DR. BOCEK: Good morning. I am
Petr Bocek, medical officer in NIH's National
Institute of Allergy and Infectious Diseases.
MRS. MOORE: I am Marcia Moore. I am with
the FDA as the executive secretary of the Food
Advisory Committee.
DR. WASLIEN: I am Carol
Waslien. I am a
9
nutritional epidemiologist at the University of
Hawaii.
DR. McBRIDE: I am Margaret McBride. I am
a child neurologist at Akron Children's Hospital.
DR. CALLERY: I am Patrick Callery, a
pharmaceutical scientist from West Virginia
University.
DR. GONSALVES: I am Dennis Gonsalves, a
scientist with USDA in Hawaii.
DR. HEIMBURGER: I am Doug Heimburger, a
physician and nutrition specialist at the
University of Alabama at Birmingham.
DR. BARACH: Jeff Barach with Food
Products Association, vice president for special
projects and regulatory affairs.
DR. NELSON: Mark Nelson with the Grocery
Manufacturers Association responsible for
regulatory and scientific policy.
MS. HALLORAN: Jean Halloran from the
Consumers Union where I am director of food policy
initiatives.
CHAIRMAN DURST: Thank you very
much.
10
One other item is that we may have some of
our members leave early on Friday, depending on the
amount of time we can spend. What I propose is
that today and tomorrow that we anticipate having
to go perhaps till 6 o'clock so that we can be sure
that we have enough time for all of our
discussions.
Okay. Let me introduce our first speaker.
This will be Jenny Slaughter, director of Ethics
and Integrity Staff at the FDA, to describe the
"Conflict of Interest Statement" and other
instructions.
CONFLICT OF INTEREST STATEMENT
AND OTHER INSTRUCTIONS
MS. SLAUGHTER: Well, good morning and
welcome. The Food and Drug Administration is
convening today's meeting of the Food Advisory
Committee under the authority of the Federal
Advisory Committee Act of 1972.
With the exception of the industry
representatives, all members of the Committee are
special
government employees or regular Federal
11
employees from other agencies subject to Federal
conflict of interest laws and regulations.
FDA has determined that members of this
Advisory Committee are in compliance with Federal
ethics and conflict of interest laws including, but
not limited to, 18 U.S.C. 208 and 21 U.S.C. 355 and
354.
Under 18 U.S.C., Section 208, applicable
to all government agencies, and 21 U.S.C. 355,
applicable to only FDA, Congress has authorized FDA
to grant waivers to special government employees
who have financial conflicts when it is determined
that the Agency's need for particular
interventional services outweighs the potential
conflict of interest.
Members who are special government
employees at today's meeting including special
government employees appointed as temporary voting
members, have been screened for potential financial
conflicts of interest of their own as well as those
of their spouse, minor child, and employer, which
are related
to the discussions of today's and
12
tomorrow's and Friday's meeting regarding the "FDA
Draft Report: Approaches to Establish Thresholds
for Major Food Allergens and for Gluten in Foods."
These interests may include investments,
consulting, expert witness testimony, contracts,
grants, research and development agreements, public
speaking, writing, patents, royalties, and primary
employment.
In accordance with 18 U.S.C. 208(b)(3),
full waivers have been granted to the following
participants, Dr. Suzanne Teuber and Dr. Soheila
Maleki, please note that all of the interests in
the firms that could potentially be affected by the
Committee's decisions.
A copy of the written 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.
In addition, the following individuals are
participating as FDA's invited guest speakers,
July 13th: Dr. Rene Crevel, Dr. Susan Hefle,
Anne Mun[MLM1]oz-Furlong,
Dr. Steve Taylor, and
13
Dr. Robert Wood.
The following individuals will be
participating as FDA invited guest speakers
tomorrow, July 14th: Dr. Pekka Collin,
Dr. Alessio Fasano, Dr. Donald Kasarda,
Dr. Cynthia Kupper, and Dr. Joseph Murray.
Lastly, I would like to report that
Dr. Jeffrey Barach and Dr. Mark Nelson are serving
as the industry representatives on the Committee at
today's meeting. They are acting on behalf of all
regulated industry.
Dr. Jeffrey Barach is employed by the
National Food Processors Association and
Dr. Mark Nelson is employed by the Grocery
Manufacturers of America.
A copy of this document will be placed on
the back table, if anybody wishes to take a look at
it. I thank you.
CHAIRMAN DURST: Thank you very much.
We will now go on to the welcome and opening
statement by Dr. Michael Landa, the deputy director
for
Regulatory Affairs at CFSAN, the FDA.
14
Mike.
WELCOME AND OPENING STATEMENT
MR. LANDA: Thank you, Dr. Durst. You
will be pleased to learn that I don't have a
doctorate or an M.D. I'm just a plain, old J.D.
(General laughter.)
MR. LANDA: Thanks again. Good morning to
everyone. Welcome to the members of the committee,
to the guest speakers, to members of the public who
have joined us today, and to my fellow FDA
employees.
I would like to give a special thanks to
the Committee members for your willingness to take
time from busy schedules to help us with your
expertise for a meeting that will be several days
long. We are all here today, tomorrow and a fair
chunk of Friday.
Let me just add that Dr. Brackett had
hoped to be here this morning, but he wasn't able
to make it. I am hopeful that he will be here for
some portion of the meeting. He was called
downtown
for a meeting this morning.
15
I am going to refer to a couple of points
on the food allergens, but the points I'm making
apply to celiac disease as well. It is just less
cumbersome to start with the food allergens. The
agenda has been making, I think, an opening
statement, of course I'm really not going to do
that.
There are just a few points I want to make
as you go into your inquiry today. The first is
virtually every FDA speaker makes at this kind of
proceeding which is what we do really is based on
science.
We talk about being a science-based
agency. It is the bedrock; it is the foundation.
In that context, I am going to paraphrase what may
be a rather obscure 19th century Senator, Karl
Shrews from Pennsylvania.
The paraphrase essentially is, Our science
correct or incorrect, when it is correct, help us
keep it correct; when it is incorrect, help us to
correct it. That is as much as anything else what
we want
from you here in terms of your expertise in
16
the science.
If with respect to the threshold in the
Draft Report, we have gotten it right, we want to
know from you that we have gotten it right. We
want your help in keeping it right. If we have
gotten it wrong, we want your help in getting it
right. That includes, as you will hear, if we have
not considered an approach that we should have
considered, we want to know that from you.
The third point I will make is that
Americans suffer from food allergies, particularly
children. There is some evidence that the number
is increasing. If you add to that family members,
you really have tens of millions of folks who are
involved. At the moment their principle means of
protection really is exquisite attention to the
food label. That is their pathway to safety I
suppose.
We are hoping that eventually thresholds
will provide another path to safety. This is the
beginning of the inquiry into thresholds, that is,
the
approaches that are outlined in the report.
It
17
is the first step in a very important process.
The last point I will make is just that
this is as much as anything else for members of the
public, the docket is going to remain open until
about the middle of August.
If people have comments, based on what
they have heard today, for example, they should
feel free to submit those comments to the docket.
Again, it is until about, I don't remember the
precise date, but it is the middle of August.
In that connection, I should say we are
especially interested, as I think is always the
case, in data. In this case, data of the type
outlined in the report.
Thank you.
CHAIRMAN DURST: Thank you, Mike. Since
Mr. Landa didn't want me conferring a doctorate
degree on him, I will not do it with Catherine
Copp, who is the policy advisor at CFSAN, also the
FDA, who will discuss the use of food allergens
thresholds.
USE OF FOOD ALLERGENS THRESHOLDS
18
MS. COPP: I was hoping. Oh, well.
(General laughter.)
MS. COPP: Thank you, Dr. Durst.
Good morning. As you know, the focus of
this meeting today and tomorrow and the discussion
on Friday is the Draft Report of CFSAN's Threshold
Working Group: Approaches to Establish Thresholds
for Major Food Allergens and For Gluten in Food.
I have been asked to provide a context for
the Draft Report in terms of CFSAN's programmatic
efforts. This is one thing that if I were a real
doctor I could do. Lawyer's don't do this.
(Slide.)
MS. COPP: Last August, Congress enacted
the Food Allergen Labeling and Consumer Protection
Act, which we refer to in-house by the somewhat
awkward acronym "FALCPA."
This new law amends the Federal Food, Drug
and Cosmetic Act, the principle statute
administered by FDA by requiring that the label of
a food product that is or contains an ingredient
that bears
or contains a major food allergen
19
declare the presence of the allergen as specified
in the law. In shorthand, the declaration is to be
in "consumer friendly" terms.
FALCPA defines a "major food allergen" as
one of the eight foods or food groups or a food
ingredient that contains protein derived from one
of these foods. Those are listed on the bottom of
this slide. By "food groups," I mean fish, tree
nuts and crustacean shellfish, which were
identified by Congress in the law.
(Slide.)
MS. COPP: The possible existence of
threshold levels for food allergens is an important
scientific issue, as Mr. Landa has pointed out,
associated with our implementation of FALCPA.
Although the law does not require FDA to
establish thresholds for any food allergen, there
are three possible ways, which are listed on this
slide, that such thresholds could be used to
implement the new law, these are: administering the
petition process provided for in FALCPA,
administering its notification process, and
20
addressing the issue or the occurrence of
cross-contact.
(Slide.)
MS. COPP: FALCPA provides two processes
by which an ingredient may be exempt from the
FALCPA labeling requirements, a petition process
and a notification process. I'm trying to read my
own slides (laughter). No, okay.
Under the petition process, an ingredient
may be exempt, if the petitioner demonstrates that
the ingredient does not cause an allergenic
response that poses a risk to human health.
Given this language for the petition
exemption standard, we believe it will be very
important for us to both understand food allergen
thresholds and to have a sound scientific framework
for evaluating the existence of such thresholds.
Under the notification process, an
ingredient may be exempt, if the notification
contains scientific evidence that demonstrates that
the ingredient does not contain allergenic protein,
or, if FDA
has previously determined under the food
21
additive approval process that the food ingredient
does not cause an allergenic response that poses a
risk to human health.
(Slide.)
MS. COPP: Given this language for the
notification exemption standard, we also believe
that it will be very important for us to understand
food allergen thresholds and to have a sound
scientific framework for evaluating the existence
of such thresholds.
(Slide.)
Finally, the FALCPA directs FDA to prepare
and submit a report to Congress. This report will
focus principally on the issue of cross-contact of
foods with food allergens and is to describe the
types, current use of, and consumer preferences
with respect to so-called "advisory labeling."
Processed in a facility that also processes tree
nuts is an example of such labeling.
Cross-contact may occur during food
production
when residues of an allergenic food are
22
present in the manufacturing environment and are
unintentionally incorporated into a food. Because
the food is not intended to contain the allergen,
it is not declared as an ingredient on the food's
label. In some cases, however, the potential
presence of the food allergen is declared by a
voluntary advisory statement.
We also believe that understanding food
allergen thresholds and developing a sound
scientific framework for evaluating the existence
of such thresholds may also be useful to us in
evaluating and addressing food allergen
cross-contact and the use of advisory labeling.
Thank you.
CHAIRMAN DURST: Thank you very much.
Does the Committee have any questions or
discussion of this presentation?
(No verbal response.)
CHAIRMAN DURST: If not, I think we will
proceed.
The next speaker is Dr. Robert Wood,
professor
at Johns Hopkins University School of
23
Medicine, who will give us an introduction to food
allergens.
INTRODUCTION TO FOOD ALLERGENS
DR. WOOD: Thank you very much. It is a
pleasure to be here. What I was asked to do is to
provide an overview of food allergens and food
allergy leading into the discussion that is going
to go on over these next couple of days.
(Slide.)
DR. WOOD: The beginning of this, any talk
about food allergy really requires that we have
some common definition that we can all agree on.
This is something that is not as easy as it might
sound and often generates a lot of confusion. The
reality is that a lot of what is called food
allergy is really not food allergy and may fall
under more of a food intolerance category.
When we are talking about food allergy,
there are a couple of key ingredients. One of them
is that there is an immunologic component to the
reaction. The reaction is typically to the protein
component
of the food as opposed to a food
24
intolerance that is more often related to the
carbohydrate component of the food. Importantly to
this meeting, exquisitely small amounts may cause a
reaction and that these reactions can be severe and
even life threatening.
(Slide.)
DR. WOOD: The pathophysiology of the
allergic response is sort of very schematically
diagramed here. What we are thinking about is a
process that begins with exposure and with most
allergy, probably all allergy, you have to have
some prior exposure to develop your sensitivity.
(Slide.)
DR. WOOD: There is a genetic
predisposition that makes some people particularly
more prone to develop allergy in general, whether
it be food allergy or respiratory allergy, than
others. There are some people who no
matter what, how, when and where they are exposed
they will never develop an allergy, and others who
with very trivial exposure may develop a severe
allergy.
25
If you are in this group who is
genetically predisposed, your immune system then
goes through a process we will refer to as
sensitization. Sensitization is most often
involving the production of IgE antibodies. We
will talk about this in a little bit more detail
about some different food allergy syndromes.
However, it is also important to note that
not every food allergy involves IgE and that there
may be differences in the types of reactions and
the doses of food required to induce a reaction in
those patients that have IgE versus
non-IgE-mediated food allergy.
Once you have become sensitized, then
reexposure to this food will lead to symptoms.
These symptoms may be abrupt, they may occur within
seconds of eating the food, or they may be very
low-grade and chronic. This is another concept
that we will come back and talk to a little bit.
With some patients it will be very easy to
determine a threshold, and in some patients it will
be
virtually impossible to determine a threshold
26
because their symptoms will not appear in a
challenge test. They may take days or weeks of
chronic exposure and then develop very significant
disease based on that chronic exposure.
(Slide.)
DR. WOODS: The prevalence of food allergy
is substantial. The numbers that we would be most
comfortable with would be 5 to 7 percent of young
children; 2 to 3 percent of adolescents and adults;
at least 10 or 11 million Americans affected.
We do believe that the prevalence is
rising. We don't believe that this is specific to
food allergy. There has been a substantial rise in
asthma and other allergic diseases as well as food
allergy.
Now, the reason that these numbers change
between childhood and adolescence and adulthood is
because a large proportion of food allergy is
outgrown over the first five to seven years of
life.
(Slide.)
DR. WOOD: There is a long list
of
27
potential food allergens out there. At least 200
foods have been identified and characterized as
truly food allergens, but there is a relatively
shorter list that are focused upon because they are
responsible for the vast majority of food allergy
that occurs.
The list on the left-hand side
representing what is most common in young children:
milk, egg, peanut, soy, wheat, and tree nuts.
Then, the list shifts a little bit as you get into
older children, adolescents and adults and is
dominated by peanuts, tree nuts, fish, and
shellfish.
The reason that this list changes from
childhood to adulthood is because four of these
most common food allergens in your children --
milk, egg, soy, and wheat -- are typically
outgrown.
Eighty to 90 percent of children will
outgrow those food allergens and not carry them
into adolescence or adulthood, whereas the peanuts,
tree nuts,
fish and shellfish are significantly
28
more difficult to outgrow, less commonly outgrown,
and tend to persist into adulthood and actually
through the patient's entire lifespan.
(Slide.)
DR. WOOD: Now, the signs and symptoms of
food allergy are highly varied. They may be
chronic and low grade as I mentioned, they may be
acute and life threatening. What I want to run
through in the next couple of minutes are just some
examples of allergic reactions that will point out
a number of things about not only the kinds of
reactions, but the exquisitely small amounts of
food that induce these reactions we are going to
show you, and the sort of day-to-day issues that
patients with food allergy are facing.
(Slide.)
DR. WOOD: The first couple of patients I
am going to show you have urticaria or hives. This
is a total body hive reaction that this boy is
experiencing, a patient I have known since he was
an infant.
He is school age at this point.
This
29
reaction occurred when he was in the grade school
cafeteria, was being teased about this food
allergy, another child blew a straw full of milk
across the table into his face, and he had this
really significant reaction.
(Slide.)
DR. WOOD: This baby here was identified
with milk allergy in the first few weeks of life.
There are some children who don't show up with food
allergy until they are two or three or four years
old, while there are others who are really
demonstrating food allergy in the first days of
life.
This was a baby who was so allergic that
he would react very acutely if his mother, who was
breast feeding him, ingested any milk protein. She
was on a very strict avoidance diet after we
identified his milk allergy, but on the occasion of
her birthday ate a piece of cheesecake, breastfed
him an hour and a half later, and he had this acute
hive reaction.
(Slide.)
30
DR. WOOD: Now, when we are thinking about
urticaria or hives, there are patients that may
have chronic urticaria. Food allergy is rarely a
cause of chronic urticaria.
However, when someone shows up with an
acute episode of hives, the chance that it is food
allergy becomes higher. Again, we are looking a
relatively short list of foods that are most
commonly implicated: peanut, nuts, eggs, milk,
fish, and shellfish.
Importantly, these reactions are usually
very quick in their onset. Ninety percent of them
or thereabouts will have an onset within 30
minutes; at least half of them, within 5 minutes;
and virtually all of them, within 2 hours.
When a patient has this type of reaction,
it is often very easy to identify the culprit food
because of the abrupt association of the ingestion
of that food with the onset of these hives.
Then, in more severe episodes, there may
be swelling or angioedema or associated
gastrointestinal or respiratory symptoms. That is
31
moving into more of a systemic reaction that we
would refer to as "anaphylaxis."
(Slide.)
DR. WOOD: Now, this is a patient here who
is having an anaphylactic reaction. When you look
at her back here, it looks just like hives. When
you see her front, though, she is having swelling
and breathing difficulty.
(Slide.)
DR. WOOD: This is a patient who was
having a reaction in the midst of a food challenge
-- not in the midst of it, after her first tiny
dose of egg protein, she went into this very
severe, anaphylactic reaction.
(Slide.)
DR. WOOD: This boy here is someone who is
having a dramatic episode of swelling. His
reaction occurred. Most patients, we should say,
who are having severe reactions know about their
food allergy and are making efforts to avoid it.
He was shellfish allergic -- he is
32
shellfish allergic. He was making efforts to avoid
shellfish, and he had been reaction-free for
several years.
Then, on another birthday occasion, he ate
chicken in a restaurant and the chicken had been
fried in the same oil as shrimp had been fried.
With that cross-contact, this severe reaction.
(Slide.)
DR. WOOD: Anaphylactic reactions are
defined as a systemic allergic reaction,
involvement of multiple organ systems. These have
an abrupt onset typically. They are related to IgE
antibodies.
You can identify these by doing a skin
test or a blood test looking for IgE. The
manifestations are not always severe. There is an
impression that all anaphylaxis is
life-threatening. Some episodes are relatively
mild, but others progress rapidly to
life-threatening or fatal reactions.
We think that there are at least 150
deaths in
the United States each year due to fatal
33
food-induced anaphylaxis. That number is probably
a substantial underestimation, but we would be very
comfortable saying that it is well identified of
100 to 150 deaths per year.
There are different types of reactions:
some are single phase and some have two phases,
where a patient may look better and then two or
three or four hours later have an even more severe
reaction than they had initially, some of those
lead to the worst outcomes.
(Slide.)
DR. WOOD: This is a patient with one of
the more chronic forms of food allergies, the
patient with severe itching due to his eczema. In
Eczema, a food allergy is often underappreciated
because there is not an obvious cause and effect.
This is one where it is more of a
low-grade, chronic reaction. Hence, this is much
harder for a patient or a family member to identify
that, yes, he ate this food and he is more itchy
now, rather it is really more of a low-grade
reaction
where you don't see these direct
34
relationships between ingestion of the food and the
outcome being their eczema or atopic dermatitis.
It is also a condition where food allergy
is underappreciated by physicians and where
patients may be treated with a variety of different
creams and lotions and only later on find out that
it was really a food allergy that was driving the
eczema.
Overall, 40 to 50 percent of patients with
severe atopic dermatitis and 20 or 25 percent with
less severe cases have an underlying food allergy.
The same list of foods: egg allergy being
most common, followed by milk, peanuts, soy, wheat,
and fish. These six foods account for the vast
majority of food sensitivities seen in atopic
dermatitis.
From our standpoint, it makes it
relatively easy to screen patients and find which
of them are allergic by testing for a relatively
short list of foods.
(Slide.)
DR. WOOD: Now, the last category
that I
35
want to mention is something that we will lump
together as gastrointestinal food hypersensitivity.
There are a variety of conditions that fall under
this umbrella.
There are some that are in the immediate
hypersensitivity category. This would be part,
say, of an anaphylactic reaction where someone ate
food, broke out in hives, had vomiting, diarrhea,
abdominal pain, or other gastrointestinal symptoms.
There is another condition called "oral
allergy syndrome" where patients have reactions
that are confined to their mouth or throat or lips,
particularly related to fresh fruits and
vegetables.
There is another group of conditions that
are lumped under a category of eosinophilic
disorders of the GI tract. There is a specific
condition, eosinophilic esophagitis, where only the
esophagus is involved. As most people in the
audience know, the eosinophil is a type of white
blood cell that is most affiliated with allergic
reactions.
36
If you take someone who is having a bad
hay fever day outside today and look at their nasal
secretions, their nasal secretions will be loaded
with eosinophils. If you take someone that is
having difficult asthma, their bronchial mucosa
will be loaded with eosinophils.
By the same token, if you have allergic
eosinophilic esophagitis, the lining of your
esophagus is loaded with eosinophils. It may be
isolated to the stomach, it may be more diffuse
where we would call it "allergic eosinophilic
gastroenteritis." This is somebody who may have
disease anywhere in their GI tract, and oftentimes
very diffusely.
There are some other conditions,
enterocolitis syndrome and dietary protein
proctitis, that are much more common in very young
babies.
The importance of presenting these
different syndromes here is that some of these
syndromes are IgE mediated and some of them are not
IgE
mediated, some of them are very acute and some
37
of them are very chronic.
It turns out that those syndromes that are
more chronic and low-grade that don't present with
any acute symptoms, don't present with any clear
cause and effect of eating the food and having
increased gastrointestinal symptoms are going to
be, potentially, the most difficult for this
Committee to grasp. That is because these patients
are often reacting to remarkably small exposures.
I will come back at the end to sort of
give a couple of examples of the dilemma that kind
of patient is going to present to us as we really
try to figure out what is safe and what is not
safe.
It also turns out in the same vein that
the non-IgE conditions in general are probably
going to be most difficult to deal with, both
because they often don't have the acute IgE-type
symptoms, and because they are predominantly
mediated by a different part of your immune system
that can recognize even smaller degrees of these
food
proteins that identifying thresholds are going
38
to be much more difficult.
(Slide.)
DR. WOOD: Now, when we are trying to
approach a patient with a food allergy, one of the
real difficulties is making an accurate diagnosis.
The diagnosis, as in most everything we do, begins
with a history, talking about the foods they
suspect are causing problems, whether we think the
symptoms are consistent with food allergy, whether
this is something that may not be food allergy at
all, or whether it may be a food intolerance rather
than an allergy. We are going to be interested in
the timing of the symptoms and the reproducibility
of reactions.
It turns out that when you do a very
careful history, most of the time it is wrong. It
will be correct in the acute reactions, where you
have a patient who comes in and says, "I fed him
scrambled eggs for the first time last week, and he
had hives all over."
"She took her first bite of peanut butter,
and
developed hives within 2 minutes."
39
It is very likely that the history will be
born out when you do further testing. However,
when you look at the bulk of patients with food
allergies, many of them will have these more
chronic conditions like eczema or the
gastrointestinal disorders. When you are looking
at those patients, you will only verify the history
when you do further testing about a third of the
time.
(Slide.)
DR. WOOD: The next set of tests we do
after taking a history would typically either be
skin testing or serologic testing. A RAST test,
"radioallergosorbent test," is the most common
serologic test that is used.
These tests have some value and they also
have some problems. The problems they have is that
there is a relatively high rate of false-positive
tests. They do not have a terribly good positive
predictive accuracy.
They are generally accurate when they are
negative. Although, they will
only be active when
40
they are negative when you are convinced this
patient has an IgE-mediated condition, because both
of these tests rely on the presence of IgE
antibodies to identify the specific food allergy.
An example would be if a patient develops
hives or anaphylaxis, which typically are
IgE-mediated, and they suspect that it is a certain
food. If you get a positive test back, it is very
likely that they have that allergy. If you get a
negative test back, then you need to keep looking.
It was not likely that food that caused that
reaction.
However, if you have a patient with
something like the allergic eosinophilic
gastroenteritis where there may not always be IgE
antibodies, you cannot stop with a negative test
and say, "We've proven you don't have food
allergy." That is something that happens all the
time, but it is often going to lead to a
misdiagnosis and mismanagement of that patient.
The bottom line is that we need to
carefully
interpret our tests in the context of the
41
overall clinical picture, and that we need to rely
on oral challenge tests as the more accurate tests,
so that we will say that they are not completely
definitive. They are more definitive but not
completely definitive.
Again, they are going to be less
definitive in the patients that have more delayed
type reactions or more chronic conditions where
they won't react in that four-hour observation
period of your food challenge.
(Slide.)
DR. WOOD: You are going to hear more
about food challenges this afternoon, but I will
just mention a couple of issues here in terms of
the way that they can be done. They can be broken
down as open challenges where both the patient and
the person administering the challenge knows what
is being given.
A single-blind challenge is where the
patient is blinded but the person administering the
challenge knows the food that is being
administered, whereas a double-blind,
42
placebo-controlled challenge is regarded as the
most accurate test because it eliminates the bias
that may occur on the part of both the patient, who
may be feeling a great deal of anxiety about this
food challenge, or on the part of the observer, who
may have their own biases about this patient's
allergy and might overinterpret or underinterpret
symptoms.
We would say that these are going to be
the most accurate tests for the diagnosis of food
allergy. We would use them, if the history and lab
results don't provide a clear diagnosis. That is
often the case, again, when we have both a history
that may not be accurate and laboratory tests that
may not be completely accurate.
Then, we also do them very commonly to
determine when an allergy has been outgrown. This
would be a patient who has been known to be
allergic to a food, and we would be monitoring them
with some regularity in determining at some point
that it is worth trying to retry that food.
We would typically do it in a controlled
43
setting, just because even in some patients you
don't expect to react at all there may be
significant reaction. Consequently, we have to do
these with considerable caution.
(Slide.)
DR. WOOD: I think I pretty much mentioned
this.
(Slide.)
DR. WOOD: Now, they asked me to mention,
briefly, a study that we published last year
looking at the risk of oral food challenges. What
we have presented in this paper were results on
almost 600 challenges, 253 of which were failed
challenges. The patients reacted in the challenge,
so that is where we can look at the risk. The
other 57 percent, the patients had no symptoms, so
it was a risk-free challenge once they might have
gotten over the anxiety of being there.
We collected a lot of information on
demographics, other atopic disease, symptoms during
challenges, treatment needed, doses at which
reactions
occurred. Even though there is a lot
44
said about safety of food challenges, there has
been very little published before this paper on
what really occurs.
Now, I'm going to say this again a couple
of times looking at the data, but I will say it up
front here, that these results are not
representative of the general population of food
allergy.
These patients that are being challenged
in this either had an unclear diagnosis, so it
wasn't a dramatic kind of situation, or they were
thought to have potentially outgrown their allergy
and were being challenged to potentially prove that
their allergy was gone.
We are really looking at very low-risk
population, and it is not representative of the
whole population of food allergy patients that are
out there. Again, I will say this a couple more
times looking at the specific data.
(Slide.)
DR. WOOD: Now, whenever we are doing this
sort of
analysis, we try to break things into
45
categories. One of the tough categories to decide
is how do you rate reactions. You will see in the
literature some different definitions that have
been used.
We chose to create our own for a series of
studies that we were doing, and talked about mild
reactions that were skin and/or oral symptoms only.
Oral symptoms is just at itching or they will often
have an obvious hive-like reaction in their mouth
or pharynx when they are having one of these
localized reactions.
A "moderate reaction" was described as
upper respiratory and or GI symptoms only or any
three systems. When we are talking about systems,
we broke that into: skin, GI, upper respiratory,
lower respiratory and cardiovascular.
Then, severe reactions were those that
were that were potentially life threatening, where
they have lower respiratory and/or cardiovascular
symptoms or any four systems were involved.
(Slide.)
DR. WOOD: When we broke things
down into
46
these different systems which were involved in
which challenges, you will see here that when we
look at this column on the right here, which is the
total in this paper we reported on milk, egg,
peanut, soy and wheat.
The greatest number of failed challenges
was to milk, 90; 56 to egg; 71 to peanut; 21 to
soy; 15 to wheat; for a total of 253. You will see
that skin manifestations were most common, 78
percent.
This is actually similar to what we have
seen and what is in the literature in terms of
reactions that happen out in the real world.
Eighty percent of food reactions, 80 percent of
anaphylactic reactions involve the skin, but about
20 percent do not.
Oral symptoms occurred in about a quarter,
upper respiratory in a quarter, lower respiratory
in about a third, GI in 43 percent. We,
thankfully, had no cardiovascular reactions in this
population.
Now, why would that be the case?
It would
47
be for two reasons. The biggest reason is that
cardiovascular reactions are not that common in
children.
The cardiovascular system of a child is
really sturdy enough to put up with the insult of
an allergic reaction without necessarily becoming
involved. Cardiovascular reactions are much more
common in adults, and this population was entirely
childhood.
The other reason that we might have seen
the absence of cardiovascular reactions would be
that we were dealing with a relatively low-risk
population.
When we break it down into those three
severity classifications -- mild, moderate and
severe -- you will see that the numbers are
relatively similar for each food. When we look at
the total category, they broke pretty close to a
third in mild, a third in moderate, and a third in
severe.
When you look across the specific foods,
the most
important point that came out of this is
48
that you can't say that one type of food allergy in
this kind of setting is more dangerous than
another.
It turned out that the greatest number of
severe reactions occurred with egg challenges.
This was important information we thought to get
out to get out to people doing challenges.
A lot of allergists will say, "I'm going
refer you, Dr. Wood, all of my peanut challenges.
I'm not touching a peanut challenge because they
are really dangerous. However, I will do egg and
milk challenges out in my office any time."
The message there is that really all of
these foods have a potential to have severe
reactions and need to be done in a setting where
you are really equipped to deal with that potential
for a severe reaction.
(Slide.)
DR. WOOD: When we looked at the RAST test
score or the median IgE level for these different
challenge results, we found that there was really
no strong
association between their IgE level and
49
the reaction severity.
Now, this is an example of where this
population is not a good one to look at for this
data. The reason is that we were essentially only
challenging people that had relatively or very low
levels.
We were not challenging people with very
high levels where they were extremely likely to
fail the challenge. There is no reason in most
instances to prove that they are allergic. When
you know with, say, 99 percent certainty that they
are allergic, we would not put that patient through
a challenge.
Consequently, if you went out in the real
world where the RAST test levels range anywhere
from zero to 100, you would typically see
escalating reaction severity with levels that are
higher. We have that data for peanut allergy where
the group of patients that had levels at 100 did
have more severe reactions when they had accidental
exposures.
(Slide.)
50
DR. WOOD: Then, I think the last thing to
present from this study is whether reaction
severity was correlated or related to the percent
of food ingested in these challenges. It turns
out, if anything, it is inversely correlated. The
more severe reactions, and none of these were
statistically significantly, but if you look at the
general trends, you will see here that the more
severe reactions occurred with milk and eggs.
As you can see, the severe reaction for
milk is 15 percent and 30 percent for eggs. When
you look at the total group here, 50 percent, 45
percent and 30 percent.
(Slide.)
DR. WOOD: What is the reason this
happens? Does this make any sense at all? Do you
have your more severe reactions with smaller
exposures? The reason we think it happens is
because it is just identifying the more reactive
patients.
It is picking out those that even though
our test
scores said that they are not so allergic
51
that they should do this, it is picking out those
that react more abruptly and have more severe
symptoms early in the challenge just because they
were higher risk patients.
Now, we have come up in our studies about
some decision making about when we would do food
challenges. This is purely for clinical purposes.
These are for those reasons of when we are trying
to decide if they are truly allergic or when we
think that the food allergy might have been
outgrown.
What we would say is that we would do food
challenges based on their history of reactions. If
they have reacted recently, we wouldn't feel the
need to do a food challenge.
We would base it on their laboratory
testing, the skin testing and the RAST testing.
Then he would base it on the importance of the food
to the diet. There are some foods that are
obviously much more important to the diet.
A family may never care whether that child
ever eats a
pea again the rest of their life. They
52
may elect to never have a pea challenge done, but
they may be jumping to do a milk or what challenge
at the first opportunity, because milk or wheat
back in the diet would make such a dramatic
difference in their day-to-day life.
Then, we have come up with some
recommendations based on RAST testing of when we
would recommend doing challenges. These cutoffs
for milk, egg and peanut are all where we found a
greater than 50 percent chance of passing the
challenge, if you have levels below that range.
For other foods, it has been harder to determine
cutoffs, and we would challenge at higher levels
for things like wheat and soy.
(Slide.)
DR. WOOD: Just to go through an algorithm
of how we approach diagnosis, then, because it does
impact on the discussions that are going to happen
here, we would first take our history.
Based on the history, we would make some
distinction whether we think this is consistent
with an IgE
type reaction or whether we think that
53
it is consistent with a non-IgE type reaction.
If it is IgE-mediated in all likelihood,
then a skin test or a RAST test will help identify
whether that food that was suspected to cause a
reaction probably did or probably didn't.
If the test is negative, because the
negative predictive accuracy is so high, we would
feel that you could stop worrying about that food
at that time. If the skin test is positive,
because there are false-positive tests that occur,
we need to do something more.
We might do a trial on an elimination
diet; we might do a food challenge in one order or
the other; and based on all of that information, we
would arrive on the specific elimination diet
recommended for that patient.
If it falls into a non-IgE category, the
situation is much more difficult because we can't
rely on a simple screening test to weed out those
patients.
They are going to need some combination of
challenges
-- endoscopy, if it is a
54
gastrointestinal symptom; elimination diets,
rechallenges, maybe a reendoscopy -- so there is a
much more difficult plan on this side of the screen
to sort out those patients.
(Slide.)
DR. WOOD: Now, I'm going to finish here
with a couple of conclusions and present a couple
of dilemmas. The conclusions are that food allergy
is very common. This is a remarkably worthwhile
initiative that is going on here, and that right
now avoidance is the only treatment plan.
We really hope in the next 5 or 10 years
that there are going to be other treatments for
food allergy. It may be enough so that even if
they don't cure the disease, that they will elevate
the threshold to a point that we don't even need to
have these meetings, that small exposures won't
even be relevant. We are not even close to their
yet, so avoidance is the only option.
Strict avoidance is essential to prevent
reactions obviously, but we also think that in many
patients it
also helps to promote the outgrowing
55
process.
Here is where we may have very different
thresholds. We may have a threshold that this
child, say, with milk allergy -- they know for a
fact that they can eat this bread that has whey as
the tenth ingredient and never have a symptom.
They are perfectly fine with it.
What we have found that getting that bread
on a regular basis may keep their immune system
more revved up to maintain the allergy so this
thing that is way below their threshold for
reacting acutely may still drive the immune system
to maintain the allergy and prevent them from
outgrowing the allergy.
The next conclusion is that food
challenges are a useful means to diagnose food
allergy and a useful means to determine threshold
doses. There are going to be some limitations of
challenges, and one of them is that as opposed to
the study that I presented that Dr. Perry did with
me, you have to include in a threshold type study
the most
allergic patients.
56
Doing the kind of patients that we are
studying on the lower end of the spectrum has
nothing to do with thresholds. It is irrelevant
data. You can't go to my study and say, "This
looks like a threshold because we are not including
in those kinds of studies those highly allergic
patients."
The greater dilemma, and this one is
solvable, there are plenty of real allergic
patients out there. They won't necessarily want to
undergo these studies, because it is not a pleasant
thing to have allergic reactions, but that part is
potentially solvable.
The more difficult thing is a
determination of the threshold doses that I
mentioned for the chronic allergic conditions,
especially those that are not IgE mediated probably
isn't possible.
To give a couple of examples, if we take,
say, milk allergy, the most common food allergy of
all, and we are talking about an infant who is on a
formula,
there are a bunch of different options we
57
could have. Some of them can have soy, but some of
them are also allergic to soy.
Some would go on to a formula like
Alimentum or Nutramigen, which is a formula where
the milk protein has hydrolyzed to a small enough
fragment that in 98 or 99 percent of kids with milk
allergy. It completely solves the problem. They
don't react at all to that level or that type of
protein that remains in that formula.
That other 2 percent, though, may react
severely to that. They are typically the patients
with the gastrointestinal disease. They are
typically very sick; they are typically not
growing; they are typically malnourished.
They are a group of patients who aren't at
risk for the acute dangerous reactions, but they
may be at very high risk for chronic disease from
their food allergy.
Those patients will typically respond
dramatically to a formula that is based in a single
amino acids as a protein source, and that is a
formula
like Neocate and Elecare.
58
Now, when you take that population, and
this is what I deal with every day, there is going
to be a group of them -- and that is probably even
less than 1 or 2 percent, it is probably only 1 out
of 500 -- who still react to the Neocate. They can
react severely to it.
We know that because of their
gastrointestinal biopsies, their biopsies that are
taken from their esophagus or stomach or intestinal
tract still show evidence of severe allergy.
What we think those patients are reacting
to would be either the absolutely trivial amounts
of, say, soy protein that is in the soy lecithin,
that is the eighteenth ingredient in Neocate, or
the trivial, trivial amounts of protein that may be
left in the safflower oil that is used as a fat
component of Neocate.
When we switched those patients off of
Neocate we can prove, and we have 15 patients now
who we have proven, that taking them off Neocate
resolved their food allergy. In this supposedly
non-allergenic formula, they were still reacting.
59
Now, whether the direction this Committee
needs to focus on is this very unusual patient or
not is sort of a separate debate all together, but
it is safe to say that there are going to be
patients out there who break all rules. No matter
what rules are established, there will be patients
who completely break them and make all of our lives
difficult from that standpoint.
I would be delighted to take any questions
from the Committee or otherwise. Thank you for
your attention.
CHAIRMAN DURST: Thank you, Dr. Wood.
Are there questions for discussion?
Suzanne.
QUESTION-AND-ANSWER SESSION
DR. TEUBER: This is Suzanne Teuber. I
had a question about your patients with the Neocate
sensitivity in terms of what the company reported
for the soy lecithin, did they have any values that
you could report back as to a chronic ingestion
threshold?
DR. WOOD: No. I mean, most of these kids
60
it is most likely the soy lecithin. SHS doesn't
have that data on the protein content of their soy
lecithin. They say it is zero. These kids when
they were switched to Neocate One Plus, which has
no soy lecithin, their disease went away. We have
to assume that there was enough there to drive that
process.
CHAIRMAN DURST: Yes.
MS. HALLORAN: Jean Halloran. Could you
say something about the process about growing
allergies? How does that work? What actually
happens?
DR. WOOD: Well, that is a very good
question. There are a number of things that we
don't understand too well. However, what we think
is that in the majority of patients we think that
outgrowing is most related to the immune system
gradually forgetting about that concern that it
earlier had.
That is where we think that strict
avoidance is likely to promote the outgrowing
process,
and with a prolonged period of strict
61
avoidance for many of these foods, the immune
system has a memory that isn't long enough to
maintain the allergy and that it will gradually
wane and then full tolerance will be accomplished.
There are probably lots of other mechanisms going
on immunologically that are not well understood.
The other question with this that we have
no great explanations for, lots of theories but no
great explanations, is why you can take a food
allergy like milk, which in early infancy can be
every bit as severe as a peanut allergy, and have
most kids outgrow that allergy, while very few kids
outgrow the peanut allergies. There is something
very different about the immunologic memory of one
food allergen versus another.
CHAIRMAN DURST: Yes.
DR. KELLY: Ciaran Kelly. I wanted to
come back to the issue of challenging individuals
with severe allergies as a method for determining a
threshold. I would like to hear your comments as
regards the feasibility and safety and whether that
would be
ethical to perform? I guess my concern
is
62
that once the threshold is crossed, whatever that
threshold might be, isn't there a potential for
severe allergic reaction?
DR. KELLY: Yes. Absolutely. There have
been threshold studies done for the biggie, peanut,
with very allergic people so it is doable. Now,
what we can say about this is that these studies
won't be done in children. It is not going to
happen.
That automatically limits your population
of people, because when you go out and try to find
your group of milk-allergic adults to do these
studies on, you are limited.
Now, they do tend to be more severe
reactors. From that standpoint, you have some
patients out there, but there is no IRB that is
going to let us do this in children. There has to
be demonstrated benefit to do a study with risk.
The safety element is one that we are
comfortable with, recognizing that you need to have
emergency management available to you because there
will be
people that have bad reactions.
63
The safety that is built into that is
starting with exquisitely small doses and working
up very gradually and aborting the challenge
whenever you see your first symptom.
That may lead you to end some challenges
prematurely. You may end up with a false
threshold, but you are obligated to stop when you
have objective signs that patient is reacting.
The ethics beyond that to me is that if it
is an adult patient who is willing to consent to
that process, I have no problem with the ethics of
doing it and have no fear that I will ever lose a
patient to a food challenge.
CHAIRMAN DURST: Yes.
DR. BRITTAIN: This is Erica Brittain.
Since you can't study children in that way, do you
know how this threshold might be different in
children, if you've got the threshold for adults?
CHAIRMAN DURST: No, we don't know that.
That data is, to my knowledge, not available in a
large enough sample to have any validity
whatsoever. It is a superb
question. The argument
64
is going to be and will always be these children
are much more reactive than the adults for most of
these foods.
For peanut allergy it is going to be the
simplest, because allergy tends to persist. We
think that people usually hit their peak level of
severity as an adolescent or young adult, so that
would be fairly easy to solve.
However, when you look at the others like
milk and egg and soy and wheat, you are by and
large going to have the highest level of reactivity
in your first couple of years of life.
When we think about those allergies, we
usually think of growing into the allergy for one
or two or three years where they are becoming more
and more allergic, and then they are becoming less
and less allergic over the next one or two or three
or four or five years as they outgrow the allergy.
It is a moving target at all points, but the most
severe reactivity is likely to be early on.
CHAIRMAN DURST: Dr. Wood, I have a
question --
this is Dick Durst -- just points of
65
clarification. On your slides where you indicated
"wheat," now this is the IgE-mediated type allergy
as opposed to our discussion tomorrow on celiac
disease?
DR. WOOD: Yes, these results are entirely
IgE.
CHAIRMAN DURST: Okay. Do other grains
cause the IgE type reaction as the wheat?
DR. WOOD: Yes, our study there, about 600
challenges, came out of about 3,000 food challenges
that we have done. There were five most common
foods that I had enough data to make some
conclusions that we were comfortable with. All of
the grains cause allergic reactions.
It turns out that wheat and rye are very
cross reactive from an IgE-mediated allergy
standpoint, and that most patients allergic to
wheat are also allergic to rye; it turns out that
about half are allergic to barley; and 10 to 20
percent are allergic to oat. Beyond those grains,
all of the other grains and grain substitutes are
clearly
capable of causing allergy in select
66
patients.
CHAIRMAN DURST: Thank you. One other
question as far as clarification at least for my
mind. One of your slides with the food challenge
decision making had the units in caps "KU/L." I
don't know if you defined that? I was curious.
DR. WOOD: Yes. It stands for "kilo unit"
of IgE in a specific assay that Pharmacia has
developed called an immunoCAP RAST. It all goes
back to this one technology that is thought to be
the most accurate quantitative measure of specific
IgE, and the results are represented in that kilo
unit of IgE, the specific IgE antibody per liter of
serum.
CHAIRMAN DURST: Thank you.
There is another question?
DR. KELLY: I have one other question.
Dr. Wood, you made a very important comment about
the potential for continued subclinical exposure to
allergens perpetuating an allergic response. How
well accepted and how well documented is that, or
is that
largely a clinical impression?
67
DR. WOOD: Very well accepted, very poorly
documented. It is widely accepted. There is very
poor information to support it. There are only a
couple of studies. The problem we have is we tried
to do the study, and we were turned down because it
is so widely accepted that to go to the IRB and
propose to them that we are going to take this
group of kids with milk allergy and keep them on
low-dose milk and take this group and have them
strictly avoid it was turned down.
Now, there is some work being done that
has identified instead of looking at the IgE
against milk globally, it has turned out that if
you have IgE against certain portions of the milk
molecule it may be more predictive of a longer-term
allergy, and if you have it toward others, other
epitopes, it may be more predictive of an allergy
that is easier to lose.
We think that it may be feasible to focus
on that population that has a very good chance of
losing their allergy, even if we make a mistake, to
be able to
do this study. It is doable, but the
68
outcome is about 10 years down.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: I have had some
experience --
CHAIRMAN DURST: Identify yourself.
DR. SILVERSTEIN: Marc Silverstein, Baylor
Health Care System in Dallas. I have had some
experience in studying the epidemiology of asthma
and anaphylaxis. In both of those conditions, your
findings are very much dependent upon your
diagnostic criteria.
In clinical medicine, we have diagnostic
criteria. You have described the criteria for food
allergy, which would involve components of:
history, physical exam, laboratory tests, food
challenge, and response to clinical management with
elimination diets.
Are there standardized criteria that you
would see moving the diagnostic criteria that you
would use from clinical practice to investigation
and publication in peer review literature and/or
perhaps the
policy in making regulatory decisions?
69
I am interested in, Is there a set of
standardized criteria that professional
organizations or clinicians would use for
investigation or for recommending policy? I
understand there is some recent work on definitions
and standards for anaphylaxis?
DR. WOOD: The definitions for
IgE-mediated food allergy are pretty clear and it
is pretty well accepted that it is if you have a
history that is consistent, you have a positive
allergy test, and you either fail a challenge test
or pass a challenge with a dose that is generally
accepted to indicate full tolerance. It is fairly
straightforward and well accepted in the peer
review literature.
It is much more difficult on the group of
patients with, say, eosinophilic gastroenteritis
where they don't necessarily have IgE. You require
a histologic diagnosis to identify the condition,
and then figuring out whether they have food
allergy driving the process exclusively, partially
or not at
all is a much more difficult process.
70
It is doable, but you have to eliminate
foods, rebiopsy, reintroduce foods, and rebiopsy.
There are studies that have done that, but it is so
much more difficult to do that there is much less
of an acceptance of an absolute diagnostic
criteria, much, much less.
It is being looked at. This is a form of
allergy that is clearly either happening much more
often or being identified much more often or both,
so that the potential is there, but it is much
further away from a definition that is well agreed
upon.
CHAIRMAN DURST: Yes.
DR. BRITTAIN: This is Erica Brittain. I
have a clarification question on the food
challenge. How is the placebo control implemented?
DR. WOOD: I think you are going to hear a
lot more about food challenges this afternoon, but
the idea, and it is going to vary depending on the
age of the patient and what they can do, but the
idea that it needs to be well disguised and
obviously
safe from the perspective of that
71
patient's allergen --
(Simultaneous discussion.)
DR. BRITTAIN: But --
DR. WOOD: Go ahead.
DR. BRITTAIN: I'm sorry. Is it by a
dose? Is a particular dose placebo, or does a
patient get all placebo?
DR. WOOD: Yes. I'm sorry I
misunderstood. The normal way the challenge is
done is to have a separate challenge for the
placebo and for the actual food being studied. The
usual way it is done is that the patient would come
in and have a day doing a placebo challenge and
come in and have a day doing the food challenge.
Challenges can be done in a matter of a
couple of hours in some situations, but to do
highly allergic people in a placebo-controlled
manner would usually take 8 or 10 hours for each
day.
CHAIRMAN DURST: All right. Seeing no
further hands in the air, I think we will thank
Dr.
Wood. We are right on schedule. Thanks again.
72
Our next speaker will be
Anne Munoz-Furlong, who is director of the
Food Allergy and Anaphylaxis Network, who will
discuss patient perspectives on food allergies.
PATIENT PERSPECTIVES ON FOOD ALLERGIES
MS. MUNOZ-FURLONG: Thank you. I would
like to thank the organizers of the meeting for the
opportunity to be here.
(Slide.)
MS. MUNOZ-FURLONG: What I would like to
do is in that time that I have been allotted is
give you a sense of who this food allergic consumer
is; the food allergen labeling from their
perspective; and then, most importantly, their way
of looking at threshold levels for food allergens.
(Slide.)
MS. MUNOZ-FURLONG: By way of background,
the Food Allergy & Anaphylaxis Network or "FAAN" is
a non-profit organization. We were established in
1991 and have 27,000 members, almost 28,000
members. Eighty percent of these people come to us
from
physician referrals, so we know we are talking
73
about IgE-mediated responses when we are looking at
our membership.
Our mission has four points: to increase
public awareness, provide advocacy and education,
and advance research on behalf of those with food
allergy.
(Slide.)
MS. MUNOZ-FURLONG: Now, as Dr. Wood said,
food allergy is believed to affect about 11 million
Americans or 4 percent of the population; fish and
shellfish allergy, 2.3 percent or 6.5 million;
individuals in peanut and tree nut, 3 million.
Consequently, between these four foods we
are talking about almost 10 million Americans.
These are the four foods, as was presented earlier,
that are lifetime allergies and also are believed
to cause the majority of the severe or fatal
reactions in this country.
The other point I want to make here is
that although we are talking about 11 million
patients, our data shows us over and over again
that most
of these patients have families who
74
follow their restricted diet. The impact is
actually many times greater than the number of
patients.
(Slide.)
MS. MUNOZ-FURLONG: When we look at
shellfish allergy, this is looking at data that we
published about a year ago now. Te prevalence of
shellfish, we found about 2 percent of the
population or 6 million Americans.
The key foods responsible for the majority
of these reactions in rank order are: shrimp, crab,
lobster, and clam. For fish allergy, .4 percent of
the population: salmon, tuna, catfish, and cod
being the primary fish that cause reactions.
However, if you look at these a different
way, these foods, especially shrimp or salmon, are
available on almost every menu that you are going
to look at in a restaurant or food service
establishment. Therefore, the risk for these
individuals is constant.
(Slide.)
MS. MUNOZ-FURLONG: Talking about
tree
75
nuts, and these most of you already know, are not
peanuts; they are different. Most people with a
peanut allergy avoid tree nuts as a precaution but
not because they are allergic to them. About
20 percent of the 20 peanut allergic population is
allergic to tree nuts as well.
When we are talking about tree nuts, it
affects about 1.5 million Americans. Again,
looking at data from our patient registry of 5,000
patients, we find that walnut, cashew, almond and
pecan are the leading cause of tree-nut-allergic
reactions in this country.
(Slide.)
MS. MUNOZ-FURLONG: What does it mean to
have food allergies? It is vigilant label reading.
You have got to read labels not just for food
ingredients but anything coming into the home.
Bath products can have tree nuts, milk or eggs in
them, for example.
Pet food, if you have ever looked at the
ingredient statement on a pet food, it can have
almost
every single one of the major eight
76
allergens.
That is something you have to worry about,
especially if you have a toddler who will pick up
food from the floor or anyplace else they can get
it. Also, medications have been known to have
allergens in them, particularly milk.
It is not just a question of label reading
for food; it is for anything. Trace amounts can
cause an allergic reaction, and that has been
proven over and over again.
Just one bite can cause a reaction.
Therefore, we can't tell by looking at someone how
allergic they are going to be or what their
tolerance will be to that food.
Currently, as Dr. Woods said, the only
cure now is a dose of epinephrine, if the patient
has a history of severe reaction. The onus is on
the patient or the family to read the label and
avoid the allergen and then be quickly prepared to
handle an allergic reaction, if they have made a
mistake or accidentally ingested the food to which
they are
allergic.
77
(Slide.)
MS. MUNOZ-FURLONG: Because there is no
cure, decisions about any part of the person's life
are centered around food allergy. This is what
makes food allergy so stressful on the family and
on the patients.
Whereas with other allergies you have
seasonal components and you might have an easy
spring but fall is the bad season or if you are
allergic to cats or dogs you can avoid those, with
a food allergy every decision every single day is
affected by your food allergy.
Food shopping can take two to three to
hours just from reading labels. Cooking, if the
family is bringing the allergen into the home, they
then have to prepare two meals, the
non-allergen-containing meal and then the
allergen-containing meal, and take precautions to
avoid cross-contact.
Decisions about dining out and socializing
are made based on not a food preference, but is the
food safe.
78
"Can the manager be trusted to give us
accurate information?"
"Can the person we are visiting be trusted
not to slip some of the allergen into the food?"
Then, the decision is made to move forward
based on the answers to those questions.
Even what school or childcare the
individual will be sending their food allergic
child to are going to first be centered on food
safety from a food allergy perspective.
Vacation and travel where you and I might
decide whether we want to go someplace warm or go
skiing in the winter, these families have to think
first about food.
"Can we ship food there?"
"Is there a safe place?"
"Can we rent a room with a kitchenette and
make some of the meals so that we can maintain some
level of safety?"
Even family relationships, there is always
somebody in the family that does not believe the
food
allergy is real, and so decisions are made
79
about whether they can visit that individual or
not.
(Slide.)
MS. MUNOZ-FURLONG: As a result of all of
this, it has a tremendous impact on quality of
life. We published a study several years ago
looking at the impact of food allergy on quality of
life.
What we found is that families who have a
food-allergic child score lower on their perception
of whether their child has good health or not, the
emotional health and family activities than the
general population.
Certainly, they scored lower or worse than
families who are looking at or dealing with other
chronic diseases such as diabetes, juvenile,
rheumatoid arthritis and attention deficit
disorder, for example.
We also looked at some of the other
influences. If the individual has a food allergy
and asthma or atopic dermatitis, that further
lowers
their score for the quality of life.
80
If a family has a child with two or more
food allergies, that group scored much lower in 9
out of 12 scales compared to those who only have
one or two food allergies that they are dealing
with.
When we look at our patient population at
FAAN, we see that it is not uncommon for our
members to report a child with a milk, egg and
peanut allergy simultaneously. You can imagine
eliminating those three foods and how it compares
to the impact on the quality of life for the entire
family.
(Slide.)
MS. MUNOZ-FURLONG: This is how, again
looking at the same data, you can see here in blue
is "General health" perception. Food allergy lower
than the normal for asthma, attention deficit
disorder and some of these other symptom scores.
Now, in talking about label reading, which
is really the cornerstone of managing a food
allergy. Here is what goes on.
(Slide.)
81
MS. MUNOZ-FURLONG: The person with a food
allergy is told by the physician, as you heard
earlier from Dr. Wood, "You have an allergy, avoid
the food." Zero tolerance. They must live in a
black-and-white world. If you are allergic, you
don't eat that product.
If the allergen is listed on the label or
the label says "Contains allergen," they are not
going to eat that product because they are trying
to avoid a reaction. As a result, they expect
ingredient labels to be consistent and, most of
all, reliable because this is what they are basing
the decision about food on. It will affect their
health and safety.
When they see the same product with
different ingredient statements, it makes them very
confused and frustrated and sometimes very nervous
because they, again, are looking for consistency in
labeling.
What we are already seeing with some of
the companies complying with FALCPA regulations is
that there
are products on the market that are
82
pre-FALCPA and FALCPA compliant with different
ingredient information regarding allergens.
Already we are getting calls from our members.
"Which one of these labels is correct?"
"What if I hadn't picked up that second
label? How would I have known?"
This is what we are heading into as we
start to change these labels.
(Slide.)
MS. MUNOZ-FURLONG: The challenge for
food-allergic individuals is that the patients are
told to strictly avoid the allergen, there is zero
tolerance or be prepared to handle an allergic
reaction. Once a reaction begins, we don't know
how severe that is going to be.
They are not aware that there are
scientific names to foods when they are newly
diagnosed. This is something FAAN spends a lot of
time doing. It will get better as FALCPA is
implemented because labels will have simple
ingredient terms on them.
We have to remember it is not just the
83
patient or the patient's family reading the label,
but it is the teacher, the scout leader, the
friends and family members. The impact for any
labeling decisions are going to be quite broad.
(Slide.)
MS. MUNOZ-FURLONG: Allergens can appear
in unexpected places. This is just one slide of a
number of examples that we have for "Common Foods
in Unexpected Places." Every one of these examples
have caused an allergic reaction to one of our
members, because they were not expecting to find
the allergen.
Just to give you an example, if you have a
milk allergy, you would not have expected that
barbecue-flavored potato crisps might have milk in
them, and you might not have read that label, or
that canned tuna might have soy in it. Therefore,
it is not as easy as avoid the food, you've got to
be looking for unexpected sources.
(Slide.)
MS. MUN[MLM2]OZ-FURLONG: We can see this
reflected
in a study that was published in 2002 by
84
Joshi, et al. They took some food-allergic
individuals, gave them products that were on the
market, and asked them to read the label for the
food they were trying to avoid.
You can see here that families avoiding
milk, only 7 percent were able to accurately
identify milk on the labels that were presented to
them; for soy, they did a little better at 22
percent; but peanut, only 54 percent got the label
reading correct, and most of this was because of
confusion about allergen labeling information.
(Slide.)
MS. MUNOZ-FURLONG: The problem with
allergen labeling information, there are no
guidelines or standards for use. This is
completely voluntary. As a result, every company
has their own decision tree and algorithm and
wording for what terms they will use and under what
conditions.
This makes it very difficult for us to
educate consumers and the others who are reading
labels on
their behalf and telling them what to do
85
and what these mean.
The proliferation of "may contain"
labeling has really caused us some problems. Just
to give you a sense of what is going on, we had one
volunteer go out in the Northern Virginia area to
one grocery store and look at products from
cookies, crackers, candy and bakery. We were
trying to follow the model of a previous FDA study.
She came back with 28 different versions
of "may contain" statements. From the consumer's
perspective, what does that mean? Can they be
trusted, or should we ignore them?
(Slide.)
MS. MUNOZ-FURLONG: The current
environment because of this, there are some
physicians that advise their patients to ignore
precautionary labeling, because it is everywhere
and there wouldn't be any food for them to eat.
There are others who tell them, "Heed the
warning and avoid those foods."
Then, there are some companies who tell
the
consumers, "It is on the package only because
86
our legal counsel has advised us to put this on
there."
Then, there are others that say, "You have
to trust that wording and not go near the product."
How does a consumer determine which is
which?
We are also seeing advisory statements for
peanut allergy only. The way the consumer
interprets these statements is that they are
shortcuts to label reading.
If they see "contains peanuts" or "may
contain peanut," they may not read the rest of the
ingredient declaration if they are looking for milk
or soy, because they think that the company
understands food allergy and would have listed all
of the allergens on there.
As a result of all of this, consumers are
confused and frustrated. Particularly what is
going on as their food choices are further
minimized is that there is risk taking behavior by
parents of kids with food allergies who decide,
seemingly
randomly to us, that some companies can
87
be trusted and others not, so they will ignore "may
contain" on the companies they trust.
Then, the teenagers, our highest-risk
population for a severe reaction, want to be like
everyone else are reporting that they are ignoring
"may contain" statements, because it is on so many
foods they have eaten the food and not had a
reaction, so they don't really believe that these
are true.
(Slide.)
MS. MUNOZ-FURLONG: This is one of the
labeling studies that we conducted with our FAAN
members during a spring meeting a year or two ago.
We asked a question. They were supposed to answer,
"I would never purchase a product that says it
contains" whatever the "allergen" is. You can see
that almost 100 percent of them would avoid a
contain statement.
However, as you go from very specific to
black-and-white to vague "packaged in a facility
that also produces," say, peanuts or nuts or
whatever
the allergen might be, only 74 percent
88
would avoid purchasing that product.
Consequently, 25 percent of the allergic
consumers are going to purchase products where they
don't really understand the precautionary labeling.
If the company is putting this on here because of
some risk, we've got a miscommunication or a
communication gap going on.
(Slide.)
MS. MUNOZ-FURLONG: Let's talk about
thresholds, then. Again, from the consumer's
perspective, their physicians advise, as you heard
from Dr. Wood, is strict avoidance or a reaction
may occur and you will not outgrow this allergen.
They are very motivated to try to strictly avoid
that food.
When we talk about thresholds to our
members, and these tend to be the most motivated
and well-educated of the food allergy population,
this is what we consistently get back. They
believe that threshold levels may put their
children at risk because their child is so
allergic.
89
They also wonder whether the threshold
levels, the whole discussion is based on the
industry or the government trying to figure out a
way not to have to clean or label for allergens.
Again, they are wary that this might be a loophole
that is trying to be directed at them.
(Slide.)
MS. MUNOZ-FURLONG: The catch 22 here,
from where we are at FAAN, is that we understand
that if we label for all allergens at all levels it
will further restrict diets. If we further
restrict the diet, we are going to increase
frustration which will yield risk taking.
It is going to undermine the integrity of
the ingredient label. As I showed already with
"may contain," we are already seeing that. They
believe "contains." However, if we put "contains"
on everything and they eat it and don't have a
reaction, we are going to diminish the validity of
that statement.
If we undermine the integrity of the
ingredient
label this will potentially lead to more
90
allergic reactions as they take more risk, which is
going to increase the number of doctor visits;
hospital visits; and, potentially, fatalities.
(Slide.)
MS. MUNOZ-FURLONG: Here is an example of
what can go on and what we see as what we may all
be facing. This is a report that came to us from
one of our members who had a soy-allergic child who
had safely eaten soy lecithin in the past. Most of
our members, although we tell them to read the
ingredient declaration on products every time they
purchase them, become brand dependent and stop
reading the ingredient label. That is exactly what
happened here.
This was a product that the child had
safely eaten in the past. The mother did not read
the label, gave it to the child, he started eating
it. She then started reading the label and saw
that it now says "contains soy." She got very
nervous and screamed that it contained soy and
asked the child to spit the food out.
Immediately, he started having itching,
91
leading to hives, and a feeling of impending doom.
The mother gave him medication and thought she was
having a full-blown reaction.
The question we have to ask ourselves, Was
this a reaction, or was it a panic attack? She
called the manufacturer and was told that the
"contains soy" is because it contains soy lecithin.
Therefore, the ingredients hadn't really changed
from the product that they had safely eaten before.
From our perspective, we do not want to
see consumers or their families subjected to this
kind of fear. Because what you don't realize is
that once this reaction is taken care of, it takes
a long time for the family to trust again. We do
have reports of children developing eating
disorders and just being very cautious about being
around other people once they have had a reaction.
(Slide.)
MS. MUNOZ-FURLONG: From the consumer's
perspective, if we are looking at developing a
threshold level, and as I said there are pros and
cons to
both sides of this issue, the key here is
92
we have got to do a good job of education. We have
got to educate physicians and registered dieticians
so that they can counsel patients accurately.
As you saw, we have done no training for
"may contain." We have got some doctors that say,
"Just ignore it." We can't afford to do that with
threshold levels.
We also have to educate patients and their
families and assure them that the food is still
safe and that they can trust the information on the
label. We also have to do outreach to the food
industry so that they can answer the queries from
food-allergic consumers in a way that will give
them confidence instead of make them nervous or
suspicious about whether they can trust the
information on the label.
(Slide.)
MS. MUNOZ-FURLONG: In summary,
food-allergic consumers want as many food choices
as safely possible. This is really why we are here
and why we are seeing some of this behavior with
advisory
statements.
93
They want to open the diet. The children
want to be like everyone else, and they want the
least amount of restrictions, but they need to be
safe.
The consumer needs to understand the
information on the ingredient statement. They need
most of all to trust that that information is
reliable and it is going to be consistent from one
product to the other. They also need a minimal
number of precautionary allergen statements and a
guideline so that they understand what these
statements mean and what they should do as a result
when they see these on products.
(Slide.)
MS. MUNOZ-FURLONG: In conclusion, the
current labeling and manufacturing practices
present enormous challenges to food-allergic
consumers. As Dr. Wood said, the number of these
patients is increasing.
To give you an example, we conducted a
prevalence study of peanut and tree nut allergy in
1997,
repeated that same study in 2002, and found
94
that in that five-year period the number of
children with peanut allergy had doubled. We don't
know how it is continuing to trend, but reports are
that it is still increasing.
(Slide.)
MS. MUNOZ-FURLONG: The bottom line is
above all we must protect the integrity of the
ingredient information. Because from the
food-allergic consumer's perspective, they depend
on this information to avoid an allergic reaction
and, most of all, to maintain their health and
safety. We already have data showing that food
allergy impacts the quality of life. We don't want
to further diminish their quality of life.
With that, I will end here and open for
questions.
CHAIRMAN DURST: Thank you.
Does the Committee have any questions?
Yes.
MS. HALLORAN: I mean, obviously a person
can survive without ever having to buy any packaged
food. I am wondering in terms of the kinds of
95
things you were talking about -- teenager's
preferences, the needs of a busy mother, et cetera
-- are there particular categories of food that are
prepared and packaged that are most sort of
important and essential in our modern life? I
mean, would it be bread or breakfast cereal or--?
MS. MUNOZ-FURLONG: If they ate
vegetables, they would be fine. How many kids want
to eat vegetables?
(General laughter.)
MS. MUNOZ-FURLONG: I think it really goes
back to quality of life. Children want to be like
everyone else, and they will do everything they can
to fit that mold.
I have a daughter that was diagnosed with
milk allergy and egg allergy when she was an
infant. I will tell you that I did everything I
could to make sure that she felt like her friends.
It is not just the patient or the child,
it is also the family wanting to not have their
child isolated or feel stigmatized because of the
allergy.
96
If everyone else is having breakfast in a
box, that is what these kids want. What we want is
to make sure that those labels are accurate, if the
family makes that decision.
Granted, there are some families that are
very cautious and will only make food from home,
make it from scratch. However, as the child gets
older and is out with friends, that is just not
doable.
MS. HALLORAN: Are there any particular
categories of foods?
MS. MUNOZ-FURLONG: No. As you saw in
that slide, "Common Foods In Unexpected Places," we
are seeing allergens everywhere. We have just got
to make sure that all of the labels are correct and
can be trusted.
CHAIRMAN DURST: Yes.
DR. KELLY: Ciaran Kelly. A question for
you from your perspective and the perspective of
the people you represent, the patients with food
allergies.
I
understand that you are frustrated and
97
find it very difficult to work with the current
system of many different types of wording. Would
it be better for you to have a two-level system,
"does not contain" and "may contain traces of" --
or even three levels, "contains" and "may contain
traces of" and "does not contain"? Would that be
acceptable?
MS. MUNOZ-FURLONG: Well, I will start
from the back end of your question. If you poll
our members or just the general consumers, they all
want "does not contain" labeling.
I would caution to you because of the
reports I've seen. This is very widely used in the
U.K., our colleagues in the U.K. have reported,
recalls to products that say "does not contain
peanuts" when they do contain peanuts undeclared.
From the way the consumer is going to
behave if they see "does not contain," they may not
read that ingredient declaration because that is
the guarantee they have been waiting for.
I am not in favor of "does not contain."
I am in
favor of let's have them read the
98
ingredient declaration and know that they can trust
if it doesn't have peanuts in that ingredient
statement, the product should be safe for them.
When we start to see different allergen
statements, we want to make sure that those can be
trusted. When we are talking about "does not
contain," that is an implied endorsement or
guarantee, which makes me very worried. If the
company makes a mistake and that is on the label in
error, we could have someone pay for it by having a
reaction.
Now, if we have two levels, "contains" and
"may contain," as along as we know what that means
and that all companies are following this
guideline, that makes it much easier. Right now,
you can go poll 12 companies and they each do
different things.
CHAIRMAN DURST: I think we need to move
on.
Thank you.
Our next speaker will be Susan Hefle,
associate
professor and co-director of the Food
99
Allergy Research and Resource Program at the
University of Nebraska, who will be speaking on
"Allergenicity: Analytical Methods."
Dr. Hefle?
ALLERGENICITY: ANALYTICAL METHODS
DR. HEFLE: Thank you, Chairman Durst.
Good morning. I am going to discuss the
basic analytical methods for allergens. The model
used is the ELISA-based model which has lateral
flow. This model has been used for several years
now. We will discuss this more later.
Our second bullet, the most successful
kids do use polyclonal antibodies but occasionally
a kit uses monoclonal antibodies directed against a
single protein. Usually, the antibodies are
directed against a crude extract of an allergenic
food not the specific proteins themselves. It is
not necessary to really measure the allergen.
The industry just cares if any peanut is
there, not if one particular protein from a peanut
is there. "Ara h 1" is a particular peanut
allergen. The industry just
wants to know if any
100
peanut or whichever peanut is there.
A lot of times a lot of the successful
kids use a much more kind of crude approach to
detecting peanut rather than specifically horning
on the allergens themselves.
There is a challenge, though, in that
different standards are used in the different kids,
depending on the manufacturer, and also different
antibodies are used in the different kids depending
on the manufacturer. It is not like a standardized
approach across the board, necessarily.
(Slide.)
DR. HEFLE: The detection limits range
from around 0.1 to 2.5 parts per million for the
quantitative methods. There are also quality
methods; however, if we are talking about threshold
levels, we need to talk about quantitation here.
Using a method that has a very low
detection limit has certain challenges. Every kit
has the ability to have a low detection limit. Ten
years ago, when I started developing kits,
Steve
Taylor and I sat around and thought about
101
what the detection limit should be based on our
years of experience in dealing with consumer
reactions and things like that.
We set a certain level with the kits we
developed; we picked 2.5. It seems to have gone
very well over the last seven or eight years since
these kits have been on the market. Some of the
other companies have a little bit lower range of
detection limit, and that seems to work okay, too.
However, if you go way too late, I mean,
they can all push these kits really, really, really
low. The problem is, Is there clinical relevance
at that point?
If there is no clinical relevance,
companies may be chasing molecules around their
processing plant. They will have all of this
positive data at a low level, and they won't know
what it means. We like to call this "paralysis by
analysis."
We want the data to be relevant. We want
the data to be useful. If the industry goes back
in and
says, "I want to fix this, but what if I get
102
all of these positive results at a low level?"
Detection limits have to be kept in mind. They
should be tied to threshold levels, whatever we
decide the threshold levels should be.
It adversely affects the quality of life
for food-allergic consumers, if you use detection
limits that are really low or push those detection
limits without a good clinical basis. Because of
the industry reaction in the form of increased use
of "may contain" label.
When they did paralysis by analysis and
they get positive results, maybe they throw a lot
of "may contain" labeling on that product that they
are worried about and so they are going to put that
on there. That decreases the number of foods that
allergic individuals can eat.
The current detection limits that are set
that the industry uses right now have worked very
well for seven years in protecting the
food-allergic consumer.
I don't think at this point there is any
need to
change them right now. But, again, as
103
science comes in and we know more about threshold
levels, there might be an adjustment here or there.
We just finished an egg threshold study.
Contrary to what Robert Wood said, you can do
threshold studies in kids, because we did this in
30 egg-allergic children. That is the only kind of
people we could find to have egg allergy are kids.
When we crunch those numbers and look at
that data, if the threshold is low enough that we
need to adjust the kids for egg out there, the
manufacturers have all said they would be willing
to do that based on the science.
(Slide.)
DR. HEFLE: Many companies are testing for
allergen residues. What they are primarily testing
is not-finished product, but they are using it to
verify sanitation procedures. They have been using
them for as long as they have been on the market.
Certainly with the new law coming up,
there are a lot more using them than used to use
them. In general in the U.S., companies are
incorporating testing using these test kits. As
104
the test kits get faster and easier to use, it is
easier for them to use them.
Again, the ELISA or lateral flow, which is
kind of like a dipstick method are the preferred
methods. Some do the test in house. They really
like it if they can do that because they can fix
things right away.
However, if you don't have in-house
capabilities, they will send it out to a contractor
lab or if they want third-party verification, they
will do that.
Most companies, as I said, are not testing
finished product. They are testing to validate
sanitation methods or doing environmental swabbing
to try to find where the problem is before they get
to the final product. They want to fix the problem
before they get there and figure out if their
sanitation is accurate before they get to the final
product.
Some testing of finished product on
certain occasions though is done, especially when
you can have
the product under full control. They
105
don't usually want to release something that they
have tested and they find out there is a problem
and they have to call it back from the marketplace
later and perhaps put consumers at risk.
There are tests that are based on DNA
detection, and they are called "PCR." We don't
advocate these for allergenic residue detection
because it doesn't prove the presence of the
protein. You need the protein to have the allergic
reaction. It just says that there is DNA from that
particular allergenic food there.
It is not practical at all for in-plant
use. You can't put one of these machines next to a
processing line. It is very expensive and requires
a lot of segregation and things. It is meant more
for a regulatory agency or a big corporate lab who
has this ability. It does not prove the absence or
presence of the protein or the allergen. It is
just an indirect kind of a marker.
There are ATP tests out there. This is a
test that is commonly used in the industry for
sanitation
assessment. Some companies would like
106
to use this to detect allergens, specifically the
ATP does not detect protein also. Right now, it is
not knowing that these correlate well with the more
specific protein-based tests.
(Slide.)
DR. HEFLE: Three peanut, like ELISA test
kits, have been performance tested by FDA through
AOAC-RI. Those companies with those tests are
Neogen, R-Biopharm, Tepnel.
Five peanut ELISA kits have been studied
in one JRC interlab trial. This is the European
Union's group in Belgium that does these sorts of
things, and they put these three tests plus two
more through a validation trial. They are
currently doing another validation trial on the two
peanut lateral flow devices. They are not finished
with that yet, but they are only doing one matrix
not several matrices. They are just testing it in
cookies right now.
(Slide.)
DR. HEFLE: FDA works with AOAC and has
said they
plan more validation studies with other
107
test kits, and that has been the case for more than
a couple of years now with no apparent progress on
this front, though.
The U.S. food industry and other
regulatory agencies -- for example, the Canadian
regulatory agency, the JRC -- has moved way ahead
of FDA/AOAC at this point. The industry is not
running validation trials themselves, but they run
in-house validation things like that.
However, there are regulatory agencies who
have said, "Well, we're going to move ahead. We
can't wait for AOAC anymore. We have to get these
things done in validated interlab trials." There
are several trials that are planned right now
internationally to, hopefully, get some of these
things "validated" in the next few years.
The U.S. industry has been testing for
about seven years now, since the first peanut tests
came out. They have increased the amount of
testing each year and, I've got to say, have spent
millions of dollars once they've gotten test
results to
change equipment, to make modifications,
108
for allergens specifically.
Before about 10 years ago, we didn't have
any tests at all to do this. Since the tests have
become implemented, they have used them to make
changes in how they manufacture food.
Health Canada/CFIA has a Compendium of
Food Allergen Methodologies. They crunch through a
lot more of these kind of in-house validations that
they do so that they can use them for their
purposes. There is a Web site for that. They use
both commercial and their own in-house methods.
(Slide.)
DR. HEFLE: Validation of kits, there are
more JRC trials coming out of the EU more likely.
We know of several that are planned, and other
groups have them planned, too. Other groups are
planning more interlab trials, some with kind of
"modeled" foods.
A lot of these tests are done where you
spike peanut into something else. It is not really
like a manufactured product, so it doesn't really
mimic the
manufacturing process.
109
A "model food" is actually where the
allergen is manufactured into the matrix, so that
it more appropriately represents what would happen
in the food industry.
Therefore, those are king of challenging
to make. You can't just make them in your back
yard or in your home kitchen. You need to make it
on an industrial level, so it can be quite an
undertaking.
(Slide.)
DR. HEFLE: Kit companies do much more
extensive validation than ever will be done by any
regulatory agency or academic center. It is
usually that the are in the process of selling
kits, and they don't necessarily share the data
like they should. I have been encouraging all of
them to go ahead and publish all of this great data
they have, and it would be a lot easier for all of
us to evaluate how good their kits really are. So
far, they still want to sell kits and not spend
time writing papers.
However, they do have liability issues.
110
Their kits have to work. They have liability
issues. They have reputation issues if the kits
don't work, so it behooves them to do their own
validations before they put a product on the
market.
(Slide.)
DR. HEFLE: Reference materials are solely
lacking for allergens. It would be really nice if
we had a bunch of reference materials we could do
all of these interlab validations with.
However, we are having a problem finding
the appropriate reference materials. There are not
many available, and they are really needed. NIST
is one source of reference materials.
Unfortunately, the NIST standards that are
available were not made for allergen testing, were
not designed for that and often do not represent
the type of allergenic materials used in the food
industry.
A case in point was the standard that was
used in the AOAC-RI-FDA study. It was peanut
butter made
by a major manufacturer. It is fine
111
for things like aphlatoxin determination and other
things. Unfortunately, the varieties are not known
with certainty, because the manufacturer wouldn't
tell FDA about every little peanut that might be in
there. They wouldn't divulge it. I'm referencing
NIST not FDA, I'm sorry.
Different peanut varieties have different
responses in the kits. It is imperative to know
exactly what is one of these standards.
Unfortunately, there aren't a whole lot of other
standards around the world around to do that.
There are other sources of materials that
could be used as reference materials, but we have
to come to a worldwide decision on what is the
appropriate criteria for considering something in
the reference material. Is something the JRC makes
in Europe representative of something we use in the
United States?
There are several of these materials
available, and we could begin to talk about going
through some interlab trials with some of these, if
they met
certain criteria.
112
(Slide.)
DR. HEFLE: Processing can have a huge
effect on extraction and kit performance. Most
kits are not validated using these model foods, so
we have to do some more of this stuff;
international call for more use of modeled foods.
The old method of spiking, which is where
you put a peanut extract into some of the matrix
and mix it together and see how it performs. This,
again, does not truly represent what happens in the
food industry.
However, the spiking does provide some
useful information, but the manufacturing of these
model foods gives the best information about how a
kit will work.
Model foods have to be made on a pilot,
plant or industrial size scale. If you make this
in your backyard or your kitchen, then it doesn't
really appropriate what a model food is in the
industry, either.
If you make many cookies in a home-size
oven or a
Suzy Homemaker or Easy-Bake Oven, it is
113
not going to be the same thing as what Keebler or
what Pepperidge do on a huge scale.
The results of these are not practical or
useful for the food industry. Let's make some real
model foods. They are involving for assessing how
a kit is going to work with a specific commodity,
how efficient the extraction method is under
industrial conditions.
It is becoming more and more important to
use these types of standards in assessing the kit's
performance for certain commodities and processing.
I think spiking is pass.
I get yelled at in my professional
society, AOAC, because spiking is the way of the
food chemists. However, we have to do some spiking
and look at things, but we have to make these model
foods and do that sort of assessment also.
(Slide.)
DR. HEFLE: The extraction method, is it
sufficient? We've got to think about it. Is it
sufficient? Is the recovery good? Can we trust
the
results?
114
Some foods are challenging. There are
tannins and polyphenols in dark chocolate that bind
protein. It is a famous matrix, one of the most
difficult matrices to do with allergen
determination.
High fat levels can hide the allergen in
other types of ingredients. If the product is
hydrolyzed, you cannot analyze hydrolyzed or
fermented ingredients in these test kits. They
were never designed for this. When you start
chopping up the proteins, the ELISA signals go
away. The methods are meant to detect intact
proteins and not peptides.
Processing, if you burn stuff, it is going
to be less detectible; it is less soluble. That is
a factor. Now, most companies don't burn their
food, but sometimes they want to detect burned
foods on band ovens or something they can't readily
clean. These are challenges to kit performance,
too.
(Slide.)
DR. HEFLE: Most kits for most allergens
115
have good reactivity with processed forms of the
allergenic food in my experiences over the last 15
years, and that is just my experience.
The use of polyclonal antibodies and crude
extracts and making antibodies against processed
forms are recipes for successful kits. There are
several on the market today that do very well.
Monoclonals are okay if they use a
heat-resistant epitope in making the monoclonals.
They can accommodate the processing changes that
occur.
Some of the egg residue kits have some
issues in this regard. The industry has been able
to adjust and adapt. Many survey the raw material
instead. Instead of worrying about the processed
egg, they will just do the raw egg and handle it
that way, or use a kit that has antibodies against
raw and processed egg, to get around that
particular issue.
Matrix effects, my lab has used all of the
ELISA-based test kits available on the market in
our own
validations and tests. It is kind of my
116
hobby so I like to do this. The matrix effects are
usually not a problem for most of the test kits out
there, for the vast majority.
Kit companies have added extraction
additives to their extraction buffers to assist.
When it was recognized dark chocolate was a
problem, they added some secret extraction
additives to help you pull the protein out of dark
chocolate easier.
Model foods, though, again are going to be
of great use in assessing the true extraction
performance of a kit. Again, I can't stress enough
we need to make more of these.
In cross-reactivity issues, even though
most methods do use polyclonal antibodies, which
those of you who know something about polyclonal
antibodies could say, "Boy, there could be a lot of
cross-reactivity problems with them."
We really don't see this happening. The
kit companies really couldn't sell any kits if
their peanut kit cross reacted with everything
else,
too. Therefore, we don't usually see
these
117
problems in that they have looked at that before
they have launched it, so we don't see the
cross-reactivity. I am not saying that there isn't
one that is going to crop up sometime.
(Slide.)
DR. HEFLE: Again, we've got a problem
with hydrolyzed proteins, hydrolyzed vegetable
proteins, hydrolyzed soy proteins. You can't
really detect them.
The industry would love to do this, to
chase them through the facility and see if they
have cleaned up afterwards because we know there
can be some residual allergenicity in hydrolyzed
protein preparations.
However, the ELISAs are pretty much
rendered useless when trying to analyze for
hydrolyzed protein. It is not what they are
designed to do. The company has had to make a
decision, "What is most of our market?" It is not
chasing hydrolyzed proteins, but it is chasing the
intact proteins. We have to balance the kits to go
towards
that, so you can't use it for this.
118
Unfortunately, a negative result in an
ELISA in this case does not mean that there is no
allergenic residue left. You have to ascertain
residual allergenicity via a different method using
human allergic IgE in something like a Western blot
or a RAST analysis.
Another related area is the analysis of
fermented ingredients: gums, Lactobacillus
cultures, starter cultures. Once they start eating
at the substrate, the proteins are partially
hydrolyzed and the ELISAs won't detect them
anymore. You need to use an IgE-based method to
just ascertain the true allergenicity.
Companies don't tell contract labs the
nature of their samples. They just say, "Here is
Sample X." They are not going to tell them it is
hydrolyzed, so we have some challenges.
I try to communicate with the contract
labs and say, "Be sure you ask the question. Just
don't give them a negative result, because it
couldn't be truly negative maybe from an allergenic
standpoint." I think this
is the minority of the
119
samples out there.
(Slide.)
DR. HEFLE: My lab performs testing for
food-allergic consumers, their physicians, their
lawyers when they call for free when they report a
reaction to a food. We work with some members of
the Food Allergy & Anaphylaxis Network when they
have a problem.
If there is an analysis I can do, I will
try to help a food-allergic consumer identify what
happened with that particular food, if they have
managed to keep it in the height of the moment.
In 10 years of doing this, we have only
seen "large" -- now notice I say "large" with a
quotation around it, I don't want to make a lot of
judgments on that right now -- amounts of
undeclared allergenic food causing reactions.
(Slide.)
DR. HEFLE: We cannot currently do
immediate monitoring in the food industry, though.
The
technology doesn't exist. It is getting
120
better. These lateral flow devices can sometimes
get down to 5 minutes now. I think in the future
they will be able to make a more immediate
response.
Right now, a lot of them are 30 minutes
long. If you are swabbing things and waiting
around for 30 minutes to see if the result is
positive and then having to go back and clean
again, it is pretty impractical for the food
industry to do.
Sanitation and verification is the most
practical, not the test and release kind of thing.
My dad is a fisherman, so I like to the catch and
release and test and release kind of analogy.
We do not have tests for some of the
allergens, and fish is a notable example. You
cannot test for the hydrolyzed or the fermented
allergen sources using these types of methods.
Some types of cross-contact are not
homogenous or 100 percent cleaning is not possible
due to the nature of the product. Food equipment
was never
historically designed for allergen clean.
121
Sometimes these facilities are quite old,
and there is no room. There is no room to bring in
different equipment. They have to try to redesign
as they can, but they can't get completely rid of
hangup areas.
You cannot take enough samples to
practically test, to be a hundred percent sure all
of the time. That is impossible. If I get a
statistician in to tell me how many samples I would
need, the industry would just spend the whole day
testing rather than trying to make food product.
In some of these cases, precautionary
labeling is justified due to the nature of the
product and the process in FARRP's opinion. For
example, dark chocolate and milk chocolate on the
same line is one example where we think
precautionary labeling is justified. That doesn't
mean we think precautionary labeling is justified
in every case.
(Slide.)
DR. HEFLE: This is a study that we
recently
completed and published in 2004 of some
122
incidents from milk allergic consumer complaints.
These were the casein levels we found in those
particular products. They range from 5,000 on up
to 44,000 parts per million in things that were
supposed to be free of milk or labeled even
"dairy-free" or "kosher," quite high numbers of
parts per million.
They also asked me to talk a little bit
about highly refined oils. What does HRO mean? In
FARRP's opinion, "highly refined oil" means
neutralized, bleached and deodorized or refined
bleached and deodorized.
The definition of what "refined oil" is,
is kind of debated a lot right now in terms of
FALCPA, opinions based on scientific review of oil
challenges with oils in the literature and what we
feel refined oil should be.
The available quantitative methods, there
are methods used in the literature including ELISA
and other methods that reports the levels of
protein in highly refined oils. None of these,
though,
have been validated in interlab trials or
123
other types of validation for protein and oil
determination to date.
Somebody will run something and they will
report it, and they will do a certain number of
samples, but no one has looked at whether that is
an appropriate method across the board for
detecting this.
There is a question as to whether a small
amount of protein in the HRO is completely
extracted in aqueous buffer. "Aqueous buffer" is
something that people often use to do these sorts
of biochemical tests. It means trying to partition
the proteins from the oil into an aqueous buffer.
If they really like oil, they might not
all come over. They might want to stay in the oil.
The question is, Does this capture the true protein
content of the oil or whether some of the more
hydrophobic proteins stay in the oil fraction, and,
therefore, do not get extracted and therefore
determined?
My lab uses an amino acid determination
based on
Edman degradation, but we also use aqueous
124
extraction. We try to maximize that aqueous
extraction.
We use heat; we use a large amount of
buffer; and we concentrate the sample. However, I
cannot guarantee that I'm pulling all of the
protein out of that highly refined oil when I
measure that.
We report the results as relative and not
a complete picture of the possible protein count
out of HR oil. I still think you are capturing
most of the protein that is there, but I just can't
sit up here and say we are covering a hundred
percent of it.
(Slide.)
DR. HEFLE: The protein levels of HRO are
reported in the literature, and there are lots of
different reports and levels. The caveats again:
The use of aqueous buffers in the determination,
how good if they use an immuno-chemical-based
method is the epitope recognition of the antibody?
Does it really recognize those soy proteins at that
level of
processing?
125
Relating "total" nitrogen, sometimes they
use the total nitrogen amount to what the protein
is. Well, total nitrogen can be free and running
around in the protein and not associated with --
free and running around in the oil and not
associated with the protein. Consequently, it may
be an overestimate actually of the protein amount.
Limitations of certain types of methods
like dye binding. "Dye binding" is a method that
will bind to certain proteins preferentially and
not bind to others as well. When you use a
dye-binding method, is it really representative of
everything that is in there? You can't absolutely
tell.
The protein levels reported in the
literature are usually a few milligrams per
kilogram, which are a few parts per million. You
will see some widely ranging estimates, though,
from different investigators. A lot of times I
question their methods sometimes or their ability
to reproduce that particular result.
I
think that is the end of my
126
presentation, and I thank you very much for your
attention.
CHAIRMAN DURST: Thank you.
Committee, do you have any questions or
comments?
QUESTION-AND-ANSWER SESSION
DR. MALEKI: Soheila.
DR. HEFLE: Soheila.
DR. MALEKI: Yes, Soheila Maleki. I was
wondering, just based on your experience and you
have been around a lot of industry, if there is any
kind of correlation or if there are any standards
between what the companies use to label "may
contain" versus "contains"? Do they use the same
2.5 parts per million that the kits provide as a
may contain or a not contain and so forth?
DR. HEFLE: They don't really use the
analytical results to make a definite decision
about that. Usually, the companies make a decision
to put precautionary labeling on through a certain
stringent set of criteria. It is something they
have tried
to clean up, and they are still having
127
issues.
They have intermittent contamination.
They would never allow something that consistently
had a significant amount of allergen in it to be
called a "may contain." They would try to clean up
more, if it is not supposed to be there.
They don't set a level like that. They
use the analytical results to help them determine
whether that is justified or not. It has to be
potentially hazardous, intermittent, hard to clean.
Those sorts of things are taken into consideration
much more than just the simple analytical result.
DR. MALEKI: Thank you.
CHAIRMAN DURST: Yes.
DR. NELSON: Mark Nelson. I just wanted
to follow up to that in response to Soheila. In
2001, the food industry, a group of associations
representing their members did put together
guidelines on labeling.
The preference is obviously and clearly
the requirement is to label the ingredient in the
presence of
an allergen when it is directly added
128
to the food. In the situation where there is a
potential for cross contact, we did establish some
guidelines before companies should use "may
contain" labeling because of the concerns we have
heard about before.
One of those key guidelines was to make
sure that we could not avoid it even after applying
good manufacturing practices: appropriate cleaning,
appropriate separation, and so on and so forth.
DR. MALEKI: I see. Depending on how much
you detected, it didn't matter, if you detected, it
went to "may contain," if it was on the line or --
well, if it contains it was directly added to the
product? I'm trying to make sure I understand that
correctly.
DR. NELSON: Yes, I think it is more to
Sue's point that we aren't necessarily measuring
the finished food so much. It is not a catch and
release situation.
DR. MALEKI: I see.
DR. NELSON: It is understanding your
system;
what ingredients are going into the food;
129
what other products might be made on that line;
validating your cleaning processes between
products; scheduling products, depending on the
ingredients that they contain; the sequence in
which you might make the product and so on. There
are a lot of things that go into it.
CHAIRMAN DURST: Anything else?
Yes.
DR. CALLERY: Pat Callery. It appears
that the allergens themselves are not that well
defined, especially when you can find in actuality
generated new allergens by treating food in a
certain way. I am wondering how you address the
analytical problem of false negatives and false
positives?
DR. HEFLE: For a lot of foods the
allergens are indeed known, and there are very rare
cases where you make new allergens through
processing. That is an extreme case in the
literature, I think.
However, false positives and false
negatives
are evaluated at the company level first
130
by testing tens of thousands of food commodities
and looking for potential issues. Also, I kind of
poke around myself and see if there is anything
that I can challenge the kits with.
In my experience, the false positive/false
negative rate for most of these methods is very
low. I can't give you a number. I can't tell you
how good that is, because I haven't done a
systematic study.
However, I think that the use of these
interlab trials with model foods will help us look
at some of those issues a little bit more, but I
don't have a good sense of how much false positive
and negative is out there.
I just know in our experience, and we use
these every day, we don't have a lot of issues.
When the occasional issue crops up, and we call the
manufacturer. We usually work through it pretty
easily.
They do tell the manufacturers to validate
or run their own in-house validations before they
truly test
the results. The manufacturers do tell
131
the manufacturers to do that, so, theoretically,
they should hopefully find some of these things.
However, every method has a chance of a false
positive or a false negative.
DR. CALLERY: I'm not sure how you do that
without standard materials.
DR. HEFLE: I'm sorry?
DR. CALLERY: I don't know how you do any
of that without standard materials to validate
them.
DR. HEFLE: Some of the manufacturers will
give you a standard to work with, either the
standards from the kit or a recognized standard or
perhaps one of the NIST standards, which is what we
are all defaulting to because we have nothing else.
DR. CALLERY: I think you mentioned that
one kit, they have some secret materials that they
put into the kit to help extract protein. This
seems inconsistent with being able to validate a
method if you don't even know what the test
material, how it was made and what the scope of the
antibodies
are that are made.
132
DR. HEFLE: Well, the extraction additive
is not a reference material. The extraction
additive is just an aid in extraction. Usually,
the companies will tell you what it is. It is
usually non-fat dry milk or soy protein. It is
secret, but it is not that secret.
It is just an additional protein in the
mix that helps pull the proteins out of oily
matrices or hard to extract matrices. The
companies know this, and they share that with
customers. However, these sorts of extraction
additives aren't really the reference materials or
the standards used in the kit.
CHAIRMAN DURST: Sue, will you be around
for discussion this afternoon?
DR. HEFLE: Yes, I will.
CHAIRMAN DURST: I think we will hold
further questions until that time because we are
running a little bit late.
DR. HEFLE: Okay.
CHAIRMAN DURST: I would like to take the
recess
now. We will take a 10-minute break and
133
reconvene at 10:45.
Thank you.
(Thereupon, from 10:30 a.m. to 10:40 a.m.,
there was a pause in the proceedings.)
CHAIRMAN DURST: We will start with our
next speaker, who is Dr. Stefano Luccioli, who is a
senior medical advisor to CFSAN, FDA. He is also
assistant professor at Georgetown University. He
will be speaking on "Oral Challenge Studies:
Purpose, Design and Evaluation."
ORAL CHALLENGE STUDIES:
PURPOSE, DESIGN AND EVALUATION
DR. LUCCIOLI: Thank you, Dr. Durst.
Good morning. Today, I really want to not
talk to you as an FDA medical officer, but as an
allergist who has experience in performing and
evaluating oral challenge studies.
(Slide.)
DR. LUCCIOLI: The goals of my talk today
are basically just to give you a basic overview of
oral challenge studies, the purpose, why they are
done, the
design and conduct, and also spend a
134
little time on evaluation and interpretation of
data, especially with regard to sensitivity of
subjects as well as clinical response and severity
and maybe present some data gaps that may be of
interest while you deliberate on thresholds
(Slide.)
DR. LUCCIOLI: The purpose of challenge
studies are manifold, but the primary reason is to
diagnose allergy, food allergy. The gold standard,
as we have already heard, is the double-blind,
placebo-controlled, food challenge.
As we have heard, also people outgrow
their allergies. They are done also to evaluate
tolerance where those individuals have outgrown
their allergies. They have also been done to
evaluate specific ingredients that are allergens in
specific populations. For instance, there have
been some studies on highly refined oils in
peanut-allergic populations.
However, in recent years, there has been a
lot of emphasis on using oral challenge studies to
determine
minimal eliciting doses. This has
135
important implications potentially to determine
sensitivities of individuals within a population,
but also potentially some therapeutic opportunities
in that, as Dr. Wood had mentioned, there is a
feeling that maybe if we can't cure food allergy,
maybe we can raise people's sensitivity levels so
that they may not react to very low trace amounts
of food.
For reasons that you are all here today,
also for establishing threshold challenges, they
may be able to provide you data on low-effect
levels and no-effect levels.
A problem in this field is that there are
insufficient animal models which are commonly used
to evaluate toxicologic ingredients and also
scattered data about case reports where there is
not a lot of information about exact doses that
cause reactions.
Very few studies are done or have been
done. One study was reported by Dr. Wood on
evaluating reaction severity, and we don't have any
current
biomarkers to predict severity. This is
an
136
important, I think, factor when we are looking at
evaluating minimal eliciting doses.
(Slide.)
DR. LUCCIOLI: I'm just presenting this
slide, but I'm not really going to go into it, to
just give you an overview that oral challenge
studies are somewhat different to traditional tox
models that are used to determine potential
thresholds or acceptable doses. I will, hopefully,
be able to highlight some of these issues in my
talk and present, as I said, some data gaps.
(Slide.)
DR. LUCCIOLI: When you are designing oral
challenge studies, obviously the selection of
subjects is an important factor. Usually, you have
populations of adults, children or infants just to
keep the statistics in order. Most studies involve
both men and women as well as are from foreign
countries and most high ethnicities.
The selection of subjects is basically
geared to what the purpose of the study is for,
whether you
want to diagnose individuals with an
137
equivocal IgE or clinical history; evaluate
evidence of outgrowth of tolerance, as we have
mentioned; and also potentially to evaluate
co-existent allergies, for instance, milk-allergic
individuals who may have soy, especially in the
infant population and also for evaluating specific
ingredients, in this case how to evaluate infant
formula.
Obviously, for specific ingredients, you
may want to pick particular populations for that.
In fact, most infant studies are done to evaluate
infant formulas, and the majority of studies are in
adults.
Another important factor is that there is
a notable exclusion of individuals from these
studies. As Dr. Wood had alluded to, there are
individuals who have a cutoff level of their IgE
where above this level they have a 95 percent or
more risk of already failing the challenge. The
challenge is basically useless. You already have
the information, and you tell those individuals to
avoid the
food.
138
However, these individuals may represent a
fairly sensitive population. Now with IRBs as they
currently stand, it is very difficult to get these
individuals tested in studies.
Also, classically individuals who have had
anaphylaxis or very severe reactions which were
fairly convincing for the actual food are excluded
from the studies, because another rule of thumb is
do no harm.
Consequently, you don't really want to
test people who could have potentially severe
reactions when you have already had a high clinical
index that they are allergic.
Of course, there are a lot of people who
self-exclude themselves from studies who may be
part of a sensitive population. I also mentioned
here unstable asthma because in any study you don't
want to test individuals who are unstable to begin
with.
Individuals with asthma tend to have more
severe reactions and are probably the group most
representative of fatal reactions.
By not
139
including these individuals, you may be missing not
only sensitive individuals but individuals who are
potentially very severe responders.
(Slide.)
DR. LUCCIOLI: With regards to test
materials, there is a variety of test materials
that can be used. Various preparations, if you
just look at peanut, you can have peanut flour,
ground peanut, peanut butter.
There is evidence that the processing
method of these various preparations may affect the
allergenicity profile of proteins within these
foods.
You may have some individuals who are more
sensitive to peanut flour versus peanut butter.
The importance, too, with choosing the material is
that for logistic purposes you want to have it for
an increased time, if you are going to be doing
challenges over multiple months or time points.
A preferred method for these types of
ingredients are dried ingredients. You get into a
problem
where dried milk or spray-dried egg are not
140
very commonly ingested ingredients in the
population. It is more common, I mean, the raw or
cooked egg or milk, liquid milk. Therefore, these
are factors that need to be assessed.
Also, fresh versus processed foods, some
individuals are more likely to react to the fresh
food versus the processed as well as raw versus
cooked. These are issues that need to be
considered when you choose a food for a particular
challenge.
Then, the dose units are different within
these challenges. Some studies report milligram
for food; others milligram for protein of food;
and, very rarely, milligram per kilogram which
would be fairly ideal if we wanted to evaluate
potential differences between adults and smaller
adults, infants.
(Slide.)
DR. LUCCIOLI: Obviously, people who
partake in these studies are people who think they
have an allergy; may have had a fairly significant
reaction; and are, understandably, under
a lot of
141
stress and are afraid.
Blinding is an important fact, since there
is unfortunately a high incidence of the "nocebo
effect," which is actually the opposite of placebo,
people reacting to a substance that they think is
going to harm them.
In blinding it is important to mask the
food, because you don't want the subject to know
what they are eating. Factors that are used are
called "vehicles" in one sense, and they are
basically other types of foods that are thick that
can hide the taste and smell and texture and that
are also pleasant tasting, you hope.
However, when you are thinking about doing
a challenge study over a few time limits, obviously
you don't want to give some of these vehicles too
much of this, too many milkshakes -- you have to
make sure that the individual is not milk allergic
-- but also they may cause some GI effects or other
things independent of what the actual food that you
are studying would have.
In some cases, they don't always mask the
142
taste. Therefore, some researchers have preferred
to use capsules, since this basically bypasses the
taste issue.
However, using a capsule is difficult,
especially if you are going in higher doses of
food, it is hard to put a serving of some food into
a capsule. I think people would know when they see
a big capsule that there is more food in that.
Also, an important factor is that you may
delay the absorption of that food putting it in a
capsule, and also you bypass the oral cavity which
may be a primary target organ for the initial
allergic response. You may have not only a delayed
response but potentially a less severe response.
I won't talk about the protocol, I think
that was basically well-mentioned by Dr. Wood, but
also a question about placebos. There are some
studies that use placebos within the challenge.
They use a dose and then the next is a placebo.
You know, it is a very complicated process
where you usually need some other people that blind
those to
both the researcher and the subject, but
143
they are used as well. However, I think the
preferred method and the easier method is to do a
separate placebo day.
(Slide.)
DR. LUCCIOLI: Now this is just a
schematic of an example of a dose protocol. I
think the important factor is this is an escalation
study of divided doses. One of the important
things, too, is you don't want to be there all day,
and you don't want the patient, too, to be there
all day.
To be able to determine a dose of food and
get up to the final dose, which is usually a
serving of the food, which is like 10 grams of
solid or 60 grams of wet food is what you want to
achieve.
If there is no response at that dose,
there is a good likelihood that the challenge is
negative. However, in many cases you still want to
have the patient come back and do an open
challenge.
Now, with choosing the starting dose, this
144
varies among studies. In many diagnostic studies,
because of this issue about not wanting to be
there, you choose a dose that is roughly half of
the dose that caused the reaction.
Now, I don't know how a lot of people
figure that out, but that is what has classically
been used as the starting dose. Even within a
study, these doses shifts. This dose usually comes
out to be in the milligram range.
Now, more recent studies that have
actually been targeted to study minimal eliciting
doses, have started in doses in the even microgram
range. However, there are a variety of studies
when you are looking at evaluating studies for
eliciting doses.
Also, in this protocol, it is important to
know the time interval differences. Usually, also
that is tailored to the patient when their symptoms
first occurred. Most allergic reactions occur
within 15 to 30 minutes, so that is usually the
time gap, but some other reactions may be a little
bit more
delayed.
145
As Dr. Wood discussed, there are
individuals who have delayed reactions as well.
Unfortunately, it is just not logistical to do a
study and wait for these people's reactions to
occur, because they might not occur that day; they
may occur on a separate day.
In this model that I use, I just use a
twofold dose incrementation, but also this could
vary. Some studies go up to even tenfold, so this
could affect also the starting dose and
interpretation of doses in the dose response.
Now, you go and you do the challenge. If
it is negative, it is negative, or you stop it
after the first objective symptom occurs. Some
studies will also record the subjective symptoms,
but that is not always the case, because the
objective symptom is the symptom that denotes a
positive allergic response.
When you record the dose, you can either
record it as the 4X, which is the discrete dose
recorded or the 7X, which would be the cumulative
dose adding
the X, 2X or 4X.
146
Just to put this also into some
perspective in terms of safety assessment, when we
are talking about LOAELs and NOAELs, the 4X would
be the low-effect level for this study. If there
are doses before that, at least for this individual
you can say that this dose did not cause a response
and could be considered a no-effect level.
(Slide.)
DR. LUCCIOLI: Some other issues are don't
do this at home. People can have a very severe
reaction. These studies are done in a clinic or an
office where there is emergency equipment and
personnel. It is not a challenge that is done out
in the open. It is in an experimental setting, so
that can also affect the interpretation or results.
Medications, too, most studies now have
people stop the medicines, but with some earlier
studies this was not a factor. Antihistamines and
other things, if people are on these drugs, may
block the early responses so that can factor in.
Fasting, too, most people fast before the
study, but
in some studies this was not necessarily
147
explained. If you have a full meal right before
the challenge, this could affect, potentially
affect, absorption of the allergen and therefore
affect the interpretation of the study.
The clinical history or reactivity, too,
is important. Dr. Wood talked about oral allergy
syndrome, but he did not mention about exercise.
There are some individuals who eat a food and have
no problem. However, if they eat the food and
exercise, they have a problem.
Some studies actually test the individual
and then put them on a treadmill and have them
exercise to see if you can elicit the reaction. I
mean, this is very rare, but that is something that
also can be done in terms of the oral challenge
setting.
(Slide.)
DR. LUCCIOLI: Statistical endpoints, I
think these are fairly straightforward for most
challenge studies. You want to just know what
percentage of individuals will react or not react
to the
challenge, or in cases where you are
148
studying reaction severity which ones will have a
mild versus a severe reaction.
If you assume that all of these
individuals in the study are part of the sensitive
population or general population, you can maybe
make some assumptions about that and decide a
percentage that will or will not react to a
specific food concentration.
Also, there an importance in this is also
when you are designing a study, you may want to try
to achieve a certain number of individuals to give
you confidence levels for the incidence of allergic
reactions.
In this example, this is a table that
shows over here (pointing) the number of
individuals that need to be tested to give you a
confidence level that the incidence will be less
than this.
For instance, if we were to design a study
with 66 people, that would give us 99 percent
confidence that 1 in 10 would potentially react, so
90 percent
would not react. Also, you could use if
149
66 is more than 59, you could also say, well, 95
percent confidence that 95 percent, 1 in 20, will
not react.
Twenty-nine has been usually seen as a
magic number for infant formulas. If 29 patients
do not react, if the infant with milk allergy does
not react to a cow's milk infant formula, that is a
basis for hypoallergenicity.
(Slide.)
DR. LUCCIOLI: I will spend the rest of my
talk on evaluation and interpretation of challenge
study data. Basically, a general interpretation as
we just talked about the statistics, many of these
studies are done in a very small population of
patients, therefore you cannot make a very general
assumption for the general population.
(Slide.)
DR. LUCCIOLI: Because some of these
studies do test the same food, there is a tendency
to group these studies together to try to get the
power higher and then potentially make some
assumptions.
150
The problem with this is that I think it
is important to note that all of the studies that
are currently available are not standardized. I
think that was a question asked just a little
earlier.
This is not standardized data. They are
not standardized to dose. Starting dose or
blinding or testing could also be a factor and also
interpretation of clinical symptoms, which I will
address a little later.
Another issue here is that all sensitive
populations, are they included. If you have
information only on adults, is that going to
predict what harm it will be to infants.
Again, in terms of statistical power, if
you get individuals who are not reactive, if you
are looking at total numbers to say "This is how
many people did not react to this dose," well, what
about people who didn't react to the challenge at
all? Should they be included in the final analysis
of individuals, or should only the ones who react
to the
challenge be part of that analysis?
151
What about foreign study data. For
instance, China has a very low prevalence of peanut
allergy, presumably because peanuts there are
boiled or fried versus in this country they are dry
roasted. If you have all of this data in the
United States about peanut allergy, could that be
transferred to data in China?
(Slide.)
DR. LUCCIOLI: I just should mention, too,
that with standardization it is important to note
that there have been some very nice reviews on
actually proposed protocols, standardized
protocols, for food challenges which have been
published in the last year or so. However, to my
knowledge, there have been no studies that have
used this protocol at least for a major food
allergen for evaluation.
Another general interpretation is that
this is an experimental exposure. It is not real
life. There could be false negatives. Individuals
who have had a negative food challenge go out and
have an
open challenge and react. It is not
always
152
a definitive assessment of allergy. Also, I think
it is difficult to predict reactions to future
exposures. I will try to talk about that as we
come up.
(Slide.)
DR. LUCCIOLI: Subject sensitivity, this
is I think an important issue to consider when
looking at evaluating food ingredients. The
genetic heterogeneity of individuals, there are
multiple allergens in food.
People can be sensitized specifically to
certain allergens within that food. If you cook
the food in a certain way or process it, you may
affect their allergenicity positively or
negatively. This may be what is apparent when they
do studies and you see this enormous gap in
responders.
You have almost a millionfold gap between
the high responders or I should say the least
sensitive who respond to low doses and the most
sensitive to who respond to high doses.
There is also this potential link with
153
severity, as Dr. Wood study has suggested and some
others, that some studies suggest that the
individuals most sensitive to low doses appear to
have the most severe reactions. Are we talking
about a specific subpopulation of individuals here
who are not only sensitive but severe? Also, there
is a sensitivity issue between foods and between
food products.
Another important aspect is that the
individual sensitivities may vary over time.
Allergies can progress and individuals with food
allergies develop asthma later in life. This
asthma, therefore, makes their reactions a little
bit more severe.
Telling somebody right now that they
reacted at a certain dose and that it is okay to
ingest doses before that may not be relevant a year
or five years from now.
(Slide.)
DR. LUCCIOLI: This just is a hypothetical
dose curve adapted from Jonathan Hourihane, who has
done some
nice research in this area, basically
154
just to show you how severity and sensitivity may
factor in. I don't really want to spend time on
that.
(Slide.)
DR. LUCCIOLI: Evaluation of clinical
responses, this is where interpretation of
eliciting doses is important with regards to
subjective versus objective symptoms as well as
reaction severity in the dose response.
This table summarizes some of the
reactions that you can see from an allergic
response. Basically, they are divided into
subjective versus objective. "Subjective" means
that they are reported by the individual or the
subject, and "objective" are responses that are
actually visible or observed by the observer.
These reactions are reported in this
manner. As I said, it is when objective symptoms
occur, that is when the study is felt to represent
a positive reaction and stopped.
(Slide.)
DR. LUCCIOLI: To just show you some of
155
these reactions, not only is there a wide range in
reactions, but there are some fairly milder
reactions, hives. You down here to shock and this
is anaphylaxis. Wheezing and syncope are very
close to systemic reaction and potential
anaphylaxis. Consequently, even within an
objective response, you may have a severe
anaphylactic response.
There are also some subjective reactions
that may be somewhat severe: throat tightness,
dizziness, sense of impending doom. I haven't had
the pleasure, fortunately, to experience a patient
with this, but I hear it is fairly dramatic. They
have this sense of impending doom and go rapidly
into anaphylaxis. It is very, very serious. It
doesn't take much for a subjective reaction to go
to something severe.
Also, there are some reactions that kind
of are in between the line of what is subjective,
what is objective: fussiness behavior, abdominal
pain. In adults, that could be suggestive of a
nocebo
effect. However, in infants, infants
don't
156
mess around. This is their symptom, so these could
be positive responses for infants.
At the same time, you could have skin
flushing or shortness of breath leading to
increased respiratory rate, which could be an
objective sign. However, many times this could be
due to also a nocebo effect. Whether these are
actual positive reactions is hard to determine.
There is some clinical interpretation differences
that can occur here.
(Slide.)
DR. LUCCIOLI: Subjective versus objective
symptoms -- as I told you, the measurable indicator
of allergic response is the objective symptom. It
has got many different endpoints, and the
interpretation may vary. This could also be true
for the subjective reactions.
Many times, subjective reactions do occur
as part of a nocebo effect. However, there are
some that are potentially indicative of an allergic
reaction.
How should these be factored into the
157
assessment? Many times they are not recorded in
the study, so we don't know if there are earlier
reactions to the objective dose, which may
represent an earlier adverse event level.
(Slide.)
DR. LUCCIOLI: Some other eliciting dose
considerations, the starting dose is important. If
the response occurs at this dose, you cannot
determine the no-effect level. Obviously, there is
no dose below that that doesn't cause an effect,
but is this starting dose the low-effect level?
Could you have given a dose a little lower and they
could have still reacted?
With dose increments, some are twofold and
some are tenfold. Using tenfold, you may miss some
increment in between that there could have been a
reaction, even maybe a fivefold difference.
Also, time intervals between doses, as
Dr. Wood has explained, some doses are delayed.
However, time intervals, if you don't give enough
time, you might not know when a subjective response
has become
a subjective response or so forth. This
158
could also affect interpretation of these eliciting
doses.
Of course, discrete versus cumulative
dose, some studies report just a discrete dose;
some the cumulative; some both, which is better.
However, how do these factor into a true exposure
assessment or prediction?
(Slide.)
DR. LUCCIOLI: I just want to just show
this, a few more slides, just to kind of put this
into perspective here, give you a mechanistic view
that allergy is a unique toxicologic response.
When you get food that gets challenged, it
causes a massive release of mediators and
cytokines. This is an amplification system that
the immune system uses to protect itself.
Now, in many cases, this response occurs
locally and may not amount to very much, but in
some cases this amplification can involve other
organs and spread systemically very rapidly.
(Slide.)
DR. LUCCIOLI: What has been
observed is
159
that the severity of an allergic response is on a
continuum. You can have subjective responses at
some point, objective anaphylaxis, and potentially
death in worse cases.
A few points to note is that this is not a
fixed response. The early objective system may
rapidly progress to something worse. Also, the
degree of amplification, this is not always
predictable or reproducible, so symptoms may not
always be reproducible on subsequent rechallenge.
(Slide.)
DR. LUCCIOLI: To end, with the reaction
severity, most studies only report the actual
symptom. You don't know where this symptom is in
the continuum of severity many times. Those few
that do report the symptoms, they report them as
mild, moderate, and severe.
You have to interpret the researchers, I
guess, response to this, how they interpret it; so,
there is some interpretation. Also, when you have
severe response, like in Dr. Wood's study, in some
cases a
third of individuals reacted and had mild
160
reactions, a third had moderate, and a third had
severe. How do you factor in those severe
responses when you determine uncertainty or other
issues?
Also, potentiating mitigating factors are
important: anxiety/stress, medications, and so
forth. These can either potentiate the reaction or
stop it.
Then, the challenge stops after the first
response. A lot of times we don't have the luxury
of knowing how far or how many more doses would
have caused a more severe response. Having that
information is important when you are wanting to
make some risk assessment decisions. Again, it is
a dose distribution, not a dose response.
(Slide.)
DR. LUCCIOLI: In conclusion, the oral
food challenge does provide data on clinical
sensitivity to minimal eliciting doses and also
reaction severity to the initial dose. However,
challenge data currently available for
interpretation is not standardized among studies.
161
The current data pool may not include
extremely sensitive populations with regards to
severity. Challenges have a proven value as a
diagnostic tool but less value in predicting
reaction severity to future exposures.
Thank you, and I will be glad to answer
some questions.
CHAIRMAN DURST: Thank you very much.
Are there any questions from the
Committee?
We will start here.
QUESTION-AND-ANSWER SESSION
DR. BRITTAIN: Yes. I have a comment on
the sample size table that you showed us. I am not
sure that is incorporating the statistical power
education we need to have more than these
individuals. Are you familiar with what I'm
talking about like the 29 there?
DR. LUCCIOLI: Yes.
DR. BRITTAIN: I'm wondering if you get
zero out of 29, then your confidence interval
excludes --
162
DR. LUCCIOLI: Well, what that 29 is, that
is usually a number that is targeted to challenge a
number of study subjects. If you show that 29
individuals with the specific allergy do not
respond to that ingredient, that gives you 95
percent confidence that 90 percent will not react.
DR. BRITTAIN: I guess what I'm saying is
that means if you observed 29, you get the desired
confidence interval. However, if you were planning
a study and you wanted statistical power to be a
certain amount, you would need to have a bigger
study.
DR. LUCCIOLI: Sure.
DR. BRITTAIN: You couldn't assume that
nobody would react.
DR. LUCCIOLI: Yes. Yes, I mean, you saw
that to be totally assured you would have to test
quite a few people.
DR. BRITTAIN: I do have another question.
You mentioned the placebos again, if someone does
have a reaction with a placebo, how is that
interpreted
in terms of if they also have a
163
reaction?
DR. LUCCIOLI: Well, yes, many times you
don't know, so then you unmask the study and then
you find out that they reacted to the placebo.
Now, technically, some studies will rechallenge
that patient again. They will have them come back
just to say, "Well, maybe" -- sometimes people do
react.
The difficulty is when they react to the
active dose, to a real challenge, and to the
placebo. If the placebo is too close to the
active, it may be that by the time you gave the
placebo, they are still having the active reaction.
Basically, if they are rechallenged and
show again, they are excluded from the analysis.
Now, that is what should happen. Unfortunately,
you never get that information a lot of times from
these challenges.
CHAIRMAN DURST: Suzanne.
DR. TEUBER: One of the aspects that we
are all very concerned about is which threshold to
use and
when it may cause a subjective reaction.
164
Actually, oral itching is a very important
subjective reaction that you didn't have on your
table up there in this presentation.
DR. LUCCIOLI: Okay.
DR. TEUBER: However, if that is
reproducible with two active challenges and not
seen with two placebos, which I think Dr. Taylor
may address a little bit later, but some of the
studies that Dr. Wensing and Bindslev-Jensen and
Dr. Hefle have been doing, they have been looking
at that. All of these have been followed by
objective reactions at higher doses.
DR. LUCCIOLI: Yes.
DR. TEUBER: I would really like people to
comment on that because this may be a much safer
way to approach obtaining thresholds to get these
extremely sensitive populations, if we can use
reproducible subjective data knowing, too, that
there are those other factors that may affect it.
DR. LUCCIOLI: Sure.
DR. TEUBER: For instance, in these
threshold
studies that are being designed
165
specifically for thresholds, people with unstable
asthma would still be excluded. I am curious if
anybody knows anything about how unstable asthma
would affect the threshold for a LOAEL that is
seen? Is it a lawful difference? I mean, is there
any anecdotal experience with how that might
change? We want safety here.
DR. LUCCIOLI: Obviously, a speaker that
is coming after me would have some information on
that, but some information from Jonathan Hourihane
would suggest -- and I think some European studies
actually do test some severe patients. Now, I
don't think that any of these patients are
unstable.
I think that they are all excluding
patients who have unstable asthma, but with asthma
in general they haven't found that these
individuals have a lower minimal eliciting dose
than other individuals. However, when they do get
a reaction, they can have a much more severe
reaction.
The assumption, though, is that because of
166
the fatalities and other things that when their
asthma becomes unstable their sensitivity could
change and become more severe very quickly.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc Silverstein. I
have two comments that deal with sort of
clarification of terminology and one comment that I
think deals with a more difficult issue. I thought
this was a wonderfully helpful and concise summary
of a variety of complex factors.
In terms of the two clarifications, in
clinical medicine from the first days of medical
school we are taught the difference between
"symptoms," which are subjective, and "signs,"
which are objective.
Some of us from the clinical side who will
be reading the report will think that subjective
symptom is redundant and objective symptom is an
oxymoron.
To help the wide dissemination of the
report and presentation, I would like to suggest
that we in
our thinking we may say "subjective
167
finding such as symptoms of the disease" and
"objective signs" is the sense that I use that.
DR. LUCCIOLI: Sure.
DR. SILVERSTEIN: I think it is helpful
because there will be a variety of readers of the
report who may not appreciate that on the clinical
side there is a clarification about that.
The second clarification had to do with
the incidence versus prevalence in the sample size
table. What we are talking about is the proportion
of subjects being tested to the proportion of
individuals in a population, so that sample size
table or the table we have is the expected number
of sample you would need. You label it "incidence"
but it is really a "prevalence" of a condition in a
population.
DR. LUCCIOLI: Okay.
DR. SILVERSTEIN: I believe that what you
are getting at is the sample size so that the lower
confidence interval is that 10 percent or 1 percent
rather than the sample size necessary to show that
two
populations differ in proportion or the sample
168
size to show how tight you are around a rate of
zero, which would be a different population.
DR. BRITTAIN: Can I respond to that?
DR. SILVERSTEIN: Sure.
DR. BRITTAIN: I don't think when you are
designing a study you want to think of it in terms
of statistical power, which would be greater than
the sample sizes.
DR. SILVERSTEIN: The third comment I
have, which is substantive and I think we may need
to address this later in greater detail, has to do
with sources of error. There are two sort of
classes of errors that we made in our inferences.
One types of error an epidemiologist or a
clinical epidemiologist may say is biased, one of
the most common sorts of types of errors we could
make would be making inferences in the presence of
certain biases. The most common of which would be
selection bias.
Of course, the selection of individuals
who are referred to a physician, who are referred
to an
allergist, who are selected for an oral
169
challenge, food challenge, study would potentially
lead to erroneous inferences if there were
non-representative selection.
That is something that in reading the
literature and making decisions about inferences
for studies or for policy I think we need to be
aware of up front, so that is an important class of
errors that we need to be alerted to.
The second would be an epidemiologist
would talk about confounding. In your example of a
study subject who has asthma, whether it is stable
or unstable and how that is defined, asthma might
be considered an extraneous factor that affects the
relationship between the allergen and the response
to the test. We could use the framework of
thinking of it as a confounding benefit.
Factors such as bias and factors such as
confounding, I think, are useful as we make
decisions about the report and the evidence for
that. I would like for us to be alert to that as
we think about the presentations.
DR. LUCCIOLI: Thank you for the
170
clarification.
CHAIRMAN DURST: Are there any other
Committee comments?
(No verbal response.)
CHAIRMAN DURST: If not, thank you very
much.
Our next speaker is Dr. Rene Crevel,
senior scientist at Unilever, Safety and
Environmental Assurance Centre in the United
Kingdom. He will be speaking on the "Threshold
Modeling Approach."
THRESHOLD MODELING APPROACH
DR. CREVEL: Well, first of all, thank you
for inviting me to share some thoughts on the work
we have been doing on modeling thresholds.
(Slide.)
DR. CREVEL: You have asked me to talk
about the following, to look at different modeling
approaches including what is named the
"hyperallergen." This is the model, and the
Bindslev-Jensen, et al., allergen model; talk about
the data requirements and underlying
assumptions
171
behind them; and then say something about
interpreting the results of applying these models.
(Slide.)
DR. CREVEL: Now, just to take a step back
and think about why we are doing this, we've got a
challenge in allergen risk management as far as
industry certainly is concerned.
We want to protect allergic consumers of
course, but we also are aware that protecting them
by certain measures of risk management such as we
have heard about this morning like precautionary
advisory labeling does actually affect their
quality of life.
We want to minimize the effects on their
quality of life, the adverse effects on their
quality of life. We ultimately also want to
maintain economic operation of food manufacturing,
because if that doesn't happen, then that will
affect the quality of life of a considerable number
of individuals and people throughout society as
well. It is an important point to bear in mind.
(Slide.)
172
DR. CREVEL: How can we meet the
challenge? Well, first of all, of course we could
label where the allergen is present, and that is
fine. You have legislation over here now in the
U.S. for that; we have legislation in Europe; and
many other regions and nations also have
legislation.
(Slide.)
DR. CREVEL: Or, we can ensure that the
residual allergen content of product is low enough
to be harmless. I put in brackets here (to the
vast majority of allergic consumers), because we
have heard here this morning some instances of
people reacting to extremely low amounts.
I think it is questionable, and I think
the Committee must address that particular
question, whether those people can be protected by
whatever we can do in the food industry. We need
to think about what alternative measures may need
to be done, whether they can ever eat the sort of
foods we can produce.
(Slide.)
173
DR. CREVEL: How can we determine what is
harmless to an allergic consumer? Well, we have
several sources of data, which I have listed on
this particular table.
We can look at case reports from the
literature, and those we have heard. We have heard
about people reacting to very low amounts.
Unfortunately, the usefulness in risk assessment,
actually an allergen risk assessment in my view is
actually quite limited.
They do establish the hazard. Yes, they
tell you that a certain amount will affect some
individuals, will provoke a reaction in some
individuals. They don't tell you in how many
individuals that will happen.
We can use control challenge studies. In
fact, those of course provide the bedrock of what
is needed, the information needed in allergen risk
assessment because the population can actually be
quite accurately describe.
You can describe them in terms of the
symptoms
they have experienced, the allergological
174
history, or the medical history as appropriate --
all of the demographics that you can think about.
Finally, dose distribution modeling, which
I am going to spend obviously some time on, also is
very useful in allergen risk assessment. But of
course it relies on the experimental clinical data
which is generated in control challenge studies.
It cannot operate in a vacuum. We do not have
enough of those sorts of data at the moment.
(Slide.)
DR. CREVEL: I have been asked to say
something about the hypoallergenicity approach. As
I understand it, it is an unofficial standard for
designating infant formula as hypoallergenic.
The original reference I found goes back
to 1991, although I think the American Academy of
Pediatrics has actually updated or at least issued
the guidance more recently, I think, in 2000 or
something of that sort.
The statistics of this approach are based
on the binomial theorem, quite simply. This shows
that, for
instance, if you have a study with 29
175
participants, as we have already heard, and you
observe no reactions, then you can be 95 percent
confident that only 90 percent of the population
from which these people have been taken will not
react.
You can also extend that a bit, so if you
observed one reaction and you added people to the
study, then you would 46 for the same degree of
confidence.
If you wanted 95 percent confidence then
fewer than 99 percent would not react, then you
have got those other numbers which already become
very challenging, pardon the pun, for a challenge
study both in terms of recruiting the people do it,
to participate, and the economic cost of actually
doing it.
(Slide.)
DR. CREVEL: However, those are very
useful data when they are generated, but protecting
90 or 95 percent or even 99 percent of the allergic
population is not sufficient as far as we are
concerned
as an objective for the food industry.
176
What we asked ourselves is, How can we
improve this? There are several ways. We could
try to look at the conventional toxicological
approach and apply a safety factor to the lowest
observed adverse effect level or the no observed
adverse effect level as the case may be, if you've
got the no observed adverse effect level.
However, that particular safety factor, I
would say, would be arbitrary because we don't
actually know enough about interindividual
differences within the allergic population to apply
a science-based factor, I think. The level of
protection still is undefined. You do not know how
many people you are protecting by applying that
particular safety factor.
What about modeling of those distribution
of minimum eliciting doses? Well, that can
actually define the level of protection for
individual allergen level. You can actually use a
safety factor there. You can use something which
is like a lower 95 percent confidence interval
instead of
using the figure itself.
177
(Slide.)
DR. CREVEL: Does modeling actually work?
We asked ourselves could we fit a curve to the
distribution of minimum eliciting doses that are
generated by challenge studies, and could that
curve be useful to predict the number of reactions
likely to occur as a result of exposure to a
specified amount of inadvertently present allergen
in the food?
What I have to say, of course, is we are
not so much concerned about "declared allergen,"
people who are allergic can avoid that, but what
our concern is about is that which is present by
cross-contact, mainly inadvertently.
(Slide.)
DR. CREVEL: This just gives a very quick
model curve. It is just used to illustrate some of
the points, right, okay. From this particular
curve, okay, we have got the data points
schematically indicated like this. The dose on
this (indicating) particular axis an the proportion
of the
study population reacting here.
Obviously,
178
it goes up to 100 percent.
Then, you have these particular points,
which I have named "ED
50" here. This would be the
dose expected to provoke a reaction in 50 percent
of the study population or 10 percent. This
particular one is an extrapolation, one way of
extrapolating, which one could use.
(Slide.)
DR. CREVEL: What is the impact of the
choice of model on the predicted minimum eliciting
doses? I should go back a bit actually and say
something else.
We collaborated actually with
Dr. Bindslev-Jensen of Denmark in the initial
development of the model. At that particular point
we used the lognormal distribution. Having the
papers published and so on, after that we decided
to go back and look at a few more parameters and
try to refine this particular approach.
Good clinical data were available for egg,
milk and peanut. We fitted the data using the
following
statistical distributions and calculated
179
ED10s, the dose which would be predicted to cause
responses in 10 percent of the population; and
ED1s, in 1 percent of the population for each of
those. We used the following linear extrapolation
from lowest observed adverse effect level to zero
dose, which I showed you that was the red line; the
lognormal model, which was the original one in the
2002 paper; the Weibull model; and the loglogistic
model.
(Slide.)
DR. CREVEL: What I want to do is to
illustrate how these variously fit using the
different distributions. This is using real data
actually from the study by Wensing, et al., in 2002
on roasted peanuts. You have got the data points
here. That is still a normal fit, which is the
original one we used.
You can fit loglogistic pretty well as
well and the Weibull as well. You can even fit a
linear -- you can even correlate these points
linearly as well.
Although I haven't got the parameter fits
180
here, I can tell you that they are all pretty good
for all of those. Basically, the fit which you use
doesn't actually tell you which is the most
appropriate one for the particular distribution.
(Slide.)
DR. CREVEL: This is illustrated in the
differences between ED10s and ED1s between studies
and models. Now, this is just using data on peanut
actually from -- in this particular case, we are
just comparing the number of studies on peanuts
including studies performed by Bock and May in the
1970s and the later study by Wensing.
What is quite clear actually is for ED10s,
which are still within the experimental zone, what
I call the "experimental zone" in one of the
previous slides.
The data actually drives what the
predictions are. I mean, there is not a lot of
difference between the ED10s, even though it is log
scale, I know, even in this particular case.
(Slide.)
DR. CREVEL: When you move away
and go
181
outside of the experimental zone to the ED1 and
even further actually, the case is even stronger
beyond that, the actual choice of model starts to
drive the predictive responses. That is an
important point to bear in mind.
This is summarized on this slide for the
ED10s in the experimental zone, that the
differences between studies is greater than between
models. In order to address that, the best way of
doing that is to focus on standardizing protocols
and having consistent patient selection criteria
for the studies which you wish to undertake.
For the ED1 values, the differences
between models are much larger as I showed and
increase of course as we move further away from the
experimental zone.
What this actually illustrates is that you
need to validate the particular approach. You need
to validate whatever model you have chosen and
adjust parameters in accordance with that. What
I'm going to talk about is actually how we might go
about doing that, what sort of data is
needed.
182
(Slide.)
DR. CREVEL: Now, there are a certain
number of assumptions underlying the values
generated by the model. We are talking here about
undeclared allergen, and that is quite important in
relation to the one of these particular points.
First of all, we assume that the
participants in a controlled challenge study are a
representative sample of the whole allergic
population. That is a very important assumption,
and one which actually is sometimes shall we say
overlooked.
We have heard a lot about whether people
are included or not included in particular studies.
I would tend to argue actually that the population
used in challenge studies, because of the way they
are selected, is actually shall we say at the more
severe, more sensitive end of the allergic
population, basically because there are people who
actually normally are referred to tertiary care
centers.
There are people whose allergies are
183
actually troubling them. They are not people who
might just get a small rash and just ignore it or
ignore the particular food that caused it. There
are people who actually need to manage their
allergy and they need some serious advice in doing
so.
The second point is actually in terms of
validating the model the allergic people actually
eat the same foods as the non-allergics. In this
particular case, it is quite important because if
they are already avoiding them, the number of
reactions that you will be able to enumerate in
epidemiologic studies will not be the correct one.
The distribution of allergic reactivity
study at the population level, now we've heard
thresholds for individuals. Minimal eliciting
doses for individuals do vary. However, what we
are saying here actually is that overall it will be
studied in these particular challenge studies.
Finally, the responses to a given dose of
allergen are similar in the clinic to those
experienced
outside. We are doing some work
184
actually with Jonathan Hourihane, in fact, to try
to quantitate the differences that may exist
because, in fact, we are very aware that particular
assumption probably does not hold entirely.
(Slide.)
DR. CREVEL: Okay. What data do we
require for validation and application of a
modeling approach? We want to arrive at the risk
assessment. We have the hazard characterization.
I would put it to you that actually what we are
doing by the modeling approach is actually
characterizing the hazard. We are establishing how
many people are likely to respond to a particular
amount, and we use all of these. These particular
factors all influence it.
However, we also need to know the number
of allergic consumers. That is quite important in
terms of prioritizing allergen management and so
on. Effectively, what the legislation does is also
to acknowledge that particular fact.
The legislation either here, in Europe or
anywhere
else does not protect everybody because of
185
course it only specifies a certain number of major
common allergies rather than all of the 200 or so
foods that may provoke allergic reactions.
We also need to know what the exposure is.
We need to know what residual allergen levels are
in the foods, residual allergen levels that are not
declared. Finally, we also need to know what the
number of reactions is overall in the community.
Taking all of that together, we can
actually validate the model. Using those sorts of
data, we can also apply it properly.
(Slide.)
DR. CREVEL: To summarize, I think the
modeling approach complements clinical studies and
it certainly compliments clinical studies to
establish minimal eliciting doses. Of course, it
relies on the data generated in those studies.
I think the advantage compared to just
using the data as such is it actually permits more
complete use of those data using the whole dose
distribution rather than just one particular point,
say, the
lowest observed adverse effect level or
186
the no observed adverse effect level.
It also, I think, makes the whole process
of risk management more transparent, I guess you
would say, allowing a more informed discussion of
risk management objectives by all stakeholders.
That is very important I think.
In order to agree on objectives, I think
people need to know how or need to see the process
by which they are reached. However, and this is a
big proviso, it does require validation before it
can be fully operational.
We are doing work at the moment to see how
we can address that. Some of the data actually I
should say will contribute to this particular
assessment will be generated by some European
projects which are currently running, but of course
it will take a few years to get there.
That was my last slide. Thank you.
CHAIRMAN DURST: All right. It is open
for discussion.
Yes.
DR. BRITTAIN: That was a really
187
interesting talk. There was one aspect of it that
I'm a little --
DR. CREVEL: I'm sorry? I can't hear you.
DR. BRITTAIN: There is one aspect of it
that I'm a little confused by, and that was in one
of your last slides with all the graphics about the
needing to know the number of allergic consumers.
If you are trying to find the dose at
which the risk of a reaction, given you are
allergic, which is what I thought we were trying to
do, why do you need to know the number of allergic
consumers?
DR. CREVEL: Well, you need to know the
prevalence of the condition within the population.
In fact, perhaps the confusion is there isn't,
because I mentioned validation as well as
prediction in this particular context actually.
For validation, you certainly need to know
how many reactions are occurring in order to see
whether the model actually predicts the numbers of
reaction which you are actually observing.
I
mean, this is a big data gap at the
188
moment. I mean, I don't think either in the U.S.
and certainly not in Europe do we have data on
actually the number of reactions that do occur.
Certainly, we do not have any information on the
total number of severe reactions or less severe
reactions.
DR. BRITTAIN: You mean the number of
reactions that occur across a population as opposed
to your study?
DR. CREVEL: Yes. No, across a
population, sorry. Sorry, that was in the
population, sorry, yes.
CHAIRMAN DURST: Any further discussion or
questions?
(No verbal response.)
CHAIRMAN DURST: If not, thank you very
much, Dr. Crevel.
Our final speaker for this morning's
session is Dr. Steve Taylor. He is the Maxcy
distinguished professor and director of the Food
Allergy Research and Resource Program at the
University
of Nebraska, who will discuss Food
189
Allergen Thresholds.
FOOD ALLERGEN THRESHOLDS
DR. TAYLOR: Well, I would like to thank
the Food and Drug Administration for giving me the
opportunity to make a presentation to this panel.
There are advantages and disadvantages to being the
last speaker of the morning. Much of what you are
going to see on my slides may just be a reemphasis
of some things that have already been said.
I think I got a rather difficult topic,
also by being the last one on the agenda, because
I'm supposed to talk about uncertainty factors,
what are uncertainty factors and how are they
derived and what is the underlying scientific
rationale for such a factor. I only wish I thought
I knew the definitive answers to all of those
questions.
(Slide.)
DR. TAYLOR: I think the National Academy
of Sciences outlined risk assessment approaches a
number of years ago, and I always like to start
with this
slide, even though I'm not going to
190
discuss all of these different points, because I
think that the same assessment can be used for food
allergens as is used for pesticide residues and
food additives and other things. This is a very
robust risk assessment approach.
(Slide.)
DR. TAYLOR: I am only going to focus on a
few things on this slide today, and one is
dose/response evaluation. I have been thinking
about this issue for probably 30 years.
This is one of the earliest slides that I
created. At that point in time we didn't know very
much, and I would argue we only know a little bit
more now than we knew when I wrote this slide a
long time ago.
Trace amounts can elicit reactions. I
would argue that the severity of the response is
directly related to the dose. The higher the dose,
the more severe the response.
I would agree that individuals can have
different
responses on different days to the same
191
dose. However, I don't think those responses are
as dramatically different, or at least I would say
that is an unproven point regarding some of the
things that have been said this morning.
There are a lot of assumptions that are
made in this field, and I think as a panel you need
to identify all of the assumptions and question
them.
Stefano Luccioli made a good point, that
individuals vary widely in their degree of
sensitivity in these controlled challenge studies a
millionfold. I completely agree with that. That
is kind of amazing in itself.
The big question is, How much is too much?
The food industry has been focusing on trying to
get an answer to this question for a long time for
some of the reasons that Dr. Crevel just pointed
out.
(Slide.)
DR. TAYLOR: I think there is another part
that we haven't heard quite enough about, and Rene
kind of
pointed it out in his presentation. It
is
192
the exposure assessment piece of the equation.
How frequently are food products
contaminated with potentially hazardous levels of
unlabeled allergens, and how frequently do
food-allergic consumers suffer reactions? We
really don't know that part very well. Only
recently, as Dr. Hefle pointed out, do we have the
methodology necessary to determine with any degree
of confidence how frequently food products might be
contaminated and at what levels.
(Slide.)
DR. TAYLOR: Gil Houben from TNO [The
Netherlands Organization] prepared
this slide, and I always like to steal good slides
from speakers that I invite to be on programs. I
think this kind of pictorially describes the
situation that exists.
We have food products in the marketplace
that contained for one reason or another some level
of undeclared allergen. This may be from
cross-contact, this may be from use of ingredients
derived from commonly allergenic foods that are
processing
aids and historically haven't been
193
labeled in most countries.
Then, we have individual thresholds for
clinical response that varied by a millionfold as
Dr. Luccioli pointed out. There is an intersection
here between products that have enough undeclared
allergens that at least the most sensitive
individuals have some probability of reacting to
those.
If I was going to draw this slide myself,
I would lengthen the tail of this curve because we
know from analytical studies that there are
products in the marketplace that are quite
hazardous for these individuals containing
comparatively higher levels of allergens that
provoke severe reactions. Dr. Hefle showed some of
those data today.
(Slide.)
DR. TAYLOR: I wanted to say just a little
bit about the different kinds of clues that we can
have for determining allergen thresholds. Stefano
already pointed this out, too.
Probably the best data we have comes from
194
double-blind, placebo-controlled food challenges or
clinical threshold experiments using double-blind,
placebo-controlled food challenges and
immunotherapy trials that also use challenge data.
(Slide.)
DR. TAYLOR: I actually don't think that
allergen cross-contact episodes turn out to be very
useful in determining thresholds, and I wanted to
emphasize that point, because there is a lot of
anecdotal material in the clinical literature about
these cross-contact episodes.
A lot of them are deficient, because the
analytical methods used to detect the residues in
those studies were probably not as accurate as the
methods that Dr. Hefle described in her
presentation, the methods that we have had for the
last few years. There is often a lot of lacking
information in the investigation of these studies.
(Slide.)
DR. TAYLOR: As I pointed out, this
question of how much is too much has intrigued out
group for a
long time in the food allergy research
195
and resource program.
I want to point out that we are funded by
the food industry. We have more than 40-member
companies scattered around the world. We began to
focus on the threshold question in earnest in the
mid-1990s and beyond.
(Slide.)
DR. TAYLOR: We have held a series of
threshold conferences. The first one was held in
1999. I was asked to say a little bit about these,
and it is really hard to summarize it in 15 minutes
or less.
I will point out the fact that the results
of the First Threshold Conference have largely been
published in the peer reviewed, scientific
literature.
The question we asked at the First
Threshold Conference is we invited a number of
clinicians from around the world to come to South
Carolina, because we thought that perhaps they had
information on low-dose challenge trials.
When you hear studies of the kind that
196
Dr. Wood reported this morning, recognize that most
diagnostic challenges start at 400 to 500
milligrams.
No wonder some people have severe
reactions at those dose levels, because those are
quite high in my opinion. We were interested in
clinicians who sometimes, because of the patient's
history, started the challenge at a much lower
level.
(Slide.)
DR. TAYLOR: What did we find out? We
found out that there was considerable data on
low-dose challenges for peanut, egg and milk in
particular and more scattered data for some of the
other foods.
The data were really hard to evaluate
because of the lack of standardized protocols. I
will come back to that in a little bit. The lowest
provoking dose -- we had 306 patients for peanut,
281 patients for egg, and 299 for milk. These
physicians brought this data to this conference.
(Slide.)
197
DR. TAYLOR: The lowest provoking dose for
peanut was about 1 milligram of peanut, which is
.25 milligrams of peanut protein. However, I have
to tell you that Dr. Hefle and I spent an entire
weekend in the conference room trying to figure out
what the doses were in these challenge trials,
because the physicians don't calculate that,
particularly carefully in some cases.
Our personal favorite is the physician
that used a drop of peanut butter as his lowest
dose. We had him send us his dropper bottle and we
tried to figure out how much that actually was.
These data look really finite when you show them
this way, but there is a lot of glorified
guesswork. I just want you to understand that.
(Slide.)
DR. TAYLOR: We determined that minimal
eliciting doses or threshold doses do exist for
commonly allergenic foods, that the threshold doses
are finite, measurable and above zero.
However, it was really difficult to reach
consensus,
and we didn't reach consensus. We had
198
about 20 clinicians at this conference, and we did
not reach consensus on what threshold doses should
be.
In fact, for most of them this was their
first introduction to this concept. We had to
teach them what NOAELs and LOAELs were. They make
risk assessments every day but not these kind.
(Slide.)
DR. TAYLOR: We also found that reactions
occur to hidden or undeclared allergens in foods.
No big surprise there. However, severe reactions
to undeclared allergens tended to occur at higher
dose levels.
We also determined that at least in these
populations with these low-challenge doses that
low- or very low-dose exposures, LOAELs, result in
mild reversible symptoms.
(Slide.)
DR. TAYLOR: The Second Threshold
Conference was held in 2002 and was geared to
address the biggest concern we had from the first
one, and
that was a lack of a consensus protocol.
199
(Slide.)
DR. TAYLOR: I don't have time to describe
the consensus protocol other than to indicate that
it has been published; it does exist; and there are
ongoing low-dose challenge trials underway around
the world using this protocol or slight variations
of it.
As Dr. Luccioli pointed out, most of those
haven't been published yet because it takes a year
to two years to do these studies to find the number
of subjects to enroll in these studies.
(Slide.)
DR. TAYLOR: We did have the Third
Threshold Conference where we tried to determine
what you do with the data once you collect it.
(Slide.)
DR. TAYLOR: I won't go into that very
much, because much of it relates around the
modeling stuff that Rene Crevel already described.
Because the binomial approaches are just plain
difficult, because it is very difficult to identify
even 29
soybean-allergic individuals in the world
200
to do a challenge trial. Believe me, we've been
there, and we know how hard it is.
It is easier to do peanut trials than
perhaps others. It is hard to do milk and egg
because young children outgrow their allergies, so
you've got to be concerned that the child, the
patient, still has the allergy that you are looking
for.
(Slide.)
DR. TAYLOR: There were a number of
advantages to modeling. I think Rene pointed those
out. I will just make the point that the consensus
of the group was that you could do modeling. Of
course, you've got to figure out which model you
are going to use.
Maybe we haven't validated them yet so we
don't exactly know; however, using this lower
confidence interval as the threshold might be a
reasonable approach to consider.
(Slide.)
DR. TAYLOR: Well, classical risk
assessment
involves determining the NOAEL for a
201
food additive or a pesticide residue or something
like that and dividing it by 100.
Classically, tenfold is for extrapolation
from animals to humans, and tenfold is for
intraindividual variation. Consequently, what
uncertainty factor should we use?
(Slide.)
DR. TAYLOR: For allergens, since you have
human subjects that can be used, the ideal thing
would be to determine the no observed adverse
effect level for specific allergenic foods among a
human population that is allergic to that food, and
then apply an uncertainty factor to get your
threshold dose.
(Slide.)
DR. TAYLOR: To do that with any degree of
confidence, you have to challenge a fairly large
number of allergic individuals. You would have to
identify the NOAEL for each patient.
You would probably also have to identify
the LOAEL for each patient to prove the person is
still
allergic to the food that is under
202
consideration.
It would be good to determine the
variation between individuals in NOAELs because it
is probably a millionfold. A standardized protocol
would be handy so that you didn't have uncertainty
about the differences in protocols.
(Slide.)
DR. TAYLOR: There is no animal to human
extrapolation needed for food allergy
considerations because we have human data. We have
already selected a sensitive subpopulation of the
human population.
The question arises, Did we include the
most sensitive individual? I think that is an
important consideration for this panel. We have
heard several speakers say, "Well, maybe we have
not."
My argument is that perhaps in terms of
representing the whole allergic population to a
particular food we have actually excluded the other
end of the dose distribution curve, and we actually
have
included a number of people from the most
203
sensitive subpopulation.
(Slide.)
DR. TAYLOR: I want to point to this study
again. People have interpreted this study as a
publication involving the dose distribution for the
whole food-allergic group allergic to peanuts,
eggs, and milk. It is not that; it is a study of
the most sensitive individuals in clinical
population.
(Slide.)
DR. TAYLOR: Well, how much data is out
there? Is there enough data to make your
decisions? I think there can be if you can wrestle
with the uncertainty factors and the differences in
protocols from one study to another.
I just went through what I think is the
most relevant literature. Some of these are in
your "FDA Report," which contains a big table at
the back that somebody very laboriously put
together. I think they actually found most of the
relevant studies.
I
congratulate them for that, because that
204
is not particularly easy to do. I went through
those studies and added up the number of patients
that are in each one of these studies that were
subjected to double-blind, placebo-controlled food
challenges and for which a published LOAEL exists.
Now, there are lots of differences in
protocols, so there are uncertainty factors with
how to plug this data into one of Rene's curves.
What you can see is there are lots of subjects.
This is for peanut. Note, I put an asterisk by our
2002 paper, and that is because that is not
original data. Some of those patients may also
appear in some of the other studies. We got
concerned about whether to count them twice.
(Slide.)
DR. TAYLOR: This is for egg.
(Slide.)
DR. TAYLOR: This is for milk.
(Slide.)
DR. TAYLOR: We have got a lot of data
points. What are the uncertainty factors? Well,
you've got
adults, adolescents, children, infants.
205
Many of the studies have been done on pediatric
populations; fewer studies have been done on
adults. You can do challenge trials on both of
those. A lot of the diagnostic challenge trials
are done on infants, but they are not done in
threshold study types of experiments.
(Slide.)
DR. TAYLOR: You've got the problem with
the nature of the challenge material and the
allergen content of that challenge material. This
is again from our 2002 study from Threshold 1.
You can see the number of different
materials: ground peanut, peanut flour, peanut
butter, egg white, dried egg white, whole egg,
dried whole egg, and raw versus cooked for most all
of those. Then, you've got whole milk, non-fat dry
milk and even infant formula as the milk challenge
materials.
In many of these cases, the physicians
didn't determine the protein content of the
challenge materials, so you've got to make
glorified
guesses. There are uncertainties about
206
the challenge materials.
(Slide.)
DR. TAYLOR: I would argue that studies
should be compared using protein content. This
failure to provide that data makes the evaluations
really difficult. If the protein content of the
challenge material was not determined or cannot be
determined using reliable data in the literature,
then the study probably has to be rejected from
consideration by groups like this.
There are well-characterized challenge
materials like non-fat dry milk, dried egg white
and soy flour that I think you can assume what the
protein level is based on standardized industry
data. Thresholds should be established in terms
that can be related to analytical methods like
milligrams of food or milligrams of food protein.
(Slide.)
DR. TAYLOR: There are also issues related
to blinding that Stefano already talked about.
Some clinicians use labial challenges. They put a
drop of the
food on the patient's tongue or lip.
207
That is often used for young infants.
I think that is particularly difficult to
interpret what the dose was. However,
diagnostically it is good procedure, but otherwise
it is kind of difficult to figure out what was
going on. Then, there is the choice of dosages
used for the challenges.
Probably the biggest uncertainty is this
issue of the fact that most of the publications
were done for diagnostic purposes, and so when you
look at the published literature you get the LOAEL
and not the NOAEL. I actually think a lot of the
NOAELs are clinically available; they are just not
published.
There is more uncertainty in using a LOAEL
rather than a NOAEL to established threshold doses;
there is patient selection criteria; exclusion of
people on probably both ends of the curve; and
there is variability in individual threshold doses.
Diagnostic challenges tend to report only
the LOAELs; the NOAELs in some cases may not be
recorded. As Dr. Wood pointed
out to us in his
208
study, in many cases the patient reacted to the
lowest dose administered.
However, if it was 400 or 500 milligrams,
that is a pretty sizeable dose. I think there is a
lot of uncertainty if you use that as your LOAEL to
try to try and figure out what the threshold dose
might be. You are much better off to focus on
lower dose challenges where there is less
uncertainty even if you have to use the LOAEL.
How far above the NOAEL is the LOAEL; and
if using a LOAEL, how big should the UF be? I
think that is the question that they wanted me to
try to answer.
(Slide.)
DR. TAYLOR: I got bold and I did try to
answer it. If the LOAEL is based on subjective
symptoms, "My mouth itches," then I don't think we
have to be very concerned about uncertainty
factors, because in the limited experiences that
exist in the literature there is a ten- to a
hundredfold variations between the doses that begin
to provoke
subjective symptoms and the doses that
209
tend to provoke objective signs. I learned
something today. I'll try to say "signs."
Now then, if you have a LOAEL based on
objective reactions, what uncertainty factors
should you use? Well, then I think you would need
to have very careful expert analysis of the
clinical study you are looking at.
I could argue that if you looked at one of
these clinical threshold trials that have been done
using microgram and low-milligram dose level, that
you could use a very low uncertainty factor.
However, if you are going to rely on
publications like Perry, et al., from 2004 where
you only have data on the reactions that occur at
the lowest diagnostic challenge dose and it is 400
or 500 milligrams, then you've got a much bigger
uncertainty factor because you could be a long ways
above the NOAEL.
I don't know what you would do in this
particular case, so I put a question mark by it. I
actually think those kinds of studies are not very
helpful.
210
In fact, if you read Perry, et al., they
don't tell you what the lowest challenge dose is.
I just think they follow the standard protocol, and
it is 400 or 500 milligrams. Obviously, if you had
NOAELs, that would be better yet.
(Slide.)
DR. TAYLOR: Well, what about this patient
selection issue? I think that is another key
uncertainty. I'm not sure that the published
diagnostic evaluation are representative of the
whole population of allergic individuals.
Someone mentioned that this referral
clinic bias, if the go to a referral clinic, then
they are more seriously affected individuals in the
first place.
Those are the ones that we tend to publish
data on, and even we tend to publish data on
individuals that are selected from that population
because their history suggests they may react to
lower doses.
I would say that the clinical threshold
studies
that are published in the literature are
211
distinctly skewed toward the more highly sensitive
patients.
Now, have some people actually been
excluded from diagnostic evaluation and clinical
threshold trials? Yes. People with history of
severe allergic reaction, people with histories of
unstable asthma.
There is no way you can involve an
unstable asthmatic in one of these trials; they
will react to everything you do including the
placebo. In all likelihood, the ethical thing to
do is to see if you can get their asthma under
control.
Some physicians exclude severely affected
individuals, but I think it is discoverable to
figure out how many. I think this panel needs to
know the answer to that question.
Is that 1 percent of the population,
5 percent of the population, .1 percent of the
population? I think that is discoverable, but we
don't have the information.
(Slide.)
212
DR. TAYLOR: I present this information to
you because I think it is very relevant. This is a
paper from Scott Sicherer and Hugh Sampson and
Hugh Sampson published a few years ago. I only
picked out the soy allergic data from this paper.
It is a double-blind placebo. They
purport data similar to that in Perry, et al. It
is a double-blind, placebo-controlled food
challenges of 53 soy-allergic people. I wanted to
point out that 28 percent reacted to the first
dose, which was 400 or 500 milligrams. Although,
good luck figuring out how many it was 400 and how
many it was 500; it is not in the publication.
Fifty-three percent reacted at some
intermediate dose and 19 percent reacted at the
final dose, which was either 2 or 2.5 grams or an
open challenge with like 8 grams.
That tells you that there are a lot of
individuals that are in these very high dose
ranges, at least for soybeans, that is their
individual threshold doses. We tend to focus on
these
people, but just remember this is 25 percent
213
of the population.
(Slide.)
DR. TAYLOR: Another deficiency with this
paper is they don't tell you whether the milligrams
are soy protein or soy flour, so I'm not sure. It
is probably soy flour, but that is just a guess.
Then, this is a study from the French group,
Moneret-Vautrin's group. I just wanted to show
this to point out that the levels, the individual
threshold doses for individuals, can vary
enormously in big, clinical trials. This was 103
individuals.
(Slide.)
DR. TAYLOR: Have they been severely
affected? People have been excluded from challenge
trials? Do they have lower or minimal eliciting
doses? Do they experience severe reactions at very
low doses? Or, are they simply individuals who
have made big, dumb mistakes in their avoidance
diets? I mean, I think that is a considerable
possibility.
(Slide.)
214
DR. TAYLOR: This study was mentioned,
Jonathan Hourihane's study. He took individuals
with asthma and without asthma and those with
food-induced asthma are more likely to have a
severe reaction. That is pretty well documented.
You can see that there is not a big
difference in threshold doses for asthmatics and
non-asthmatics -- a little bit of difference down
here, but it is not all that dramatic compared to
the other uncertainty factors.
(Slide.)
DR. TAYLOR: Now, Wensing's study gets
mentioned a lot, too. The thing I want to point
out here is there are only five subjects in this
study that had objective symptoms. For all of the
others, Wensing, et al., stopped the study with
subjective reactions, "My mouth itches." That is
going to have a big impact on the minimal eliciting
dose.
They did look at people who had histories
of severe
reactions versus people who had histories
215
of mild reactions. Remember, most of these are
subjective reactions. You can see that maybe there
is a 10- to 100-fold variation amongst these
individuals.
(Slide.)
DR. TAYLOR: In conclusion, I would say
that there is a lot of uncertainty factors. I
think the biggest ones are the use of LOAELs versus
NOAELs in the published information and the patient
selection biases in these studies.
I do think we have a lot of information
out there in the clinical literature, but whether
that data is that of an appropriate form to allow a
regulatory agency to make a reasonable decision,
I'm not sure.
I do know that there is lots of clinical
threshold trials underway around the world, that
within a few years we will have more data done with
a consensus protocol or some minor variation of
that, and that might make some of this easier to
interpret.
Thank you.
216
CHAIRMAN DURST: Thank you.
Are there any questions or discussion for
Dr. Taylor?
(No verbal response.)
CHAIRMAN DURST: All right, I guess not.
Thank you, Dr. Taylor.
Marcia Moore has an announcement to make.
MRS. MOORE: I guess that is the hardship
of going just before lunch as you said.
(General laughter.)
MRS. MOORE: For the public comment period
that we have at 2:15, can I see a show of hands of
the folks who are here right now for that and will
be speaking. If you could stay when we break for
lunch for about 5 to 10 minutes, it appears that
several of you didn't get the full instructions.
We want to go over the instructions with you for
that.
That's all I have.
CHAIRMAN DURST: Okay. Thank you very
much.
I
guess if there is no further discussion
217
at this point, we will break slightly early for
lunch and reconvene at 2 o'clock as the schedule
indicates.
Thank you very much.
(Luncheon recess.)
218
A F T E R N O O N P R O C E E D I N G S
CHAIRMAN DURST: Before we begin our
public comments, we have one final presentation,
and that is by the lead author of the document that
we are discussing today, and that is Steve Gendel.
Dr. Gendel is a senior scientist in the
National Center for Food Safety and Technology of
the FDA and he will describe the overview of
approaches to establishing thresholds for
allergens.
Steve.
OVERVIEW OF APPROACHES TO ESTABLISHING
THRESHOLDS: ALLERGENS
DR. GENDEL: Thank you. I guess I would
like to start by acknowledging that I am aware of
the awesome responsibility that goes with being the
first speaker after lunch.
(General laughter.)
DR. GENDEL: I am going to try and be
quick before everybody has a chance to drift off.
Also, the purpose of what I'm doing here, since the
report has
been out for several weeks and I'm sure
219
that everybody on the Committee has had a chance to
review it in great deal, I'm not so much going to
present an overview as a refresher or a reminder
for you as to what is in it specifically today on
the parts related to food allergens, with the idea
of sort of setting the stage leading into the
discussion for the Committee later this afternoon.
(Slide.)
DR. GENDEL: To start, what I would like
to do is look at the purpose of the report, why we
wrote it. This is important for the Committee to
think about because the purpose of the report was
to identify approaches that could be used to
establish thresholds for the major food allergens
and for gluten, with the emphasis on "approaches."
The report was not intended to make a
decision about whether to establish thresholds or
to choose an approach, and it was not aimed at
discussing thresholds for individual allergens. We
were interested in identifying the approaches that
are available and looking at the advantages, the
disadvantages and the data needs for each approach.
220
It is something to keep in mind when we look at
what the contents of the report, the "Draft
Report," actually are.
(Slide.)
DR. GENDEL: The overall organization is
fairly straightforward. The mandatory introductory
material which in this case put the report in
context as to why we were doing this and how this
relates to the FDA's mission, then there was a
scientific review of what was known about food
allergy and celiac disease, and then discussions of
the approaches that they Working Group identified
for establishing thresholds, so very
straightforward.
(Slide.)
DR. GENDEL: In terms of the scientific
review of food allergy, we considered a lot of
factors, some of which are listed here and there
were some others beyond this.
Two points I think to bring out are under
the area of exposure. We did talk about the
effects of
processing on allergens, how that
221
affects both consumer responses to the substances
and also we discussed the methodology related to
the detection and quantitation of the major food
allergens, and, again, how processing affected
that.
Then, as Dr. Taylor mentioned, we spent
some effort at trying to identify and discuss the
clinical literature, the published challenge
studies, which are the fundamental basis for any
discussion of understanding how the allergic
consumer responds to these foods.
(Slide.)
DR. GENDEL: In terms of the approaches
that we identified, there were four of them that
the Working Group identified: analytical
methods-based, safety assessment-based, risk
assessment-based, and the statutorily derived
approach. I'm going to say a couple of words about
each of these as we go along.
The analytical methods-based approach is,
as the name implies, one in which any thresholds
are established
based on the sensitivity of the
222
methods available.
This approach is useful for those
allergens where validated methods are available,
but the Committee was cognizant of the fact that
this method, this approach, is not linked to public
health outcomes or public health concerns directly.
The safety assessment-based approach is
one which we have heard a lot of discussion of this
morning. In this case, it would involve using
published values for LOAELs or NOAELs as the basis
for establishing thresholds and applying
uncertainty factors.
As we heard, the appropriate uncertainty
factors would be dependent upon the gaps that were
identified in the data, how much data was
available, and what was contained in that data
would determine what the appropriate uncertainty
factors would be. This is an approach which has
moderate data needs.
The risk assessment-based approach, on the
other hand, is one which would use clinical
response
distribution data, that is, information on
223
responses across the whole spectrum of
concentrations of allergen.
We were referring to this in the
quantitative sense of quantitative risk
assessments, where by the use of modeling and other
techniques such as we discussed before, the
approach could be used to derive quantitative
estimates of risk and of the associated uncertainty
at any particular level you might be interested in.
This is scientifically a very powerful
approach, but it is also an approach which has the
greatest data needs. Again, this morning we heard
some discussion about what those data needs are and
what the limitations of the available data are.
Finally, the statutorily derived approach,
the statutorily derived approach is one in which
thresholds are determined based on language that
appears in a relevant law as promulgated by
Congress which is then used to extrapolate
thresholds from that language.
In the case of the FALCPA, there is
language
which exempts highly refined oils from the
224
labeling requirements, so the statutorily derived
approach could be used the same based on protein
levels in those highly refined oils. Those levels
could serve as the basis for establishing
thresholds in other foods besides the
highly-refined oils.
This approach is also one in which the
links between any potential thresholds and public
health issues and public health outcomes is not
clear, although it is an approach that could be
used.
Based on the review of food allergy that
was present in the "Draft Report" and based on the
discussion of the approaches that we were able to
identify, the Working Group came out with five
findings related to food allergens.
The first one, which I think is an
important point to make, is that whatever decisions
are made regarding the establishment of thresholds
and the approaches that might be used to establish
thresholds and any thresholds that might be derived
using these
approaches need to be reevaluated
225
periodically and probably frequently as new data
and analysis methods become available.
We heard a lot today about ongoing
clinical trials, ongoing studies, developments and
new methods, so whatever decisions are made now
need to be reevaluated as these new data become
available.
Secondly, the Working Group found that the
analytical methods-based approach could be used to
establish thresholds for allergens, if the
validated methods were available.
However, we felt that if this method is
used, it should be replaced by thresholds
established using one of the methods with a link to
risk and public health as soon as that is possible.
The Working Group found that the safety
assessment-based approach is a viable approach for
the major food allergens using published LOAELs or
NOAELs, using a standard of the initial objective
symptoms in clinical trials as the basis for
determining LOAELs or NOAELs, and, as I mentioned,
appropriate
safety factors which would be
226
determined by analyzing the literature.
The risk assessment-based approach is,
obviously, potentially the strongest scientifically
of the different approaches. We realize that this
approach is one which is just now being applied to
allergens for the first time, and we still feel
that there is a need for more data and more
analysis of the appropriate assessment tools,
modeling tools, and ways of analyzing the data at
this time.
Finally, the statutorily derived approach
could be used to set thresholds, but based on the
levels of proteins that are found in the highly
refined oils it is possible that this approach
would provide thresholds which are unnecessarily
protective of public health.
We felt that the Working Group felt that
if this approach was used, that the results should
be reevaluated again as soon as possible when the
data became available on the methods for using one
of the risk assessment-based approaches for
establishing thresholds.
227
That is, briefly, the reminder of what is
in the report.
QUESTION-AND-ANSWER SESSION
CHAIRMAN DURST: Are there any questions
or comments for Steve at this point? I'm sure we
will involve him in our discussions later.
Yes.
DR. BRITTAIN: This is Erica Brittain. I
want to commend the group together that put
together the report. It is really easy to read and
very interesting. One part of it that I found a
little confusing that I didn't really understand
was the analytical method.
Am I correct or not in understanding that
to be basically the level of detection? If
something is below the level of detection, it would
be considered a threshold, or have I misunderstood?
DR. GENDEL: Yes. Basically, as I said,
the idea was we were trying to identify all the
available approaches. As we mentioned in the
report, there are some examples where effectively a
threshold
has been set at the level of detection of
228
the methods available.
DR. BRITTAIN: Thanks.
CHAIRMAN DURST: Anything else for Steve
while we've got him up there?
(No verbal response.)
CHAIRMAN DURST: Okay.
DR. GENDEL: Thank you.
CHAIRMAN DURST: Thank you, Steve.
I guess now we can get into the public
comment part of our program. We have a number of
speakers lined up. Just as a reminder, each
speaker will have three minutes, and then the hook
comes out.
(General laughter.)
PUBLIC COMMENTS
CHAIRMAN DURST: There will be additional
time for questions beyond the three minutes. Okay,
our first speaker will be Tracy Atagi from the Food
Allergy Anaphylaxis Network.
MS. ATAGI: Hello, my name is Tracy Atagi.
I am actually not from FAAN, I'm a member, but I'm
speaking
here for myself. I am a mother of a
229
six-year-old boy with a severe peanut allergy.
I am speaking here today because I have
four specific concerns with the methodologies that
are discussed in the draft paper. Due to time
constraints, I will try and summarize these
briefly, but I hope the Committee will also
consider my longer written statement.
My four concerns are, first, the draft
paper fails to consider sensitization as a health
endpoint of concern. Second, the oral challenge
data are unacceptably biased, because they are
likely to only represent the least allergic
individuals excluding not only the most sensitive
individuals but also your average allergic
individual.
Third, contrary to the findings of the
"Draft Report," the use of initial objective
symptom is not generally protective.
Fourth, the proposed methodology for the
statutory based threshold does not meet minimum
data quality requirements. The data on oils with
no
detectible protein were arbitrarily excluded and
230
the data on protein levels that were included in
the paper appear unrelated to highly refined oils.
The issue of sensitization is important
because without sensitization there is no food
allergy. Parents of children with a family history
of food allergies are advised to delay introduction
of allergens to help the immune system develop
fully.
When I read labels, I read it both for my
allergic son and also my, hopefully, not allergic
daughter. For my son, it is a matter of life and
death. He has had an anaphylactic reaction. I
hope never to see that again.
However, it is also in a way a matter of
life and death for my daughter, because if delaying
introductions of an allergen can keep her from
developing that food allergy, then the risk to her
life is greatly reduced. Thus, I would urge the
Committee to consider sensitization as a possible
health endpoint for the health-based methodology.
Apart from the issue of sensitization, the
safety
assessment-based threshold contains serious
231
biases. The "Draft Paper" explains that the oral
challenge study data are used for diagnostic
purposes, but fails to reach the obvious
conclusion.
Individuals who would volunteer for these
studies are those whose initial diagnoses are in
doubt. In other words, these individuals who are
volunteering are likely to be the least allergic in
the population, not only are the most sensitive
individuals like my son not included but also your
average allergic individual.
This bias is compounded by the
recommendation that the threshold be based only on
the initial observable symptom -- I'm sorry,
objective symptom.
As the draft paper notes, a particular
dose could result in mild symptoms on one day and
life-threatening reactions the next. Excluding
data on subjective symptoms is unprotective, given
the range of reactions even within the same
individual.
Finally, the methodology on the
statutory
232
derived approach is fatally flawed. The draft
paper offers no evidence that the oils examined in
the study are highly refined, and the decision to
exclude all oils with no detectable protein appears
arbitrary.
Frankly, I would assume that oils that
have no detectible protein would be the only ones
that would meet Congress' intent in exempting
highly refined oil. Instead of using protein
levels in different oils to define the threshold,
FDA should use the lack of protein in an oil to
define whether it has been highly refined.
Thank you very much.
CHAIRMAN DURST: Thank you.
Are there any questions or comments?
(No verbal response.)
CHAIRMAN DURST: Okay. Well, we will move
on.
Our next speaker is John Carroll of the
Enzyme Technical Association.
MR. CARROLL: Good afternoon. I am from
the Enzyme
Technical Association. I am the current
233
chairperson from that group. As you can tell from
the title of the association, this is about
enzymes, which are Mother Nature's wonderful and
ubiquitous tools.
I wish to thank you for letting us,
allowing us, to give a brief presentation here
today. We also wish to thank and compliment the
Committee and the FDA for this effort here.
Anybody who is at all looked at any of this stuff,
and we have tried for a year or two, this is a
complicated, complex area, a full gamut including
emotion. This is a very difficult task that you
have, but we know that our FDA is up to it.
We are going to talk about where enzymes
fit and the view of the Enzyme Technical
Association. We put this in a question-and-answer
type modality.
Our first question is, Where do enzymes
fit within the scope of allergen labeling as
defined by FALCPA? Our answer, after quite a
lengthy period of trying to evaluate this is, no,
they don't
fit.
234
After reviewing FALCPA, after looking at
the "Draft Report," which is excellent, plus a
multitude of allergen literature, we have come to
the conclusion that enzymes do not fit, and here is
why.
Enzymes are not proteins within the Big 8
allergens. Some enzymes, but not all, are
manufactured using fermentations in which raw
materials obtained from one or more of the Big 8
are used to feed the microorganism from which the
enzymes are extracted.
Enzyme products obtained from
fermentations are not directly derived from the Big
8 list. They are derived from microorganisms fed
on media that may include protein from one or more
of the Big 8 list.
Furthermore, enzymes are normally purified
to remove the biomass and to achieve a certain
concentration. Why are we here today? is our
second question. Why is the Enzyme Technical
Association here today talking to the Committee?
Well, the Enzyme Technical Association has
235
been asked whether enzymes need to have allergen
labeling, because the enzyme industry uses some of
the Big 8 allergens for enzyme production, as I
explained, as food for the microorganisms.
While ETA is convinced that FALCPA never
intended to regulate the labeling of enzymes, as an
as association we are prepared to share the
information we have collected to support our
conclusions.
We would also like to point out in the
form of a question, What is the policy of other
regulatory bodies in the international arena? The
United States, like every country, tends to think
we are the center of the world; it is not true.
There are other people who, as we have
heard today, have addressed this question. They
have actually addressed it also specifically in the
case of enzyme products.
The U.S. needs to understand that both the
EU and Japan, the regulatory bodies in those
countries, have concluded that enzymes are not
required to
have allergen labeling.
236
CHAIRMAN DURST: Your time is up. Can you
conclude?
MR. CARROLL: This is the last point.
Indeed, the European Commission Health and
Consumer Protection Directorate has clearly stated
that enzymes are outside the scope of their
Directive 2003, which was November 2003, a similar
directive, very similar to FALCPA.
Thank you.
CHAIRMAN DURST: Well, I have a question
as far as the enzymes. Are they used in a way that
they can be considered a food? Are they in a form
that is eaten, or are they just used then as a
method of processing?
MR. CARROLL: They are used as a method of
processing. As it sounds like you're aware, they
are used to catalyze reactions, biocatalysis. They
are used as processing aids. They are used at
levels, like any catalyst, that are very low.
Roughly, the enzyme protein in a normal
process would be at a maximum of 1 part per million
of the
enzyme protein itself. Part of the
nature
237
of that is the nature of biocatalysis that they use
at very low levels.
CHAIRMAN DURST: Okay.
MR. CARROLL: No, they are not an
ingredient. They are not part of the food, per se;
they are processing aids.
CHAIRMAN DURST: They are purified so that
initially they have small amounts of any
potentially allergenic proteins, and then in
addition they are used in even smaller quantities
in the processing, or they come through in--?
MR. CARROLL: If you step through it, the
first thing is any allergenic protein that might be
part of the raw material used, of the fermentation
that is being used, is food. The first thing is it
is consumed.
We are trying to make enzyme protein.
Just like you and I at lunch are trying to make
hair or skin or human protein, we are trying to
make enzyme protein. That is our business; and if
we don't do it, we lose.
Then, the next step is we are talking
238
about purification of the biomass of any residue
non-enzyme protein material because that is our
interest is that enzyme activity.
Furthermore, if you look down, it is the
way a biocatalyst is used. They are used at very
low levels and that is why they are not typically
ingredients. They are processing aids to achieve a
reaction, to achieve an effect. They are not in
the final product for a purpose --
(Simultaneous discussion.)
CHAIRMAN DURST: Do you perceive that
there would ever be a situation where their level
of allergenic protein would be at a point where
they would be considered an allergen in a food?
MR. CARROLL: We have looked, and that's
why we said we are willing to talk with FDA about
our overall analysis. However, the levels that we
are talking about are orders of magnitude below
anything we've heard today.
CHAIRMAN DURST: Okay.
Did you have one?
DR. MALEKI: Yes.
239
Just a comment as far as I know, to the
best of my knowledge, they haven't been reported as
allergens, enzymes that are used in processing.
Most of the allergens are pretty well characterized
-- well, not necessarily characterized but groups
of enzymes or proteins that fall under that
category of allergens have been recognized.
As far as bioprocessing, I don't think,
and one of the clinicians can probably comment on
that, but I have not heard of a reported reaction
to something like that.
MR. CARROLL: We have looked into the
literature, and there are no cases of enzymes as
food allergens. They are not basically food
allergens. They are ubiquitous.
DR. MALEKI: In foods, I realized that
they are used very ubiquitously. I think if there
was a reaction, that they probably would have been
reported.
MR. CARROLL: Also, in the apple --
actually if you eat some nice, raw vegetables
today, you were taking in all sorts of DNA
and
240
enzymes, that is where we are at. We are just
actually using Mother Nature's tools for specific
applications.
Anything else?
DR. KELLY: Yes, a question.
MR. CARROLL: This is great (laughter).
DR. KELLY: Do you want to make the point
that enzymes should be outside of the exemption
standards?
MR. CARROLL: I guess the easiest way to
capsule it is out of the scope of FALCPA. It is
not intended to be part of it, because we are not
ingredients.
DR. KELLY: You would prefer not to engage
in the notification process?
MR. CARROLL: Right, I mean, I don't think
it is actually appropriate in this case.
DR. KELLY: How does that differ from
sharing your data with the FDA?
MR. CARROLL: Well, we can share it in
terms of showing them how we got to this
conclusion.
241
DR. KELLY: Isn't that what the
notification process consists of?
MR. CARROLL: No. I think in this case it
would be more appropriate to be ready to meet with
them to show were we are. I think it is so
straightforward that it is not -- that would be a
misuse, I think, of the system.
DR. KELLY: Yes.
MR. CARROLL: I mean, they are going to be
very busy getting this right. From what I see --
and I've actually tried to study this also
personally, taking it as a hobby, it is quite a
fascinating area -- this is a hard job. I think it
would be disingenuous to use even the
administrative system for such a case.
CHAIRMAN DURST: Could you put some
information together for the Committee as far as
these points that are being raised? I think at
this point we are getting off track, and we want to
get back onto the main thrust of our work, and that
is, the consideration of the different approaches
for setting
the thresholds.
242
MR. CARROLL: Right, I agree.
CHAIRMAN DURST: Thank you very much.
MR. CARROLL: You're welcome.
CHAIRMAN DURST: All right. Our next
speaker will be Diane Castiglione from the Food
Allergy Anaphylaxis Network.
MS. CASTIGLIONE: Good afternoon. My name
is Diane Castiglione. I promised myself I wasn't
going to do this (weeping). Oh, well.
My 13-year-old son is allergic to milk,
eggs and wheat. While I know that gluten is the
subject for tomorrow's hearings, I should also note
that I have celiac disease and maintain a
gluten-free diet.
My son's allergies were diagnosed shortly
before his first birthday. The message from his
allergist was clear. He must avoid all foods
containing milk, eggs and wheat. This task is even
more daunting and challenging than it sounds,
especially given the prevalence of milk and wheat
in food products.
Fortunately for me, Michael was so young
243
that he had barely started to eat table food. I
was able to do my research before I introduced new
foods to him.
Since his initial diagnosis, a lot has
been accomplished with regard to food allergy
awareness, and I have been pleased to see the
voluntary efforts made by food manufacturers with
respect to identifying allergens on their labels.
However, at the same time the hodgepodge
of labeling methodologies create a confusion for
those of us who depend on the accuracy, clarity and
transparency of these labels (weeping).
When a product that my son has been eating
for years without any problems suddenly begins to
carry a "may contain" statement, more questions are
raised in my mind rather than less.
Has there been a change in the ingredients
or in the processing? Has the allergen always
potentially been present in the product without my
knowing it? Or, the skeptic in me wonders has
nothing changed, and the statement merely reflects
a lawyer's
concerns about potential lawsuits? I
244
must make the difficult decision of continuing to
purchase the product or removing it from my son's
already limited diet.
I cheered when the new labeling law was
passed. At last some rationality and clarity would
be established so that I could read food labels
with confidence. My life would be simplified at
least a little.
However, the subject of this hearing
raises doubts in my mind and makes me uneasy. How
will these thresholds be established? What will it
mean if an ingredient falls below the threshold
levels? Will manufacturers begin to implement
their own set of statements resulting in a
hodgepodge similar to that which exists today? How
am I then to interpret those statements?
When I told my son about today's hearing
and asked his opinion, after all he is the one who
lives with allergies, he told me that if an
ingredient list on a product that he consumes
suddenly included something to which he is
allergic,
while he might regret having to give up
245
the product, he would not have a problem doing so
as long as he knew that the label was based on
established fact.
While we know that the medical and
scientific communities have not yet established
specific universally applicable thresholds, I think
my son's comments raise two key points about this
process.
The process of establishing thresholds
must be transparent. The thresholds must be
clearly defined so that all manufacturers are held
to the same standard. The question of how to
handle products in which the allergen falls below
the threshold must be addressed in order to avoid
the development of inconsistent disclaimers on
packaging such as currently occurs.
Food labels are our lifeline. We depend
on them for the health, safety and well-being of
our children and ourselves. When reading a label,
there should be no doubt in our minds as to its
veracity and accuracy.
There should be no doubt in our minds as
246
to the motivation and rationale behind any
statements regarding the ingredients and/or the
processing of the product.
There should be no doubt in our minds that
we are consuming a product that is safe for us. If
the new law does achieve its desired effect, we
need to ensure that its implementation does not
replace one state of confusion and distress with
another.
Managing food allergies on a daily basis
is challenging. Please help us to take a step
closer to reducing that challenge and to make the
lives of those with allergy simpler and therefore
richer (weeping).
Thank you for your time.
CHAIRMAN DURST: Thank you.
Any comments or questions?
(No verbal response.)
CHAIRMAN DURST: Thank you very much.
Our next speaker is Barbara Desa from the
Food Allergy Anaphylaxis Network.
(No verbal response.)
247
CHAIRMAN DURST: Okay. She is not here,
so we will move on.
Will Duensing?
(No verbal response.)
CHAIRMAN DURST: Let's see, I don't have
his affiliation.
Bunge Milling on behalf of the North
American Millers' Association.
MR. DUENSING: Mr. Chairman and Committee
Members, thank you for this opportunity and good
afternoon. My name is Will Duensing, and I am
director of Quality Assurance and Technical
Services for Bunge (pronounced Bun-gee) Milling, a
large dry corn milling company with mills in the
United States, Canada and Mexico. I am also here
today, however, representing the North American
Millers' Association as chairman of the Technical
Committee.
"NAMA," as it is called, is a trade
association representing the wheat, corn, oat and
rye milling industries in the U.S. and Canada.
NAMA's 48
members operate 168 mills in 38 states
248
and Canada with aggregate production of more than
160 million pounds per day of milled products or
about 95 percent of the industry capacity.
As Anne Munoz-Furlong and several previous
speakers pointed out in their presentations this
morning, it seems to me it would be to us a
disservice to the allergenic population if products
that clearly have shown a long history of safe use
would be labeled as containing allergens due to
unrealistically low thresholds as a result of
FALCPA's requirements or regulations.
At issue in our industry is the presence
of trace quantities of soybean protein, which may
be present from the country in milled corn and
other cereal grain products.
While the establishment of thresholds is
obviously critical to the practical application of
FALCPA regulations, these thresholds should not be
unduly or unnecessarily restrictive to the allergic
person's food choices.
In that regard, we offer these following
comments. First, these
thresholds should be based
249
on the best possible scientific data regarding the
effect of an allergen on the allergenic individual
and certainly these thresholds should not be set at
zero.
Secondly, the use of analytical-based
methods would appear not to be appropriate as this
approach is very likely to result in a threshold
which would be unnecessarily low.
Additionally, FDA should probably avoid
the establishment of artificially low thresholds
with the "intent" of adjusting them later.
Historically, this has not taken place despite good
intentions. Additionally, any future adjustments
would prove to be confusing to the consumer and
disruptive to the food industry.
Finally, FDA must provide a clear
timetable for the establishment of these
thresholds. In our opinion, they must be prepared
to provide financial support for studies where
critical gaps exist in the current database.
Thank you for the opportunity to offer
those
comments.
250
CHAIRMAN DURST: Thank you.
Committee, any questions or comments?
(No verbal response.)
CHAIRMAN DURST: Thank you very much.
Our next speaker is Martin J. Hahn from
Hogan & Hartson.
MR. HAHN: Thank you. My name is
Martin Hahn, and I'm speaking on behalf of the
Grocery Manufacturers Association, and I do have
financial ties to the food industry and that
association.
GMA and its member companies have been
actively involved in the allergen issue. Indeed,
GMA was one of the instrumental agencies or
instrumental associations that was responsible for
the development of the voluntary allergen labeling
guidelines that Mark Nelson mentioned earlier.
Those guidelines have resulted in the use of common
English names on food labels well before FALCPA was
passed.
The established of allergen thresholds is
integral to
the effect of enforcement of FALCPA.
251
FALCPA suggests incidental additives such as
processing aids to the allergen labeling
requirements. This exemption becomes problematic
when the allergenic protein in a food is present at
such low levels that it does not pose a risk to
human health.
For example, typical uses of soy lecithin
can result in levels of soy protein from soy
lecithin in a part per billion and part per
trillion range. These foods have been consumed by
consumers without incident.
The legislation will fail the
food-allergic community if it results in allergen
labeling of foods with inconsequential levels of
protein from major allergens.
Given the time limits for today's
presentation, we offer the following brief
comments, which we do intend to supplement with
written comments at a later time.
With regard to the statutorily derived
approach, we agree with the Agency assessment that
it would be
appropriate to develop interim
252
thresholds using a statutorily derived approach.
FALCPA specifically excludes highly
refined oils from the definition of major allergen.
Highly refined oils do contain small, yet
detectible, levels of protein, which evidences a
congressional recognition that it is appropriate to
exempt from the major allergen definition products
that contain very small levels of protein.
GMA believes the statutorily derived
approach would support the establishment of 10 ppm
as an interim threshold level. We note that many
in the food industry have used this 10 ppm level
for years as an informal threshold for food
allergen labeling, particularly when it comes to
processing aids.
We previously provided FDA with marketing
data demonstrating that the presence of undeclared
soy lecithin, fish gelatin, wheat starch
contributing 10 parts per million of less than
major allergenic proteins did not result in a
measurable increase in allergenic responses over
baseline.
253
We have reviewed the published literature
and identified studies reporting various levels of
proteins in highly refined oils. This review has
identified that some oils have levels of 48 parts
per million while some of them have less than
20 parts per billion.
Because highly refined oils do have
varying levels of protein, we believe it would be
appropriate to set the threshold at 48 parts per
million, a level that is present in oils.
While we believe that may be appropriate,
we would advocate the establishment of 10 parts per
million as the interim level, because that is the
level that is in the midway point of allergenic
proteins found in products.
With regard to the method of analysis
approach, we believe it would be inappropriate to
se the threshold on the basis of validated methods.
We only have one validated method, and that is for
protein.
We also are concerned that as new
methodologies become available there will be
254
ever-increasing sophistication of the analytical
method which sets a number which is constantly
changing.
CHAIRMAN DURST: Your time is up. Thank
you.
Any questions or comments?
(No verbal response.)
CHAIRMAN DURST: Okay. Thank you very
much.
Our next speaker is Ann McKay from the
Food Allergy Anaphylaxis Network.
MRS. MOORE: Next.
CHAIRMAN DURST: The next speaker is
Peggy Mockett from the Food Allergy Anaphylaxis
Network.
MS. MOCKETT: Hello, my name is
Peggy Mockett. I am the mother of Alexander, a
10-year-old boy who has life-threatening food
allergies to tree nuts, peanuts, and corn. He is
also allergic to soy, penicillin, latex, and has
asthma.
I
have administered epinephrine to him
255
during one of his anaphylactic reactions. My son
has gone into anaphylactic shock before,
experienced anaphylaxis three times, and managed
through reactions involving skin rash, vomiting and
hives
Two of my son's anaphylactic reactions and
four of his milder reactions were due to labeling
issues. We have been seen by five doctors, and all
five instructed us to completely avoid his
allergens. We were advised to decline food
challenges to his major food allergens.
It was stressed and has been experienced
that the smallest amount can cause a serious
reaction in our son. There is no room for error
for us. We have a rule that says you read it once,
twice, and then again before you eat it. If you
cannot read it yourself and I didn't make it, don't
eat it.
Unfortunately, reading the label is not
always enough. There have been times when
ingredients were omitted because it wasn't
considered
a significant amount of the total recipe
256
or it was simply done in error.
Shopping for skin, hair and food items is
a lengthy process. You must read each item every
time and more than once, because mistakes are not
an option for us. Even with perfect disclosure,
ingredients change and must be checked.
Toothpaste is risky, because flavoring is
not a detailed ingredient. Medicine flavoring is
especially difficult, because pharmacists don't
always know the added ingredients and the type of
flavoring is not specific.
We are sometimes told, "It is not crucial
to the product, so don't worry about it." We have
to worry about it. Our son reacts quickly to
minute amounts of his allergens. For him buying
prepared foods is no longer an option.
Our past labeling issues have made it
impossible. Even with flour and cream cheese, I
have to call the manufacturer to be certain that
the details are accurate.
I cannot imagine allowing someone who
doesn't
fully understand my son's individual
257
situation to determine at what level he will or
will not have a reaction, a decision that could
take his life. Setting threshold levels at
anything higher than zero would be tantamount to
playing Russian roulette with his life.
Thank you.
CHAIRMAN DURST: Thank you.
Any questions or comments?
(No verbal response.)
CHAIRMAN DURST: Thank you very much.
Our next speaker is Kim Mudd, Food Allergy
Anaphylaxis Network.
MS. MUDD: Good afternoon. My name is
Kim Mudd. I am a nurse at University of Maryland,
and I am also a research study coordinator. I am
on the Program Committee for the Food Allergy and
Anaphylaxis Network.
I have been working with food-allergic
patients and their families for over 14 years. I
think I have performed thousands of food
challenges. The integrity of food labels is
important
to the FDA, and it is important to the
258
U.S. consumer.
For the food-allergic consumer, the food
labels are part of a life-and-death decision. When
a patient is diagnosed with food allergy, they are
counseled to read every label of every food when
they buy it, when they serve it, and when they eat
it.
If a food label contains an offending food
protein, they are told to avoid it completely.
This results in extremely limited diets with
significant impact on basic nutrition.
The precautionary labeling terms such as
"may contained" or "processed on the same line"
force families and patients to contact
manufacturers to try to gauge the risk of certain
foods or to avoid them all together. As a rule,
most of our patients and families decide on a zero
tolerance approach, resulting in even more dietary
restrictions.
If we are going to try to address the
current confusion in labeling with threshold
levels, we
have a significant amount of serious
259
work to do. We do not have enough data to discuss
NOAELs or LOAELs. The studies that have been done
absolutely exclude extremely allergic subjects.
No one wants to do food challenges on
somebody with a history of anaphylaxis. If you
doubt this, ask yourself, "Would you sign a consent
form that listed 'death' as a possible risk?"
Could you sign that form for your child and let me
feed that child, your food-allergic child, a food
that you know has caused anaphylaxis in the past?
If we do ultimately end up with threshold
levels, I need to know what to tell my patients and
my families. We know that the severity of reaction
and the dose required to elicit these reactions
varies from person to person.
We don't have the data to tell these
families what to expect. Food labels are the only
tools that food-allergic consumers have to keep
themselves and their children safe. If the
food-allergic consumer loses faith in the integrity
of these labels, they will be left with a very
dangerous
practice called "trial and error."
260
Thank you.
CHAIRMAN DURST: Thank you.
Any comments or questions?
(No verbal response.)
CHAIRMAN DURST: Thank you very much.
Our next speaker is Kim Mulherin from the
Food Allergy Anaphylaxis Network.
MS. MULHERIN: Good afternoon. My name is
Kim Mulherin, and I have an 11-year-old daughter
named Courtney who is severely allergic to milk
protein. Courtney's CAP/RAST test for milk is
greater than 100, always has been. Since her limit
exceeds the upper limits of the test, we cannot
determine the exact numerical measurement.
Scratch tests for milk cannot be performed
on Courtney, since the test itself poses too great
a risk for someone with such a high sensitivity.
The severity and the reality of my daughter's milk
allergy goes far beyond theoretical numbers
collected year after year.
Instead, her allergy is a very real
day-to-day struggle where the seemingly
simple and
261
necessary act of eating presents continuous,
life-threatening dangers most people don't ever
have to experience.
The prevalence of milk products in our
society not only as the main ingredient but also as
a filler or flavor enhancer makes avoidance
especially difficult.
Since prepared foods and restaurant dining
is essentially off limits, the accuracy and clarity
of ingredient labels is critical for Courtney's
well-being and safety.
Despite our very best efforts to avoid
milk ingredients, Courtney has suffered severe
anaphylactic reactions from ingesting both
undeclared and minute amounts of milk protein.
In one instance, Courtney suffered an
anaphylactic reaction when she was given
turkey breast luncheon meat which, unbeknown to her
caregiver, contained a very small amount of
caseinate which was later discovered as one of the
last ingredients on the label.
On another occasion, Courtney suffered an
262
immediate and violent reaction when she ate simply
one bite of shrimp from a precooked package of
shrimp cocktail purchased in a grocery store.
There was absolutely no mention of milk protein on
the label.
When subsequent tests and patient history
ruled out the possibility of a shrimp allergy, the
remaining contents of the store-bought shrimp which
caused the severe reaction was sent for analysis to
Mount Sinai Hospital.
The analysis revealed that the shrimp
contained undeclared caseine and whey. To this
day, none of the parties involved in the chain of
production admit adding milk to the shrimp.
Just as Courtney's IgE level to milk
protein is too high for the CAP/RAST test to
measure with exactness, it is very possible that
her immune system is indeed more sensitive than any
laboratory test devised to predict a reaction.
Courtney's sensitivity to milk is so high that we
simply don't know what her safe threshold level is.
Without
this knowledge, any minimum threshold level
263
established by the FDA is nothing more than a
statistical estimate.
Unfortunately, Courtney has already
learned the hard way that a statistical estimate is
far from a guarantee. Statistically speaking,
since 80 percent of the approximately 3 percent of
milk-allergic children outgrow the allergy by age
5, Courtney has managed to fall into the 6/10ths of
1 percent of children with a lifelong, anaphylactic
milk allergy.
It is simply unconscionable for the FDA to
ask such a person to bet her life on statistics
rather than facts. When I explained to Courtney
that the FDA was considering establishing minimum
threshold levels, she anxiously replied, "Now I
won't need to use an EpiPen after almost every
meal."
Can you look her in the eyes and tell her
with absolute certainty that she is wrong? That is
the real minimum threshold level you need to
establish for Courtney and every other person with
severe food
allergy.
264
Thank you.
CHAIRMAN DURST: Thank you.
Any comments or questions?
(No verbal response.)
CHAIRMAN DURST: Our next speaker is
Kim Sclarsky from the Food Allergy Anaphylaxis
Network.
(No verbal response.)
CHAIRMAN DURST: Our next speaker is
Linda Webb from the Food Allergy Anaphylaxis
Network.
MS. WEBB: Hello. I am Linda Gabel Webb.
Thank you for giving me this opportunity to talk to
you and for trying to do the right thing for people
with food allergies.
I have food allergies. They are not too
terrible, but I do have to avoid apples, pears,
onions and garlic so I don't have asthma all the
time. Naturally, they are my four favorite foods.
On a more serious note, my five-year-old
son is allergic to peanuts, nuts, shellfish, and
less so to
seeds. His numbers are all way up high,
265
so that he actually can die from eating those
things as opposed to just being itchy or wheezing
like me.
The first time we figured out that he has
this problem was when he almost died when peanut
butter cookies were being baked in the house.
Thank goodness he didn't eat them.
Once we found out, which was when he was
about two, we have practiced complete avoidance to
the best of our abilities by reading labels, and so
on, cooking from scratch. We have been very
fortunate that he has not had any incidents since
then.
I actually am so strict that I don't even
allow these things into the house, and I don't eat
them myself, even though I'm not allergic to the
same things because I want to be able to kiss him
without killing him.
I have really come to count on some of the
big food manufacturers who for a long time have
voluntarily done this labeling, and I think very
well.
266
I wish they would put "May Be Manufactured
in the Same Plant" way up top in huge letters
rather than at the bottom, but I really take that
to the bank.
We have been very fortunate, and we are
very grateful to them for that. I am looking
forward to labeling getting even better and more
thorough as it does become mandatory.
I have also tried to thank them, where
appropriate, when I call their 800 numbers and talk
to people and get further information about things
like flavors, like one of the other mothers
mentioned.
I am very grateful, and I don't buy their
product (laughter). It is kind of a mixed blessing
for them. However, I do have even greater
confidence when I see that same company's products
not having those ingredients listed.
One final note personally in addition to
the life-threatening aspects of his allergies, my
son, Charlie, who is five -- I'm not sure if I
mentioned
that -- also has a developmental disorder
267
that makes it very difficult for him to integrate
socially with his little peers.
You know, I can't tell you how much it
means that he doesn't have to be different in one
other way at school where mothers that want to
support him and support me can look at the list and
know that he can have this brand of Fig Newtons
and everybody else can have that, too, for a snack.
You know, it doesn't take away from the
fact that he is "different" or that he has got his
big, red emergency kit with him all the time, but
it is just one way for him to fit in.
I have complete faith that he is going to
continue to learn and grow and have a great life.
My main concern is keeping him alive. Obviously,
anything that the industry can do to make that more
possible I am very grateful for.
Thanks a lot.
CHAIRMAN DURST: Thank you.
Any questions or comments?
CHAIRMAN DURST: Okay. We will move on to
our next
speaker, Jupiter Yeung from the Food
268
Products Association.
DR. YEUNG: Good afternoon. I am
Dr. Jupiter Yeung, and I serve as the principal
scientist for the Food Products Association in
Washington, D.C. FPA represents the food industry
on scientific and public policy issues.
Protecting the public from health risks
while maintaining a viable food industry in an open
society is a daunting task. The "Draft Report"
provides a reasonable perspective of pros and cons
of various options towards establishing allergen
thresholds and helps to keep the public informed of
the deliberative process.
While the report is a reasonable view of
conceptual options for establishing thresholds, FDA
should also consider the recent European Commission
directive of providing a temporary three-year
exemption for certain food ingredients derived from
major allergens such as fish gelatin.
This directive was based on the scientific
opinion of the European Food Safety Authority that
these food
ingredients are extremely unlikely to
269
induce an allergic reaction.
While an avoidance diet remains to be the
most effective, too, for the allergic consumers, it
is generally that there are threshold doses for
allergenic foods.
Clearly, sufficient data are available to
conclude that thresholds for certain major
allergens are finite, measurable and above zero.
Hence, the assumption of zero tolerance for food
allergens places an unnecessary and unachievable
burden on the industry.
The declaration in labels of all
perceivable levels of major food allergens
including biologically insignificant amounts will
cause confusion to allergic consumers.
For example, small amounts of soy lecithin
can be used as a releasing agent during processing
but is not included in allergen labeling under the
current requirements. Some allergic consume who
previously had been safely consuming this product
will unexpectedly find the same allergen
declaration
on this product as they expect to find
270
it in other soy-containing products.
Unfortunately, this is likely to put the
sensitive individual in the position of either
further restricting their food choices or choosing
to ignore the label information.
Risk management is vital to the protecting
the well-being of allergic consumers. Clearly,
decisions must be based on current available
knowledge, even with less than perfect and complete
information. Without information on thresholds, it
is difficult for the industry to optimize their
quality control efforts to protect allergic
consumers.
A reasonable certainty of no harm standard
should be applied towards establishing threshold
levels. It is not intended to ensure nor is it
possible to ensure safety with absolutely
certainty, and it does not mean that no individual
under any conditions would be protected from any
harm. Therefore, uncertainty factors that are
reasonable should be applied, and only when needed,
based on
the relevance of the available data.
271
CHAIRMAN DURST: Your time is up.
MR. YEUNG: Pardon?
CHAIRMAN DURST: Your time is up.
MR. YEUNG: Can I make another minute.
CHAIRMAN DURST: Not another minute, but
one more sentence.
MR. YEUNG: Okay. For example, the
uncertainty factor is not necessary for
intraspecies for peanuts because more than 10 of
the studies were done in both male and female and
also in adults and children.
Neither should a standard uncertainty
factor of 10 be applied to the sensitive
populations, since children and sensitive subjects
were included in the clinical trials.
Since the lowest, not the mean, dose for
an objective symptom is being used to estimate
thresholds, an uncertainty factor of 2 may be
justifiable to give added protection to the highly
sensitive subpopulation.
Thank you very much.
CHAIRMAN DURST: Thank you.
272
Any questions or comments?
(No verbal response.)
CHAIRMAN DURST: Did we miss anyone as far
as the public statements?
(No verbal response.)
CHAIRMAN DURST: We are scheduled for a
break after the public comments. Even though we
are a bit early, we will take the break and
reconvene at 3:15. That will give us almost 20
minutes.
Thank you.
(Thereupon, from 2:55 p.m. to 3:15 p.m.,
there was a recess in the proceedings.)
COMMITTEE DISCUSSION:
REVIEW OF THE CHARGE AND QUESTIONS FROM FDA
CHAIRMAN DURST: I would like to reconvene
our session.
All right. This is the section of our
meeting today where the Committee can, I guess, ask
questions of any of the speakers that have
presented earlier, and also discuss any of the main
thrust of
this. I would just like to establish a
273
couple of ground rules.
We had slightly gotten off track at one
point today where we had gotten into labeling.
This is not the purview of this Committee to decide
any issues on labeling nor is it the purview of the
Committee to try to come up with numbers as far as
threshold values.
We are here to basically assess the report
that the Threshold Working Group has put together
as far as approaches and give our learned opinions
on the report itself.
You have in front of you or everyone
should have the charge to the Committee. I will
just read the charge to begin with, and then we can
get into the actual discussions.
The Food Advisory Committee is being asked
to evaluate the "Threshold Working Group draft
report, "Approaches to Establish Thresholds for
Major Food Allergens and Gluten in Food." The
Committee should advise the FDA whether the draft
report is scientifically sound in its analyses and
approaches
and whether the draft report adequately
274
considers available, relevant data on major food
allergens and on gluten. In addressing these
issues, FDA requests that the Committee consider
the following specific questions.
Now, again, for this afternoon, we are
going to focus on the allergens. Tomorrow, we will
be on gluten. You have in front of you some
general points that we should consider and then
some questions that the FDA would like our opinions
on.
At this point, I would like to open up the
discussions to the Committee, if there are any of
you that still have questions for any of our
previous speakers or would like to make some
comments or statements about your opinions on this.
Yes.
DR. BARACH: Yes. Jeff Barach with the
Food Products Association. I would like to commend
the presenters this morning, but I have questions
for Dr. Wood and Dr. Taylor. Both reported on the
composition of the challenge studies in a different
manner, and
maybe they can clarify this a little
275
bit.
In Dr. Woods presentation, he said that
the most allergic patient was not in his studies.
Yet, Dr. Taylor reviewed many studies and said,
yes, the sensitive individual is included and had
an explanation of why. I thought that perhaps one
or both could address that issue?
CHAIRMAN DURST: Dr. Wood had to leave
early. I hope Dr. Taylor is around.
Yes.
DR. TAYLOR: Well, I think I can answer
for both of us because I think I understand Dr.
Wood's point of view as well. It is an individual
clinician decision as to which subjects in a clinic
would be subjected to diagnostic challenge trials.
In the United States, it has now become
the practice that only challenges will be done on
those patients who are below the 95 percent cutoff
level for the CAP/RAST, at least in some clinics.
That very well could be true in Dr. Wood's clinic
at Johns Hopkins, I am not entirely sure.
On that basis, he was correct in saying
276
that the most highly sensitive individuals would
not be subjected to challenge because in the U.S.
you cannot get by ethics forums.
In Europe the situation is different.
There are groups that challenge on a diagnostic
basis every patient that they encounter as part of
their standard diagnostic practice, at least that's
what they tell me. That seems true from the
publications that they have put in the peer
reviewed literature.
Consequently, I think it varies from
clinic to clinic, investigator to investigator, and
report to report making the work of your panel even
more difficult.
CHAIRMAN DURST: Yes.
DR. MALEKI: Dr. Taylor, Soheila Maleki,
USDA. Can you comment on the soy lecithin? We
heard a lot about that in the questions and
comments. I was wondering if you know of any
allergic reactions to that?
DR. TAYLOR: Yes, I have actually looked
pretty carefully
at the clinical literature on soy
277
lecithin reactions. I should start by saying that
some highly respected clinicians like Hugh Sampson
do not advise their soy-allergic patients to make
any attempt to avoid soy lecithin.
Soy lecithin is acknowledged to contain
residual protein at levels that might be somewhat
debatable but probably in the range of 100 parts
per million.
You would use soy lecithin in direct
ingredient applications where it would appear on
the label anyway because it has a functional effect
in the finished product at 1 or 2 percent. You are
talking about 1 or 2 parts per million soy protein,
if you started with 100. In these processing aid
applications, the levels would be several orders of
magnitude below that.
There are two reports in the clinical
literature of allergic reactions to soy lecithin,
both of them involve both pediatric cases from
Europe, I think both of them are from Europe,
involving infants exposed to -- I know in one case
it is soy
formula and I think the other case is the
278
same.
Unfortunately, in my view, we don't know
the protein level of the lecithin because the
clinical investigators used an inappropriate
method. They attempted to determine the protein
level of the lecithin using the Kilnaught
(phonetic) procedure which would pick up the
nitrogen and the phospholate fractions. They got
huge numbers, but the numbers are not valid in my
opinion.
DR. MALEKI: All right, thank you.
CHAIRMAN DURST: Yes.
DR. KELLY: I just want to return,
briefly, to the issue of challenge studies, which
is important I think because they may well be used
to determine acceptable levels.
My question has to do with an individual
who doesn't need a diagnostic challenge study,
because the clinical presentation is so clear. Are
they included, in general, in the challenge
studies? Secondly, individuals with very severe
reactions,
anaphylactic reactions, would they ever
279
be included in challenge studies or are they almost
by definition excluded?
DR. TAYLOR: I think that there are
clinicians in Europe who tell me that they
challenge every potential food-allergic patient
that crosses the threshold of their clinic. I'm
taking it on faith that is true.
Certainly, if you look at the list of
symptoms that their patients present with when you
read their papers, that would appear to verify the
fact that their challenging everyone or nearly
everyone.
There definitely are clinicians in both
Europe and the United States who do not choose to
challenge subjects who have had life-threatening
reactions in the past.
As I alluded to in my comments, I think
that it would be very good to know what percentage
of the referral patients fall into that category.
I mean, we have heard from the parents of some of
those children this afternoon.
I
have to respect the clinical judgment of
280
those physicians. If they don't feel comfortable
doing the challenge in their office, then that is
the way it ought to be.
It is only the specialized clinics that
challenge these severely affected ones. However, I
don't know what percentage, even of these referral
clinics, are excluded from challenge. That it
discoverable, it is just that the question hasn't
been asked.
CHAIRMAN DURST: Soheila.
DR. MALEKI: Just a quick comment. I
think there are still some clinics, of course like
you said it would be wonderful to know the
percentage, of the clinics that do this type of
work and the percentage of the allergic
individuals.
I do know some clinics and especially
hospital settings and research places that do
actually challenge people that do have anaphylactic
reactions as well. Particularly in like one of the
anti-IgE studies, I know that they used patients --
(Simultaneous discussion.)
281
DR. TAYLOR: In the immunotherapy studies,
I should have pointed that out, were these anti-IgE
studies, the Tannock study and others. They have
tried to actually enroll people who have very
severe peanut allergy into those trials. They
wanted to find out if the therapy had any benefit,
and that would be the best group to make that
judgment.
CHAIRMAN DURST: Okay. Any more questions
for Dr. Taylor while he is up there?
(No verbal response.)
CHAIRMAN DURST: No? Okay.
Yes.
DR. BRITTAIN: I have just kind of a
big-picture question. Is that appropriate now?
CHAIRMAN DURST: Sure.
DR. BRITTAIN: It is going to more a
comment. It is really hard for me to think about
this without defining what the goal is of the
threshold is in very precise terms. Are we talking
about a threshold where only 1 in a 1,000 of very
sensitive
people would react? Are we talking
about
282
a threshold where 1 out of 100 all allergic
patients would react? Without specifying that, it
is really hard to talk about what the threshold
should be.
CHAIRMAN DURST: Yes. Well, there again
we are not talking about what the threshold should
be, it is how to best determine it.
DR. BRITTAIN: I don't see how you -- I
don't mean the actually --
CHAIRMAN DURST: Value?
DR. BRITTAIN: Yes, I don't mean the
value. Like, later on when we talk about
uncertainty factors, I don't see how you would go
through that exercise without establishing what
your goal is of the threshold, not what the
threshold value is. I don't know whether we should
ask the FDA that or--?
CHAIRMAN DURST: Steve, can you address
that or--? Steve is in consultation.
(General laughter.)
DR. BRITTAIN: It just strikes me that is
the first
step.
283
CHAIRMAN DURST: Yes, in some ways this is
like a bootstrap operation. How do you get to a
level without knowing what the level is?
DR. GENDEL: This is Steve Gendel for the
record. I guess all I can say is we are not at a
position to really address the question that you
have raised.
In the terminology we use, that is
considered a risk management decision that would
take into account the scientific information and
the kinds of analyses in these reports and other
factors in making that decision.
Right now, we are simply interested in
trying to identify the approaches that could be
used. Once a decision is made on whether to
establish thresholds and which approaches to use,
then we would be in a position to get to the kind
of specifics that you are asking for.
DR. KELLY: Let me ask a related question,
then, if I may. Assuming that whatever
methodological approach one took, one would arrive
at a
certain threshold level where it would be a
284
0.1 or a 0.01 percent risk of a significant event.
There will still be individuals who fall
outside because of being highly sensitive, because
of their situation at the time, unpredictable
events that are outside of the curve or at the very
far end of the curve.
Is there a mechanism to also accommodate
those events or to gather information about those
events in an anecdotal way? Can that ever be
considered to be part of the methodology? For
example, for drugs we have reports, very rare
events, of drugs.
People make reports, and at certain points
the reports mount to the level where there is a
pattern. We may only be talking about 12
individuals, but 12 individuals who died, and a
drug may be taken off the market. Have you
considered any approach like that?
MR. GENDEL: I think that is one of the
things that we have asked you to discuss, so I'm
just going to turn that question back on to you.
(General laughter.)
285
MR. GENDEL: We would like your input on
how we should go about thinking about those
questions.
CHAIRMAN DURST: Yes. I think it is
farther down the line where we have to -- and
probably this Committee won't do it -- I believe
EPA, for example, uses the term "acceptable risk,"
an with these parents behind us I am sure none of
them would say that there is any acceptable risk,
that this has to be very safe for everyone.
In reality there is the economics and many
other considerations that come into this. Again,
this is not something that we have to consider
during our deliberations today, but we want to get
into the approaches that are. DR. GENDEL: The
one other point I think I would like to make, as I
mentioned, one of the things that we are trying to
do is to evaluate the advantages and drawbacks data
needs of each of the approaches. Clearly,
questions like that are relevant to making those
evaluations.
CHAIRMAN DURST: Carol.
286
DR. WASLIEN: Carol Waslein. I would
think any kind of approach should include a
mechanism for establishing new methods, new
guidelines once data becomes available -- not just
saying once data becomes available but some kind of
mechanism that says "Now data is available."
Whether that is effects or symptom reports
or it is the results of clinical trials that are
underway or whatever that is, it might be that our
stance or position here is to say "Do this when
this becomes available, do this when this becomes
available." This would set up a system for
evaluating ongoing cases, for evaluating data that
must be available in the trials but was never
reported. That could be part of our approach.
Because the approach gives us a choice of
four, and I personally like choices of 1.5, 2.5 or
a combination thereof for the approaches because it
says go back and look at safety data.
Well, can't you set a standard based on
existing safety data now and not have to go back
and look at
it, if safety data exists? You use a
287
combination of approaches and a mechanism that also
says at a given time we will go back and look.
When a certain amount of test data becomes
available, you go back and change it.
CHAIRMAN DURST: Yes, Suzanne.
DR. TEUBER: I actually have a question
for Sue, for Dr. Hefle, and this relates to the
fact that in the data that has been presented on
LOAELs and NOAELs, of course most of these
challenge studies were done in diagnostic settings
where, as you were pointing out, not all of the
patients with severe, severe, life-threatening
allergy would have been included at all; they would
have been excluded.
When you have been involved in some of
these threshold studies that are designed for this
purpose of safety assessment, some of the studies
that were mentioned like Dr. Wensing was the lead
author on, in those situations then the studies
were stopped with the subjective symptoms before
any objective sign.
This actually would bring up the fact that
288
the studies that you are involved in would add a
number five approach, because it would be a
modification of finding three of the safety
assessment approach.
Right now, it is written as a suggestion
to use objective signs for the LOAEL. The data
that you have, you have actually been able to
recruit more patients with a history of severe,
life-threatening reactions.
It seems to me that if we were to suggest
yet another approach, the one that you have
outlined may be very appropriate. I am wondering
if you can comment on the recruitment of these
patients to us? This might help address this great
concern that people with severe anaphylaxis aren't
included.
I'm thinking that the adults that I know,
I have hundreds of adults with severe,
life-threatening tree nut allergy. They are eager
to participate in threshold challenges, if they
know that it would be stopped at their first
symptom of
any tingling in the mouth. That is
289
their usual symptom in the real world. They would
be happy to participate. I think I would like to
hear more about your recruitment.
DR. HEFLE: Well, I have to give a lot of
recognition to my European collaborators, because
I've got to say that this is way easier to do in
Europe.
They have patients beating down their
doors to do this that are severely allergic, even
parents offering their children up because they
have a greater sense of the greater good over there
in comparison to American people I think in the
later respects.
They will have a lot of recruitment. It
is easy to recruit because they are told exactly
what will happen and they are told exactly that
they will stop with these mild reactions.
Now, Dr. Wensing, they made a decision
that they were going to stop at that level, but not
every physician makes that same decision. I just
let the physicians make the decisions. I don't
have
patients, so I'm not qualified to make those
290
decisions as to when to quite a challenge.
Actually, the people that do participate,
we have found in the last couple of years that they
find thresholds beneficial to their day-to-day
maintenance.
Carsten Bindslev-Jensen will give talks
about how he uses thresholds in educating his
patients. He says he has two patients with the
same IgE levels and things, same size skin tests,
one can eat half an egg and one can't have any at
all. The advice you give is much different and the
restrictions you can have in one versus the other
are much different.
We see more and more people actually
seeing if they can be in these challenges and
wanting to do them and feeling pretty comfortable.
Now, that is not to say it is necessarily really
easy to go find 300 people to do this and
especially for soy and some of the other allergens
where we have a challenge.
However, we have gotten some fairly
severely
allergic people to participate. They
felt
291
comfortable but they have to feel comfortable with
their physician and comfortable that the right
precautions are taken. I can understand why
someone would not want to do this.
Yes, it is really individualistic as to
when the physician is going to stop. As a
physician, I'm sure you can understand when you
make that kind of judgment call, too. It is based
on years of experience and thousands of challenges,
and not everybody is comfortable doing that.
I hope I've kind of addressed your
question. As I said, it is a lot easier to do this
in Europe. They seem to take the whole population
in there versus the United States.
Here, it seems much more difficult to get
people to do this, to make them feel comfortable
that this is going to be okay, and that they will
be able to go through it and not experience really
adverse reactions.
DR. TEUBER: I think it would be actually
easy to get people here. Like I said, I have
hundreds of
people who have expressed interest in
292
this sort of thing with severe, severe allergy, but
it wouldn't be for a diagnostic challenge. It
would have to be in the research setting.
DR. HEFLE: Right.
DR. TEUBER: Therefore, it would be laid
out that it would be stopped at the most mild
symptom. This brings up another point, then. If
you stop at that mild symptom, can you trust the
results?
I believe in those studies they used two
active and two placebo for each. Are you familiar
with any data that that has not been a correct
assumption for stopping a challenge?
DR. HEFLE: I am not aware of any other
data that is an incorrect assumption. That was
their approach, and I decided to let them go with
it because they know better than I do.
Perhaps, other physicians with other
research would approach it a different way, but I
am not aware of any other data that would impact on
that or would show that is, indeed, the right way
to do it.
293
DR. TEUBER: I would just note for the
record, for those of you not involved with food
challenges, Dr. Allan Bock wrote an office manual
on food challenges that was published back in, I
think, 1978. In there for subjective symptoms, it
was suggested that multiple challenges be done to
make sure that it was a "real reaction."
During the same setting period, once
somebody has had, say, a symptom of itching in the
mouth, then it would be blinded as to whether the
next challenge they had was again an active one or
placebo, but you would repeat this several times.
In practice, we use this for instance when
somebody is concerned that a headache may be
triggered by food, or it can be used in this
setting of coming up with a threshold. For
something like headache, it would have to be done
on multiple days.
Rather than just doing one active and one
placebo, there are multiple given. I am, again,
hopeful that the multiple challenges that were done
you could
get more people as you did with severe
294
reactions to help establish a threshold.
DR. HEFLE: It would be nice. At our last
threshold conference in Majorca we had 20
clinicians who do this from around the world
sitting around. A lot of them felt that if you had
a subjective reaction, you actually should go to
the next one to get an objective reaction because
they are usually pretty mild at that point, too.
They felt as a group not every single time
that it might be a necessary thing to actually go
beyond the mild, subjective reaction when you are
trying to get a threshold study done. That was
kind of the consensus of the clinicians.
DR. TEUBER: Thank you.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: I have a couple of
issues that I think are important to clarify our
thinking, but I'm not sure how they would
specifically be addressed, so let me mention the
issues and then maybe you can see. It is related
to the whole issue of testing.
In clinical medicine, we often use tests
295
that are not perfect, but they are pretty good.
Some of the tests we use, the tests themselves are
not a gold standard.
If we want to test for anemia, we would
test for a hemoglobin and say we know what anemia
is because we define it by the absolute value of
the test. However, there are many other tests
which are for conditions that have some other
criteria for the diagnosis.
We can set a threshold for the test, and
we often do set a threshold. When we set the
threshold low, the test may be more sensitive and
less specific; and when we set the threshold high,
it may correspondingly differ.
It seems to me we have a choice with using
symptoms, subjective findings, and signs, objective
findings. With a symptom, we may be more sensitive
and less specific; and with a sign, we may be less
sensitive. Did we get that correct?
DR. TEUBER: Mm-hmm (affirmative
response).
DR. SILVERSTEIN: It may be less
sensitive
296
and more specific. I believe that there is some
inferences we can make from the existing literature
about how a food challenge may perform as a
diagnostic test for the presence of food allergen.
The caveats and questions there, though,
Does the test perform in the general population the
same way it performs in the studies that are
published? Of course, it may or may not perform as
well, depending on whether there is some selection
bias.
To the extent to which published
literature tells what the selection was or the
reviewers for the report can provide that
information, we would be able to be more or less
confident that the tests and the inferences about
the thresholds are strong.
In that regard, some guidance might come
from the study I believe the Agency for Healthcare
Research and Quality funded a study to evaluate
systems for evaluating the strength of evidence.
I think Kathy Lohr and the Research
Triangle
Institute was responsible for that.
They
297
set sets of criteria questions to ask when looking
at a question that would be answered by a
randomized control trial, by a case control study,
a cohort study, or a diagnostic test.
I think the report might be strengthened a
bit if we could look at some of the criteria that
was proposed by that study for looking at
diagnostic tests.
As I looked at it, most of the issues that
they covered were considered by the FDA in the
report, but it might be useful to look at that,
which is out in the literature. It has been out
now for a couple of years.
The second thing I want to do is to
clarify our thinking from how a test may perform to
diagnose the presence of food allergy so that a
clinician and a parent or a patient can together
decide what is a course of treatment, from the
prognostic value of what would happen in the future
in the real world when the patient's family or the
patient tries to adhere to dietary restrictions.
The question we would have is, What is the
298
prognostic value of a positive or a negative food
challenge test? If, for example, we were to accept
either symptoms or signs as our threshold, in those
patients who are positive in symptoms or signs
reproduced and a diagnoses of food allergy is made
and the clinician says, "This is what you should do
for your diet," what is the future risk and
occurrence of subsequent episodes of anaphylaxis,
since we know some of those patients will indeed
experience episodes?
In the patient who is reassured that, no,
they don't have a food allergy because they did not
react positively to a food challenge test, do we
have literature about how reassuring that is? In
other words, does the negative food challenge test
provide sufficient assurance of future risk for
those patients?
I suspect there is very sparse literature.
However, if there were some literature that looked
at long-term outcomes in food challenge test
positive and food challenge test negative
individuals, we might know whether the thresholds
299
used in the test for those individuals could be
used to set policy.
DR. TEUBER: I can partially answer that.
In terms of if somebody has a negative challenge,
you are getting back again to using food challenge
as a diagnostic measure not for risk assessment in
somebody you already know has an anaphylactic
sensitivity to foods. It is really kind of a
separate thing.
In that situation, we would do an open
challenge with the food as they would normally eat
it because what was used in the challenge setting,
and Steve Gendel did write about this, may not
reflect what is really consumed by the patient.
For diagnosis, it is still different than
having someone you already know who has anaphylaxis
to food. That is where I'm thinking that the
possibility of using the subjective symptoms for
your LOAEL may be very reasonable, because we also
talked about how there are other factors that may
influence somebody's reactivity on a particular
day.
300
Asthma I think was brought up, alcohol,
inflammatories, exercise, even the time of year.
Some people may have more histamine-releasing
activity in terms of their mastocytes and basophils
after the spring pollinosis season, if they also
are highly allergic to pollen. Those factors could
go into that uncertainty factor.
If you then say that you are only going to
accept objective symptoms from the data, that means
a lot of Wensing's data on threshold would actually
have to be thrown out, because only 5 patients out
of the 29 or so actually had gone up to objective
signs.
This was one of the few studies where
because these patients were told, "We're going to
be extremely safe, extremely careful, and we're
going to stop before you have anything severe,"
they were able to recruit the people with
anaphylaxis that we want to protect by recommending
a safety assessment approach here.
I mean, that is why I keep bringing up
this issue
about can we accept that for the issue
301
of safety assessment, if you have blinded
challenges that are repeated.
I think it is a really different issue
than diagnosis and different than the performance
of food challenges as how reproducible they are.
I'm not enough of an epidemiologist or a risk
assessment person to go into that. I'm looking at
this from the patient care viewpoint. Does anyone
else want to elaborate? Actually, anyone out there
can, too.
DR. SILVERSTEIN: Well, so let me ask,
then, if we were to use symptoms, which is more
sensitive, and you had an individual whose parents
and the physician recommended a food challenge and
the food challenge test was negative, no reaction
or symptoms, and you knew what the threshold was,
then that would be sufficient to make
recommendations, or then the person might get an
open food challenge?
DR. TEUBER: I'm sorry, that person would
actually not have a negative challenge because,
again, to
be included in a database that would be
302
adopted by the FDA for determining a threshold, the
person who had a negative challenge in the studies
would not be included.
See, you have to be getting up to a
response, either a subjective response that is
reproducible or to something objective, lip
swelling or nausea or vomiting or something else.
You wouldn't even include that individual in your
evaluation.
DR. SILVERSTEIN: There would be a
population of food allergy patients who may have a
negative test but might yet have the diagnosis of
food allergy?
DR. TEUBER: Again, they may be someone
who has developed tolerance now, and so they would
be challenged openly for food as they would
normally eat it. If they can eat that, then they
no longer have a food allergy. Or, they may be
somebody with a special situation such as
exercise-induced anaphylaxis that is food
associated where they only have a reaction in a
certain
context.
303
CHAIRMAN DURST: Comment?
MS. HALLORAN: I think that Dr. Teuber,
though, is getting to an important issue, which is
a concern that I had listening to all of this
testimony, which was that the repeated issues as to
questions that the data on LOAELs and NOAELs just
is not that good.
It is better for peanuts and eggs and
milk. However, in the other categories, though,
everybody was saying that the data is really not
sufficient. I'm interested in Dr. Teuber's
suggestion of actually recommending to FDA that
possibly they could conduct some research to
establish NOAELs and LOAELs. She proposes a
methodology that appears to possibly get around
some of the medical issues.
DR. TEUBER: None of this is my proposal.
This is all proposed by people already doing it.
Again, a lot of these studies are underway right
now. I take absolutely no credit. You are looking
at some of the people over there who are doing
these
studies.
304
It is just that the studies designed
specifically for this issue, there area a few that
have been mentioned that were done in this way or
they are underway right now.
There hasn't been any funding to do them.
For instance, for tree nuts there is only one on
hazelnut, and none of the other nuts have been
addressed at all. We see Dr. Hefle nodding her
head over there.
Again, just to be recommending some
approaches right now, I think a hybrid approach of
a 3.5 of accepting the LOAELs for some of these
subjective reactions might be very reasonable, but
then I guess some other methods will have to come
in for those foods not covered at all.
MRS. MOORE: I'm sorry, I want everybody
to remember to say your name.
DR. TEUBER: Oh, I forgot to say my name.
Suzanne Teuber.
MS. HALLORAN: Jean Halloran, sorry.
MRS. MOORE: Okay. For the transcriber,
she can
probably pick it up with the voice.
Okay,
305
do you remember to say your name.
DR. TEUBER: I'm sorry.
DR. KELLY: Just a follow up briefly.
CHAIRMAN DURST: Your name?
DR. KELLY: Ciaran Kelly, sorry. A brief
question about this issue of positive result on
challenge or maybe more specifically a negative
result on challenge. Then, it is frequent that
there would be a real life challenge with regular
food?
DR. TEUBER: Yes.
DR. KELLY: How often would the real life
challenge would be positive where the laboratory
clinical challenge was negative?
DR. TEUBER: That sort of data is, indeed,
in the literature and in some of the literature
that Dr. Gendel has cited here, some of the
follow-up studies by the Johns Hopkins group.
Unfortunately, that statistic is not on
the top of my head, so I would be venturing, but
certainly there are folks -- and in Dr. Bock's
series as
well -- who tolerated the dehydrated food
306
in challenge and then reacted upon eating the real
deal. I can't give you a percent.
Again, those folks would not be included,
their data would not be included for this sort of
risk assessment that we are really trying to decide
on approaches for them here today.
DR. KELLY: It clearly speaks to the
validity of one of the tests that they've used to
establish a threshold.
DR. TEUBER: Again, the people that would
be used -- this is Suzanne Teuber again -- the
people who would be, hopefully, enrolled in studies
to establish a threshold would be those who very
clearly have had anaphylactic reactions or a range
of reactions that very clearly is to the food in
question and where a diagnosis has already been
established. It would not at all be to use just
data from diagnostic challenges.
A diagnostic challenge, I think most
people would want to go to an objective sign when
you are trying to figure out a difficult case,
like, is it
sesame or was it the peanut in the
307
Asian food in this 34-year-old who has a new onset
of allergy?
You think it's probably sesame, because
most peanut allergy has its onset in childhood, but
you would really want to be sure because that
really determines which food is this person going
to avoid, sesame or peanut.
In that case, as a physician, I would want
to go for a mild, objective sign rather than
stopping for a symptom. Again, that is a different
issue than trying to give advice to the FDA of
which approach to choose for labeling.
CHAIRMAN DURST: Yes.
DR. MALEKI: Soheila Maleki here. It
seems to me like with all of the methodologies that
have been outlined in this report that everybody
seems to be looking at or interested in the
threshold of those studies.
I think it is pretty much a consensus out
there that the threshold dose studies need to be
done, and that would be the practical approach to
go about
determining this somewhere down the line.
308
That seems to be the most important I think to
establish as far as the patients go.
On that line, I would like to ask
Dr. Hefle if she could tell us how they would go
about this and how long does it take?
I think it seems like, and of course this
is my opinion in this case, that before you can
take any methodology to determine, say, "Okay, this
is the limit of detection of our analysis," well,
our technology is so high that our limit of
detection can be down to 1 molecule.
In other words, you can probably find
peanut dust on this (pointing) tablecloth, if you
wanted to. Therefore, at this level we can't say
the limit of our detection is going to be what is
going to establish this. It is going to have to be
human studies.
DR. HEFLE: You are asking about your
average threshold study? How long does it take?
What is required?
(Simultaneous discussion.)
DR. MALEKI: Yes, how long does
it take
309
and how much money.
DR. HEFLE: Yes.
DR. MALEKI: How do you get the money?
what do you do? what is limiting? and so forth.
DR. HEFLE: Nowadays, 29 patients for an
allergen you can find pretty easily like peanuts,
at least $200,000 U.S. dollars. That primarily is
clinic cost and hospital cost.
The hospitals are charging more. They
have costs. They have to have a crash cart ready;
they have to have nurses ready; they have to have a
lot of things ready. Therefore, in most cases, we
do this in research centers, so a lot of that is
clinical cost. That is the vast majority of it.
We have to make standardized materials and
send these to everybody. We have to find the
patients and make sure they are the right kind of
patients.
For something like soy, it is one of the
"Big 8" allergens and there are a lot of kids out
there allergic to soy, but they are all mostly
infants.
310
To find 29 soy-allergic people, which we
are trying to do right now, for our soy threshold
study is pretty daunting and we have to go to the
ends of the earth to try to do that.
It can take from concept to actually
getting the challenges done and getting through the
ethics board, maybe two years. Depending on the
ethics board you are dealing with, they might take
six months to get an approval; it is very
individualistic.
Denmark has got two ethic boards they have
to go through, so if we hope to get any patients in
Denmark, they've got to go through twice as much
and get translated in Danish and all sorts of extra
things.
But even just developing the food vehicles
in a double-blind manner and doing the sensory
analysis in the studies we need to make sure that
it is truly blinded and available to clinicians.
To test 29 patients can take easily 6 months to a
year to develop the correct vehicle, choose the
right
representative food to use. It can
easily
311
take two years even for a really great allergen we
can find lots of patients for.
Then, the funding, there is no
governmental funding for this to date. All of the
funding to date for threshold studies, I've gotten
a little bit of USDA. Steve and I have gotten a
little bit of USDA funding out of this. The food
industry has paid for the majority of these studies
to date because they really want the answers, so
that is where the funding comes from.
It is kind of difficult for them to
identify funding for this, too, rather than just
throw "May Contain" labeling on the products. You
know, what is the choice here? For some companies,
it is easier to say, "I'm not going to cough up
$50,000 to help you. I'm just going to put
labeling on my products."
We have gotten a lot of support from the
food industry, and we are moving ahead as best we
can. It has been kind of slow in getting this data
out. We need a consensus protocol before we can
move ahead.
312
There are some centers in Europe that are
choosing to go ahead and do some threshold studies
and kind of work that in, if we provide the
materials, as they can without having a huge amount
of financial support from us, as they can work it
into their patients, if they are truly interested
in it.
For a specific study, it probably will
take at least two years for any one allergen and at
least $200,000. Those costs are just going to
continue to go up. One clinical investigator that
I like to use a lot in Europe just told me that now
they are required to have insurance for the study,
and that is only going to be $10,000 U.S. dollars
for this one study. And that is only for about
three patients. We will have to do another $10,000
the next time we want to do a threshold study. It
is getting more and more costly to do.
CHAIRMAN DURST: This is Dick Durst. I
would just like to pick up on one comment that
Dr. Maleki made concerning the sensitivity of the
analytical
methods. It is true that for a great
313
many of the allergens we are talking about, we can
get down to very low levels.
We don't want to get into the situation
that we had with the Delaney clause with
carcinogens. At one point you set a level based on
the state of the art, which may have been parts per
million, and the law says, "Well, as much as you
can trace or detect, that is the limit."
The analytical methods got better and
better, and it got to parts per billion and
trillion and quadrillion. Therefore, the
analytical methods, per se, probably are not the
way we want to establish a threshold. However, you
do need the analytical methods, then, to verify
that the foods that the thresholds are set on
actually conform to it.
I think, again, we have to keep going back
to these challenge methods, you know, the actually
biological studies to set the threshold, and then
the analytical methods can provide the validation.
DR. MALEKI: Soheila Maleki. I agree with
you a
hundred percent that we definitely need the
314
analytical methods once the thresholds are
established or a range is established in order to
determine if we can comply with that -- in other
words, compliance -- but I don't think that alone
they could be used in that way. Since, as you
instructed, we are supposed to be evaluating some
of these methods, that is the point I was making.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc Silverstein. I
would like to follow up on the "N" equals 29
patients for a modest size study. That would be
assuming that the hypoallergenic formula, or a
percentage of 10 percent, was an appropriate
prevalence of a reaction in the population of
generally allergic individuals that you are
testing.
However, I think we need to say -- it is
different for us to say that we believe that only
10 percent or fewer than 10 percent of patients
like those tested will go on to experience an
episode of food allergy, which could be of very
different
severity even if only a third were
315
severe.
I think we need to say the sample size in
power calculations to have meaningful assessments
are as a risk that is probably important to
patients would be much greater, orders of magnitude
greater.
In Dr. Luccioli's handout, there is a
slide where the top row is 10 percent, which then
equals 29 for a 95 percent confidence interval.
The bottom line, as I can read it, is "1/5,000" or
"1/10,000." We might want to have very high levels
of confidence, more than 95 percent, if the true
rate may be less than 1/1,000 or 1/10,000 who would
have such an event. I do think that you are being
very optimistic, and even so will just be confident
about a rate of 10 percent.
CHAIRMAN DURST: Okay. Petr and then
Margaret.
DR. BOCEK: Petr Bocek. I have actually
one question and one comment. Regarding the
analytical methods, I absolutely agree that we do
need
them. We talk about 1 part per billion
or
316
million. What is that part?
I would like to know the analytical
method. Does it relate to the major allergen,
let's say, RH1/RH2, polyclonal serum ELISA? What
is the physiological relevance? I'm missing that
point as far as the analytical methods.
DR. HEFLE: Well, the analytical methods
were not originally designed to find the allergens.
That wasn't the purpose of the food industry. They
wanted to find out, Do they have peanut, or do they
not have peanut? It is claimed? Is it not
claimed? In that case, then, it is not necessary
and when we are designing these to look for the
allergen specifically.
In addition, not every allergy is known
for every food yet, either. If you target just
one, you could miss the rest of them. The approach
that has been very successful is to use polyclonal
serum, a more crude extract in general, and they
seem to work very well at picking up peanut/no
peanut.
The parts per million varies from kit to
317
kit as to what it really means. It can mean parts
per million peanut, which is the whole food. What
does that mean? It can mean peanut butter or
whatever.
In some cases, the companies will say that
means part per million peanut protein. What that
means is the soluble proteins from the peanut that
can be detected in an aqueous situation. That is
one of the debates about what these numbers mean
when they are crunched out at the end. What is it
expressed in? How do you relate that to other test
kits? That is a challenge. However, they are not
specific for the allergens.
CHAIRMAN DURST: Petr.
DR. BOCEK: Petr Bocek again. There was a
comment, which was a clinical comment, which
relates to point number three on the food allergens
of the charge, which is basically asking whether if
we have any specific data for one of the major
eight allergens, if it can be easily transferrable
to others.
Obviously, that is not an easy answer, but
318
we know from clinical studies as far as development
of tolerance, outgrowing actually a food allergy,
there are significant differences between these
eight groups, specifically peanut stands out.
Frequently, kids who outgrow peanut
allergy, which current studies show it is up to
about 20 percent, still retain their high levels of
specific IgE, which is absolutely not true for milk
and egg.
At least as far as development of
tolerance we can be certain there are differences
between these eight allergenic groups, and it may
also apply to thresholds of these eight allergenic
groups.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: Hi, this is Eric Brittain.
Back to the sample size. I guess obviously there
is a concern with the 29. You are very limited in
the statistical conclusions you can draw. I think
the presentation that talked about the modeling may
be the way to go if you are wanting to rule out
very, very
small rates of reactions. I don't see
319
any other way to allow very, very small risk.
CHAIRMAN DURST: David.
MR. ORYANG: Yes, David Oryang. Can you
stay there, please?
(General laughter.)
MR. ORYANG: Yes, I'm just going to back
to this just briefly. You mentioned that detection
levels should be tied to threshold levels in your
presentation earlier. Until the threshold levels
are determined, we need to know what the detection
levels are in order to determine threshold levels.
However, this analytical methods-based
approach I am just wondering whether there have
been any studies that have looked at the detection
levels, taken the detection level, let's say,
2.5 parts per million for peanuts and then taken
it, whether it is peanut butter or a whole peanut,
and at that detection level maybe looked for a
specific protein within the peanut that an
individual reacts to?
You take that detection level and you
design your
study and challenge people at that
320
really low level and increment from that point as
opposed to increment from a much, much higher
level. I don't know whether there are any studies
that have done that and whether there have been any
results that have shown any positive results?
DR. HEFLE: There have been no studies
that have started out at a detection level for a
commercial study and then decided to challenge at
those levels. That decision has not gone from that
aspect of it.
When we sat around and thought about the
consensus protocol, the levels were designed to try
to incorporate what we felt were good starting
levels and lower starting levels than normal.
When you calculate from those levels -- we
came up with starting at 10 micrograms or starting
at 100 micrograms, which 100 micrograms is kind of
a magic number that has been used out there for
subjective symptoms reported as causing subjective
symptoms in peanut-allergic people -- when you
calculate what you can detect, then 100 micrograms
is
appropriate in the detection limit of the
321
assays, around 10 parts per million or so.
Where those subjective symptom numbers
lie, the test kits can easily do that level. Right
now, actually they are better than that. However,
no one has designed a study to actually see if the
detection limits are protecting human health at
this point. We think that they are lower than what
they need to be, but we've never designed a study
that way.
MR. ORYANG: Okay. David Oryang again.
Just following up on that, I see the
analytical-based approach at least beginning to set
some of those lower limits. If industry has
already looked at these things, there is some value
in at least starting there and then adding on with
some of the other methodologies the challenge test
to really find out whether people react and
starting to understand the dose response.
Why I'm talking about these analytical
methods-based approach, I think it has implications
on other allergens that have cumulative effects as
an example.
322
DR. HEFLE: I'm sorry? Other allergens--?
MR. ORYANG: That have cumulative effects.
DR. HEFLE: I'm not as good a person to
ask that question of. I guess I would point to one
of the physicians.
DR. TEUBER: Suzanne Teuber here. Yes, in
a situation of disorders like chronic atopic
dermatitis, there may certainly be effects from
small doses ingested.
(Simultaneous discussion.)
MR. ORYANG: Small doses?
DR. TEUBER: Yes, you have exacerbation.
Some of the challenge studies that are in the
literature, actually symptoms don't show up for
three days to seven days. That is also true with
some of the gastroenterological disorders, it may
take a little more time.
CHAIRMAN DURST: Yes.
DR. NELSON: Mark Nelson. I just wanted
to make sure we understand what we are talking
about when we mention the analytical approach or
the
analytical method.
323
As I read it, it reads that we would set a
threshold based on whatever we can measure in a
validated way, and then next week if we can measure
something 1/10th of that, then that is the new
threshold. It is not necessarily connected with a
reaction or a lack of reaction.
MR. ORYANG: Yes. David Oryang. Yes,
that is true, and that is why I am not saying that
they should be used to set the threshold levels.
I'm just saying that this should be a starting
point I believe that will enable more studies to be
done, the challenge tests, and so forth. I think
it is a good starting point, if that is the only
thing that one has.
DR. NELSON: This is Mark Nelson again.
That raises a question I wondered, Sue, if you
could clarify. You mentioned 100 micrograms was
the magic number for a challenge test, and then it
was equated at 10 ppm in the test. Was that 100
micrograms of peanut, or 100 micrograms of peanut
protein versus 10 micrograms of peanut, or 10
micrograms
of peanut protein?
324
DR. HEFLE: I'm going to pass that. I'm
going to pass that to Dr. Taylor.
(General laughter.)
DR. TAYLOR: When we published the
"Threshold Paper One," 10 parts per million is
10 milligrams per kilogram. If we then assume that
the serving size for the food is 100 grams, and we
could have a whole day's debate on serving sizes
for food, but if we did that, then that is one
milligram.
DR. NELSON: Gotcha.
DR. TAYLOR: If we look at the clinical
threshold trials that have been done, 1 milligram
is in the neighborhood of where the most sensitive
individuals that have been reported have the onset
of these mild, objective reactions.
Therefore 100 micrograms, where the
subjective reactions have started in some of these
studies equates to 1 part per million, which is
about the lower detection limit of some of the
analytical methods.
That is why we think that the analytical
325
methods are pretty much in the order of magnitude
of sensitivity that they need to be because of what
we do know about threshold doses.
If you get below the limit of detection in
one of these analytical methods, you can be
reasonably certain as a food industry that you
don't need to declare the presence of milk or
peanut or whatever it is on the label of that
product.
CHAIRMAN DURST: Doug, did you have
something?
DR. HEIMBURGER: Yes. Doug Heimburger. I
don't know if this will shift the discussion, it is
a little bit related but not entirely. With regard
to the question raised by Ms. Atagi, the first
person that made public comment, urging FDA to
consider sensitization as a possible endpoint of
concern, how much is known about sensitization?
Are there levels that can be associated with
sensitization as opposed to not? This may be for
Suzanne or anyone else. I don't know, maybe you
can
dispense with it quickly, and say we know
326
nothing.
(General laughter.)
DR. TEUBER: Yes, you see my smile and I'm
shaking my head. Oh, gosh, there is a vacuum here.
There is great concern that there is sensitization
via breast milk. There is concern that in some
cases because of first-exposure reactions as a
neonate with first feeding that there has been
sensitization in utero.
There is concern about cutaneous
sensitization. This is an area of tremendous
research right now of just the environmental
presence of peanuts causing sensitization
transcutaenously in kids who do have atopic
dermatitis or some breakdown in the skin barrier.
In terms of the amount that causes that --
oh, my goodness, yes, I can say that we just are
not there at all to be able to make that an
endpoint.
DR. HEIMBURGER: Okay.
DR. TEUBER: It is a wonderful point that
she raised,
but I don't think we have the science
327
to be able to do that. Again, this is Suzanne
Teuber.
CHAIRMAN DURST: Petr.
DR. BOCEK: Petr Bocek. Just a comment.
Probably if you draw blood on all of us sitting
here and do a RAST for the eight major allergens, a
number of us will have, I don't know, 3 kilo units
per liter to various allergens.
We eat those foods, and we are completely
fine, but we are sensitized. It is very difficult.
That is why the RAST is always something what has
to be considered with the clinical picture.
The "sensitization," first of all, how do
we define it? We define it by level of specific
IgE, if we talk about immunohypersensitivity.
Then, we have to go what is the level when we say
that we are sensitized? Is that more than zero of
the CAP/RAST that Pharmacia has, let's say.
Sensitization is not really practical, I think.
DR. BOCEK: It is not practical?
DR. TAYLOR: It is not because if you
define it a
RAST to some extent without any
328
clinical histomorphology, what does it mean?
DR. HEIMBURGER: Right. Doug Heimburger
again. Are you saying that because we would find
that all of us had specific IgE to various ones of
these allergens but we wouldn't have had any
knowledge of how much exposure we'd had, therefore
we wouldn't know what doses had been required or
what exposure levels had been required to create
the sensitization that you pick up in the RAST
test?
DR. BOCEK: Petr Bocek again. Well, as
far as the exposure levels, anybody with a regular
diet is exposed to tons of major allergen groups.
DR. HEIMBURGER: Right. Right, so you
couldn't set a threshold in that case because we
have been exposed to a lot and perhaps we have
developed a little bit of specific IgE.
DR. MALEKI: Again, Soheila Maleki. There
are still theories out there about low-dose
exposure kinds of sensitization at an early age and
others say high-dose exposure is protected.
High dose frequently is protected, and low
329
dose at low frequency or intermittent, that is
sensitization. Right now, all of this is being
challenged, and it is all theory, so there is
really not much speculation about determining a
threshold for sensitization because we really have
no idea how it happens in the first place.
CHAIRMAN DURST: Petr.
DR. BOCEK: Petr Bocek again. Just in
connection to that, there were current reports by
Gideon Lack's group from the Royal College for
London where they looked at kids in Israel and kids
in England and looked at peanut allergy.
Surprisingly, there is about more than an
order of magnitude lower peanut allergy in Israel
than in Europe. One of the possible reasons, which
is now being intensely investigated, is the fact
that Israeli children, Jewish children, have early
exposure to high doses of peanut protein through a
snack called Bamba, which basically since most of
them starting at six months of age start sucking on
it and eating it and eat basically 2 full grams of
peanut
protein a week.
330
There is certainly high-tolerance probably
happening, and it is currently in a clinical trial
by Gideon Lack in London looking at that.
DR. BRITTAIN: I haven't really heard
anybody talk about this, but just because something
is a serving size doesn't mean somebody is going to
eat just one serving size. Someone might eat 20
cookies. It seems like that should be taken into
account. If something is labeled essentially by
the absence of saying it has peanuts in it or
whatever, people may think it's safe and then they
eat 10 servings worth. That should be taken into
account.
CHAIRMAN DURST: David.
MR. ORYANG: Yes, David Oryang. Just
going back to methodology, just briefly, the
analytical methods-based approach. The issues that
FDA has put before us here that need to be
considered when using analytical methods-based
approach.
Just touching on one of those issues, I
don't know
whether Dr. Taylor could comment on
331
this, if anything has been done, but someone had
earlier brought up the issue of sensitivity and
specificity of the methods and of the kits, the
fact that there were varied kits and a lot of them
hadn't been specifically validated. Are there any
that you know the specificity of and the
sensitivity? Is this standard published before you
start using the kits?
DR. HEFLE: Well, these are proprietary
products, but when people ask questions
manufacturers are glad to provide things that
aren't apparently trade secrets. They will provide
manufacturers and others with information on
cross-reactivity.
You can get tables from them. They have
done all of this. If you ask for it, you can get
the data. It is not something they put in the kit
inserts that the average person pulling off the
shelf can read about all of the cross-reactivity,
so they test out with a matrices.
There is specificity and sensitivity known
and
cross-reaction amongst things, but I guess you
332
have to call the manufacturer and ask the
questions. Some people aren't willing to do that.
They expect it to be out there and everywhere.
That has been one of the hurdles in getting people
to just call and ask.
For most of the companies that I know of,
they are willing to share this information with
somebody that is truly interested and not just
looking for trouble. That information should be
available from the manufacturers, to my knowledge,
and be available from the government, too.
MR. ORYANG: The methods have been
validated by the manufacturers?
DR. HEFLE: Yes. By the manufacturers,
yes.
MR. ORYANG: Okay.
DR. HEFLE: The only validation that
hasn't really been done in a lot of cases is in an
interlaboratory kind of trial to make sure that it
performs the same way in different -- that is
pretty much the way I understand the validation
that needs
to be done.
333
MR. ORYANG: I see. Is there any move to
do that or--?
DR. HEFLE: There are lots of efforts
going on around the world not so much at FDA right
now, although I know they have been working on as
best they can, given the budget that they have.
Yes, if we could get past this validation,
I think everybody could be comfortable that we
could use the methods for a lot of different
things. It is already being used and being
validated in other parts of the world. Germany has
their own system.
They do their own validations. They do
ring trials to get it done, and they use it. I
think we just need to get some more of these
international trials done. There are efforts.
Again, that takes money and time and
materials and reference materials, too, which is
why some of this has not been done yet. There is
no funding available to do these. That is a pretty
substantial amount of funding to run one of these
and
coordinate one of these, so that is not
334
inconsequential.
CHAIRMAN DURST: Pat.
DR. CALLERY: Pat Callery. To follow up
on that, it looks like there will probably be some
good advancements in this area. The concern about
sensitivity and specificity comes in part from the
comment I think I heard a few minutes ago, that in
fact this test is related to peanuts rather than
the allergen itself. The specificity might very
well be to deal with the specific allergen.
In our writeup that we were given, in the
preliminary information, there is one reference by
Shefcheck that is on the confirmation of the
allergenic peanut protein, Ara h 1, in a model food
matrix using liquid chromatography/tandem mass
spectrometry.
This is a technique that is incredibly
sensitive and specific, and if they can look for
the specific protein, I think that there will be
great advancements. I think the method was not
supported much in the writeup, because it is a
potentially
expensive, time-consuming method, but
335
it has a chance of providing the information that
we are after.
DR. MALEKI: Soheila Maleki. One,
manufacturers as well as consumers wouldn't really
necessarily care if there was a specific allergen
in there. They just want to know if that food is
in there. Particularly, the different allergens
and the different proteins interact with different
processing in different ways.
For example, Ara h 1 becomes highly
insoluble in the case of roasting. You can't test
it if you are just testing for that. You have a
much better chance of detecting peanut protein or
something in there if you are actually targeting
the peanut protein, in other words, you have much
more sensitivity. You have really high specificity
to detect small amounts.
Now, if you had large amounts of something
else in there that it possibly would cross react
with, then you would get a non-specific response.
However, when you have small amounts and you are
trying to
detect trace amounts, in that case
336
cross-reactivity is very rare. I don't know if
that helps.
DR. CALLERY: Pat Callery. If you are
trying to set a value, it is best to look for a
single entity that is not going to be changed from
matrix to matrix.
DR. MALEKI: That is a good idea, but it
won't work because those individual allergens will
change from within one matrix to another. Like I
said, you have a much better chance of detecting
them, if you can detect multiple proteins rather
than just one.
That way if it is there, you will always
know. Even if Ara h 1 doesn't go in the solution
or Ara h 2 falls out of the solution or is broken
down, you still have a chance to say, yes, there is
peanut there. There is less chance of error,
actually. That is pretty much well known within
the industry and the manufacturers.
CHAIRMAN DURST: Yes.
DR. KELLY: That brings me to another
comment or question.
337
CHAIRMAN DURST: Name?
DR. KELLY: Ciaran Kelly.
(General laughter.)
DR. KELLY: Ciaran Kelly. That is, the
issue when we are talking about validation of
assays, we also need to consider standardization of
assays. They are not quite the same. Someone may
have done a lot of work to validate and demonstrate
that their assay measures what they say their assay
measures.
However, we also want to be in a world
where if different assays are being used, they can
be cross referenced. I think that is very
important.
There are also important methodological
considerations there, particularly when we are
talking about polyclonal reagents. That is
something that I think also needs to be addressed,
because ultimately it is likely that those assays
will be used to measure whatever threshold levels
are being used.
CHAIRMAN DURST: Dick Durst. Along
338
similar lines, the matrix effect is one of the most
serious problems I think with these assays. The
assays in buffer solutions, and so on, can show
tremendous specificity, sensitivity, and so on.
However, when you have the matrix effect,
that can greatly affect the extraction of the
protein that you are interested in and cause
interferences, and so on. That is where a lot of
the problems come in. A lot of work also has to be
done in the development of protocols for extracting
the active ingredient, the allergen that we are
interested in.
DR. MALEKI: Soheila Maleki. Just in
answer to Dr. Callery, again, to reference what you
are talking about between standardizing between the
kits, that has come up a lot.
It is an issue that I think is going to be
addressed in developing some type of standard by
maybe one manufacturer that can allow all the kit
manufacturers to standardize their kits, so that
later that can be related to actually what the
threshold
doses are, which is what they are
339
determining now. That is one thing.
As far as the matrix effect, there is
really not a whole lot you can do with that except
as technology increases. Right now, the extraction
methods are getting better and better.
Better buffers are being used and better
treatments, whereas you are getting a lot more
consistent results between the kids and by the kids
themselves. Therefore, when you do the
experiments, you are getting more, essentially,
consistent results, and so forth.
CHAIRMAN DURST: David first and then
Ciaran.
DR. KELLY: Ciaran Kelly. This is on a
different topic, so I don't know if there is
another question on the same topic.
CHAIRMAN DURST: Okay. David had his hand
up.
DR. KELLY: You might want to continue.
MR. ORYANG: Well, it is similar, about
the sensitivity again. I just wanted to follow up
with Dr.
Taylor or anyone else, again, just
340
highlighting this analytical methods-based. What
allergens have, let's say, caused a response in
individuals at the levels of detectability of some
of these methods? Do we have a list of that so
that at least we can begin to say, okay, the
analytical methods-based approach could be used on
these things, because right now we know that the
level of detectability is similar to--?
DR. TAYLOR: Well, when we worked to
develop the detection levels of these tests, it was
absolutely our goal that no patient would react at
the limit of sensitivity of the test. I am
actually quite hopeful that I will never find that
case, because we were trying to be conservative.
If you get a negative result on this test,
you are going to advise the food industry to go
forth and not label this product. Why? All of
these people are going to buy this product and you
don't want their children to react to it. We don't
know that anyone reacts to reasonable serving sizes
at those levels, limits, of detection.
MR. ORYANG: Okay. The follow up, what
341
allergens react to, let's say, hundredfold levels,
a hundred times the level of detection?
DR. TAYLOR: Again, that is kind of a hard
question to answer.
(General laughter.)
DR. TAYLOR: Help me work through this
analytically, 2.5 parts per million, a hundredfold
higher than that, 250 parts per million. Two
hundred and fifty parts per million would be
250 milligrams per kilogram, 25 milligrams.
If I looked at all of the data, and again
I'm assuming a 100-gram serving size -- a heck of
an assumption, but we will go with that because the
math I can do in my head in the late afternoon --
if we look at all the data on all of those studies,
I would say that a relatively modest percentage of
the challenge patients with published data would
react at 25 milligrams to peanut, milk and egg.
We have almost no data on wheat and
soybean and fish and crustacean shellfish. In
fact, there wouldn't be any data out there, limited
as it might
be, on soybean to suggest that 25
342
milligrams of soybeans is hazardous to anyone.
MR. ORYANG: Thank you. I just wanted to
get some kind of reference point for the
applicability, direct applicability, of the
analytical methods-based approach.
DR. TAYLOR: Yes, I mean, I see what
you're driving at. It would be my view that if you
use the 2.5 part per million level as your interim
threshold level, that would be a very conservative
approach.
Like I said, I hope I never meet the
person that would react at that level, because it
was the intent for that level to be safe for
virtually everyone, if not everyone.
DR. KELLY: Ciaran Kelly. Actually,
Dr. Taylor, you may want to address this question
also. I wanted to return to the question of the
sensitivity of the challenge studies, particularly
the question as regards whether symptoms or signs
are used.
I am a physician also and I reiterate
Marc's
comment that for a physician about objective
343
symptoms versus subjective symptoms. It burns a
hole in our --
(General laughter.)
DR. TAYLOR: I usually call them
"reactions," so I guess I get away with it either
way.
DR. KELLY: In any event, can you give us
a sense of where the field is at present? Because
the objectives may be different in terms of clearly
signs are going to be much more objective and much
more specific, but we perhaps would have a greater
desire to have sensitivity in identifying
thresholds that may cause an allergic reaction.
Are you aware of any studies that are
specifically looking at that, looking, for example,
at what is the difference in dose between a symptom
but then goes to a sign? Is that being looked at,
or has the field sort of abandoned symptoms?
DR. TAYLOR: Well, I don't know if they've
abandoned, maybe neglected it. Dr. Teuber made
this point earlier, and she is absolutely correct.
Many of
these studies that I referred to and that
344
Rene[MLM3] Crevel used in drawing his curves are actually
diagnostic challenge trials.
If you are trying to diagnose a patient to
determine if they actually have a given food
allergy, you want to see signs. Almost all of
those clinicians, I think, would proceed to
actually physically observable symptoms.
However, that doesn't mean they wouldn't
pay attention to subjective symptoms that might
occur along the way as they are increasing the
doses and the person says, "My mouth itches" or "My
stomach hurts." I think you would pay attention to
that because it would alert you to the fact that
the guy might have a more significant event the
next dose.
There have only been a limited number of
studies where people have done threshold trials
where they actually went through the subjective
symptoms and got to the objective signs.
The study we did with Jonathan Hourihane
and others on peanut thresholds published in 1997
was one of
those. Admittedly, it was modest. It
345
was the first threshold trial that ever got done.
It was 14 subjects, 2 of them reacted with
subjective symptoms at 100 micrograms. They got
several doses after that, and one of those
individuals first developed mild, objective signs
at 2 milligrams and the other at 5.
As you wrestle with this, in my view,
whether you use signs or symptoms, it is a question
of how much uncertainty you assign to those
numbers, how big the uncertainty factor is.
As I alluded to this morning, I would
advocate using a smaller uncertainty factor if you
go with subjective symptoms than you would if you
went with objective signs.
Although, it is still not even that
simple, because if the person had objective signs
at 500 milligrams in a diagnostic trial, I am real
concerned about what might happen at levels far
below that.
DR. KELLY: The consensus protocol, how
does that address this issue?
DR. TAYLOR: The consensus
protocol that
346
we published last year, the consensus was to go to
objective signs in these threshold trials, but to
pay attention to subjective symptoms and record
them, record the doses at which they occurred.
I mean, these studies cost a lot of money.
I believe in capturing every conceivably
significant data point, because I don't know how
regulators are going to use this information, so
let's give it all to them and let the wisest people
decide what to do.
DR. KELLY: Ultimately, I guess that is my
point, that these data, hopefully, will be gathered
and it will be possible to look at subjective
symptoms as a secondary endpoint and see how it
relates.
DR. TAYLOR: Yes. Another point I didn't
make is that I am convinced that even though
clinicians have only reported LOAELs in their
studies, that many of these clinicians have NOAEL
data on their charts. They just haven't taken the
time and effort.
In fact, I asked Dr. Sampson that question
347
last week and he said, "Yes, I have more than a
thousand charts. If you'd like to send me some
money so I can have someone sit down and look at
these charts, I would be able to give you the
individual NOAELs for all of the patients who did
not react at the first dose. I have never
published that data; I have never collated it; I've
never computerized it. It is all on paper charts."
CHAIRMAN DURST: Okay. One more question
from Marc, and then I would like to move on to the
specific questions that FDA has asked us to
address.
Marc, do you want to just finish up?
DR. SILVERSTEIN: I wanted to ask the
scientific rationale for an uncertainty factor? Is
it just giving you a wider range to be right about
the prognostic value, that is, the likelihood that
in those who are positive or negative their
subsequent events, whether it be anaphylaxis or
other food allergy related events?
Is the scientific rationale for
uncertainty
factors just being careful, or is the
348
scientific rationale based on what we saw earlier,
intraspecies individually between species and
within individual variations, or is it between
symptoms and signs? What is your best judgment
about the rationale by which you can provide the
uncertainty factors?
DR. TAYLOR: I think uncertainty factors,
the old standard -- I went to school in toxicology
-- was this hundredfold uncertainty factor. It was
tenfold for extrapolating from mice or rats to
humans and tenfold for interindividual variations
among humans. That is mostly very arbitrary.
Although I was told in graduate school, and never
went back to look it up, that it actually has a
basis in fact.
It came about from some famous drug
contamination episode called the "elixir of
sulfanilamide episode," back in the 1930s, where
they actually had animal data and they actually had
human data from the poor, unfortunate souls that
succumbed to this contaminated drug. It has some
basis in
fact, but it is a lot of expert judgment
349
not so much biologically based in some cases.
DR. SILVERSTEIN: Let me comment, then,
and again highly relevant to the FDA with that
historical example, this would be inferences drawn
from toxicologic studies where live proportions of
the population might be susceptible to some range
of exposure?
In contrast, though, in allergic diseases
we are dealing with not a large proportion of the
population but a substantial fraction of the
population that might have within individuals much
more range in terms of sensitivity.
What I'm leading to is I might want to be
more cautious about taking from a toxicologic
exposure to an allergic disease mechanism the same
range of uncertainty.
DR. TAYLOR: Yes. It is hard to address
that point, because most of our experience with
uncertainty factors deals with toxicologic
exposures where the whole entire population is
conceivably at risk. Here, admittedly, we have a
smaller
proportion of the population that is at
350
risk.
Conceptually, I don't have a problem with
using uncertainty factors, because the goal is
still the same: Protect a fraction of the
population or protect the whole.
I think I'm bringing you back to what Rene
said about using the models and then doing a better
job of documenting whether the decisions that are
made are appropriate by attempting to validate
whether the model is correct or not.
We actually have a lot of data now
accumulating very rapidly from all of these
analytical determinations that are being done in
industry and in academic laboratories and
government laboratories about levels of allergens
in products that do not have adverse reactions
associated with them.
Now, you could probably get even better
data if you could analyze what some of these
consumers have actually eaten that did not make
them sick. Based on my experience, I am almost
sure that
they eat tiny, tiny amounts of milk and
351
egg periodically, even though they don't know about
it. That would help you determine whether the
numbers you selected were achieving the goal you
wanted to reach, and I don't know how to determine
that otherwise.
DR. SILVERSTEIN: Dr. Crevel is not here.
Could I follow up with one question about the
modeling approach?
CHAIRMAN DURST: Okay.
DR. SILVERSTEIN: I found that modeling
approach very interesting. He selected an ED10 and
ED1. Is there a rationale for having the ED1,
which for me would be saying we're looking to see a
threshold that would affect 1 percent of the
population?
DR. TAYLOR: One percent of the allergic
population?
DR. SILVERSTEIN: Yes.
DR. TAYLOR: Yes. Well, the ED10, your
model should predict that because if you've got 29
observations, you've got the ED10. If your model
doesn't
predict an ED10, it is truly a lousy model.
352
The ED1, I can't remember the binomial
distributions, but you've got to have a lot of
participants to get to the ED1, so you have to
extrapolate.
I'm not much of a statistician, but you
are going to get a lot more variability in guessing
ED1, and you get even more variability if you tried
to surmise what the ED 0.1 is.
But then if you used one of those, my
argument is you could see what the experience is of
the allergic individuals in the population. If you
choose well, then all of the allergic individuals
stay well; and, if you don't choose well, some of
them are going to get sick. That is why I think it
is important to follow this up and see whether we
chose well enough.
CHAIRMAN DURST: Okay. Thank you very
much.
I think, as I mentioned, we really do have
to address some of these questions put to us by the
FDA, since our time is going to be limited
tomorrow. We will be focused on
glutens, and then
353
Friday will probably be a somewhat truncated
session. Hopefully, we can get through a number of
these questions before 7:00 or 8:00 tonight.
(General laughter.)
CHAIRMAN DURST: I think the general
questions probably can wait until we've had the
gluten discussion because they probably address
both aspects, but, specifically, the food
allergens. Why don't we just take these questions
one by one, and, hopefully, come up with some kind
of conclusion or consensus for the FDA.
The first one: "Are there distinct
subpopulations of highly sensitive individuals
within the allergic population for each of the
major food allergens?"
Would anyone like to address that?
(No verbal response.)
CHAIRMAN DURST: My goodness, what
happened to that talkative group?
(General laughter.)
DR. HEIMBURGER: This is Doug Heimburger.
Clinically,
anecdotally, yes, people do respond,
354
allergic people within the subpopulation. There
are subpopulations who respond both more severely
and at lower levels, but it sounds like we really
don't have nearly enough data to be able to say
just how we identified those people; is that
correct?
DR. BRITTAIN: Erica Brittain. Yes, I
don't know how you would distinguish between a
subpopulation versus a continuum. I mean,
obviously there is variability and sensitivity,
that's for sure.
DR. HEIMBURGER: Yes.
DR. BRITTAIN: Whether it is a continuum,
I certainly don't know.
DR. MALEKI: Soheila Maleki. I think that
Dr. Wood, who unfortunately isn't here, really
addressed that question fairly well this morning,
showing the range of the reactions and the
populations.
However, I also think the answer to that
is, yes, that there are individuals that are highly
sensitive
that can be set apart from the rest of
355
the group in some ways.
Generally, I think if we go back to that
presentation that it would be very sufficient in
explaining the percentages as well as the range of
reactions going from IgE-mediated to
gastrointestinal and other types such as celiac
disease.
CHAIRMAN DURST: Does the Committee feel
that this applies to each of the allergens or--?
DR. MALEKI: I think so. I mean, I think
even, for example, in some cases when egg and milk
are outgrown as an infant, there is a severely
allergic population that will not outgrow it.
There are always the exceptions or the highly
allergic. Maybe Sue or one of the clinicians may
be able to address that.
DR. HEIMBURGER: Doug Heimburger. The
fact that they grow some of those means that they
are at some points in their lives more sensitive
than they are at other points in their lives. The
answer is, yes, there are definitely more sensitive
and less
sensitive.
356
DR. MALEKI: Yes, I agree.
DR. KELLY: Ciaran Kelly here. Sorry to
disagree and maybe pick on words, but are there
distinct subpopulations? How can we identify these
individuals?
If there are individuals who at one point
in their life are very sensitive and later less
sensitive, then to me they are not distinct; they
merge one into another.
I think my clinical experience is that it
is a continuum, that there is not a group of
individuals who are highly sensitive, a different
group who are moderately sensitive and another
group who are not sensitive at all. There is a
whole population. I don't think we can subdivide
them into subpopulations.
DR. WASLIEN: Carol Waslien. Can you
divide them on the basis of how many epitopes they
are sensitive to? Some are sensitive to only one
of the proteins in peanut protein, some are
sensitive to two, some are sensitive to three, and
some are
sensitive to soybeans as well as peanuts.
357
There is that kind of subpopulation, and
those are not on a continuum. Those are distinct
characteristics. There is that kind of
differentiation on the basis of some of the
differences.
DR. HEIMBURGER: Doug Heimburger.
(Simultaneous discussion.)
DR. MALEKI: Soheila Maleki. Oh, I'm
sorry.
I was just going to say that right now,
they are doing microarray analysis on
individualized epitope mapping in relation to what
relationship that has to the type of reactivity
that these individuals are having. They have
identified specific dominant epitopes that are more
likely to occur -- their IgE is more likely to
recognize, if the individuals have severe
reactions.
Again, going back to what you were you
were saying -- and I would like to hear from the
clinicians, maybe Suzanne Teuber, about the fact
that, yes,
there are definitely subpopulations that
358
are severely allergic. Does anybody else have a
comment on that?
CHAIRMAN DURST: Petr.
DR. BOCEK: Petr Bocek. Well, I think the
question is posed in order to then actually follow
with the uncertainty factor. It is not whether we
can define this subpopulation by a specific
biomarker, but it is asking whether the eight major
food allergy groups, are there people with severe
allergy? The answer is yes.
It is basically asking within the
population of people who are allergic to these
foods, what is the range, what is the factor we
apply in order to be safe? I think the simple
answer to the first question is yes.
DR. MALEKI: I agree.
CHAIRMAN DURST: Okay. David.
MR. ORYANG: Yes. Just following up on
Dr. Bocek -- David Oryang -- I think the sensitive
individuals, the allergic population, has already
been divided up. The children react differently
from adults to a lot of the allergens, so
there is
359
already those subpopulations.
Beyond that, maybe there are even
subpopulations within that. Right now, are the
safety factors to be applied to children the same
as the safety factors to be applied to adults or
not? That is the question. Should they be the
same? I don't know.
CHAIRMAN DURST: By the "safety factors,"
are you talking about these uncertainty factors?
MR. ORYANG: The uncertainty factors,
right. Yes, the uncertainty factors.
DR. HEIMBURGER: Severity of response
factor as well.
DR. MALEKI: Soheila Maleki here. I think
that one, not all, but maybe some of the allergenic
substances for adults and children will be the
same. However, there are specific allergens that
are adult allergens that are not child allergens,
for example, egg and milk. I don't think we should
consider the safety of a child more than we should
consider the safety of an adult. I think life is
precious.
360
MR. ORYANG: That's true.
DR. MALEKI: I don't think that is the
term to subdivide it. If you were going to divide
it into anything, it might be the different foods
to consider. Even in that case, I don't think we
should make that distinction. I think everybody
should be protected or that's who we should
consider.
MR. ORYANG: You are saying we shouldn't
divide it into any subpopulations?
DR. MALEKI: Well, I think severe reaction
versus non-severe reaction but not, like,
separating children versus adults or men versus
women, and so forth.
MR. ORYANG: That's an example. If there
is a real difference in their reaction or an adult
response, and so forth.
DR. MALEKI: Oh, I see.
MR. ORYANG: I mean, if there are major
differences, if you can break the whole population
up into different ways in which they react to the
same dose,
a child versus an adult, are they going
361
to react the same? Then, also, the exposure maybe
also needs to be considered and all those things.
The safety factor I think in children's
food, isn't there a much higher safety factor for
some of those kinds of things than other
commodities? I don't know whether some of the
industry people can respond to that.
CHAIRMAN DURST: Okay. Suzanne and then
Doug.
DR. TEUBER: I had a specific question. I
was just going to bring up that between children
and adults, for instance, most of the deaths are
caused by peanuts and tree nuts and then seafood
for a smaller percent, at least that is in our
culture.
As time goes on, Sicherer in that
Johns Hopkins group and now Mount Sinai have shown
that in follow-up interviews for many of the kids
who have peanut/tree nut allergies, the reactions
actually became more severe with time, but we don't
know what happens to the thresholds. I don't think
we have
that kind of age data, and I don't know if
362
anybody is studying that right now.
DR. HEIMBURGER: Doug Heimburger. To
point back to the question again, as Petr did, the
question is not asking us to identify
subpopulations; the question is asking us is 10
times 10 equals 100 a sufficiently wide range.
That is a different question from can we identify
them.
CHAIRMAN DURST: What is the answer?
DR. MALEKI: Soheila Maleki. I just
wanted to add a comment to Suzanne's comment, that
they have actually identified, they have
determined, that individuals between 11 and 33 are
more likely to suffer anaphylaxis and have fatal
anaphylaxis, because that is when they start
experimenting with food. That is the age range, if
that was a question. Again, the bottom line answer
to this is pretty much yes.
CHAIRMAN DURST: Yes?
DR. BRITTAIN: Well, are you asking to
answer the factoring question.
(General laughter.)
363
CHAIRMAN DURST: Yes, the statistician,
please.
DR. BRITTAIN: Well, to me it feels really
arbitrary. It goes back to the question I posed at
the beginning of the discussion. I mean, I don't
know if we are aiming at -- we want to make sure
there are almost no reactions in the most sensitive
population. If that is our goal, that affects how
we would choose the uncertainty factor.
We would want a bigger uncertainty factor
if we are really trying to focus on the
supersensitive patients. If we are just trying to
say something about all allergic patients, then you
might not need as big an uncertainty factor.
It also depends on what data you used
amongst the studies. Are you only including those
studies in allergic patients? That is all part of
it, too. It is sort of hard to answer this
question in isolation.
CHAIRMAN DURST: She asked and answered
it.
DR. BOCEK: Petr Bocek. Well, I think at
364
least what I'm hearing is we agree that the safety
assessment-based approach is good and valid and it
is fine. The concern I have, and we have already
addressed that, whether the current data is
targeting the right population.
At least in this country even considering
the more aggressive approach in Europe, we're still
certainly missing the most allergic patients
because we are doing diagnostic challenges, the
majority of them.
If you want to base the uncertainty factor
on that, on the LOAEL determined from these
studies, and you think about, let's say, 2,500
milligrams being the LOAEL in these studies -- I'm
just pulling a number -- and then you have a
patient, anecdotal evidence of kids anaphylaxing
and adults anaphylaxing just to the peanut powder
when somebody opens a bag of peanut, and there are
case reports of that, that certainly is more than
100, less milligram exposure than 100 milligrams in
those challenges.
I'm not sure, you may not like me, but I
365
think the hundredfold, if I were thinking about the
current data from the current double-blind
challenges, I don't think it is sufficient.
DR. BRITTAIN: Yes. Adding to that they
mention there is one millionfold, the previous
statistic today, one-millionfold range in
sensitivity, so I don't see how the hundred address
that.
CHAIRMAN DURST: Anything else on this?
DR. MALEKI: Soheila Maleki. Just to
comment, yes, there is a range of one-millionfold
of sensitivity. On the other hand, just like zero
levels of a particular allergen in a food is
virtually impossible for the industry and
manufacturers, I think to set your statistics on
zero tolerance, that nobody is ever going to have a
reaction, is also unachievable.
You want to determine threshold levels,
that means the most severe reactors, and then pick
a level severalfold below that, and that might
increase the safety factor.
With the knowledge and what we have today,
366
I don't think it is possible to say we have to pick
a level of a millionfold less. I know, I
understand why you're saying it, that it is
probably because of the range that is different.
However, if you pick the lowest level then --
DR. HEIMBURGER: Then, a hundredfold
uncertainty factor applied to that, then perhaps it
is sufficient.
DR. BRITTAIN: If you had the right data?
DR. HEIMBURGER: If you have the data on
who is the most sensitive person and who is that at
one millionth of the other person, and then you
have a hundredfold uncertainty factor. The
question is, Is that a sufficient uncertainty
factor? It is sounding a little more sufficient, I
think, if you phrase it that way.
DR. MALEKI: Soheila Maleki. Just one
comment again. Being able to test these people,
most of the data that has been shown or is
available is based on diagnostic challenges.
The threshold studies that are actually
going to be
valid for the first time or some that
367
have been done, maybe there are two studies, this
is a beginning type of study going on.
Right now, there may not be all of that
data available, but I think they are going up the
right track where they are picking the most severe
reactors and they are treating them and waiting and
recording subjective and then objective data. That
is going to give us the closest we can get with the
funds and opportunities and what we know available.
CHAIRMAN DURST: Suzanne.
DR. TEUBER: Again on that, I would hate
to see some of the subjective symptoms thrown out
of the analysis. There are going to be individual
physicians who are involved in these threshold
studies who are not going to go above that, at
least this is what I had heard. They are going to
be more comfortable if they have a reproducible,
subjective symptom in stopping.
Again, if we talk about the safety
assessment as it is written, it would throw out all
that data and throw out these patients who may be
exceedingly
sensitive, and this is some of the
368
population that we want.
I think this just keeps coming up as a
concern for the FDA in evaluating what approach is
to be used and how the future data comes in to be
evaluated.
CHAIRMAN DURST: Okay. Anything else?
Erica.
DR. BRITTAIN: Erica Brittain. I guess I
just wanted to make a general comment about the
report. The report seemed to me, if I understood
it, the recommendations in the report seemed to be
feeling that the modeling approach wasn't really
ready for prime time, if I understood the
conclusions they drew.
I guess I'm a little confused why this,
which seems, you know, just like a very vague
standard or just finding some uncertainty factor,
why that would be preferable to the modeling, even
if it hadn't been completely validated. I just
wanted to make that comment.
CHAIRMAN DURST: Is there anything else on
this?
369
(No verbal response.)
CHAIRMAN DURST: I guess we've answered it
to their satisfaction.
Yes.
DR. BARACH: Jeff Barach. I have one
comment to add to it. I think it is probably a
little bit premature that we should start to set
values for these uncertainty factors of tenfold or
whatever.
We heard from Steve Taylor that he was
looking at uncertainty factors of maybe one or two.
I think that reflects the fact that if we go with a
10 and 10, we are using a standard approach that
has been used for pesticide residues in the food
system for a while, so there is some comfort level
associated with that.
However, I don't think we really have the
comfort level from the data and the population
studies and the challenge studies to really pin
down these numbers.
I would say that using uncertainty factors
will be a
benefit, but I don't think we are really
370
quite ready to even identify the magnitude of those
uncertainty factors is at this point.
CHAIRMAN DURST: David.
MR. ORYANG: Yes, David Oryang. I concur
with Dr. Barach in a sense, but I add that I think
more work could be done to try different safety
factors and apply it in the context of the model
that evaluates how many people might come up with
symptoms, if the safety factor was a certain value
for a specific allergen, given people's reactivity.
We can begin to capture the outliers, in
other words, those highly reactive people. I think
there is some data which indicates the percentage
of people that would probably react up to the
million times more than the average person.
DR. TEUBER: There is that, that is what
has been brought up.
MR. ORYANG: Okay. There is that data, so
I think some modeling probably could be done to
find out, to determine, how many cases would come
out of setting a safety factor at a specific level,
if the
appropriate models were developed to do
371
that. That is where the risk assessment-based
approach is.
I think we can begin to start doing some
of that, if we put in the distributions even the
safety factor, but the NOAEL could be put in as a
distribution as opposed to a point value, as an
example, and you can then run a model to determine
how many cases there would be of reaction at a
specific safety level.
I think that is the kind of thing that FDA
could do to take this a little bit further as
opposed to just deciding.
I mean, it is impossible to decide just
like this, to say, well, is a hundredfold good
enough? There has to be a basis for saying that it
is good enough.
The basis might be, well, we've reduced
the number of cases tenfold or reduced it a
hundredfold or we've reduced the number of cases to
less than one in a million, or whatever the case
is, and then you can decide that you have taken it
to the
right level.
372
CHAIRMAN DURST: Okay.
DR. WASLIEN: This is Carol Waslien.
Maybe because there are so many studies, it sounds
like they are almost ready to be reported. Using
some of the kind of data that we would need to set
uncertainty factors, maybe we can say that, yes,
there may very well be differences, but we can't
tell what they are right now.
However, when that data becomes available,
we should be able to say what they are and make
those calculations for differences using subjective
and objective, using prognostic information.
Therefore, we should then use the correct
scientific approach to determine uncertainty
factors in something besides pesticide residues
that all of us are sensitive to.
CHAIRMAN DURST: Erica.
DR. BRITTAIN: I think you would also want
to think about maybe doing both approaches, both
modeling and uncertainty factors, and hope to see
some kind of agreement in the approaches. I want
to
emphasize for both you need the right data.
373
CHAIRMAN DURST: Jean.
MS. HALLORAN: Yes. I think very good
comments have been made here about that. This type
of uncertainty factor is very different from
pesticides. For one thing, we are not
extrapolating from rats to humans. We are working
with human data to start with.
Another one we are not dealing with sort
of variability from an average person. We are
trying to start with the most sensitive person and
set a safety factor for them.
It is a really different task, but it is
also a task for which we don't have the data that
you need to start with, which is the number for the
most sensitive person.
Perhaps, as a principle, we could suggest
to FDA something like what Steve said, which is
basically: the better the data, the less of an
uncertainty factor you may need; the worse the
data, perhaps the bigger the uncertainty factor
that should be built in.
DR. MALEKI: Soheila Maleki. I just want
374
to ask, I know the Food Allergy and Anaphylaxis
Network has helped in a lot of research studies
because they have 27,000 members of food-allergic
people.
I wonder if anybody has done, or are there
any studies done to divide up highly severe to
moderate to low allergic individuals? It seems
like that is one of the questions that David was
asking.
MS. MUNOZ-FURLONG I have not done that
with our membership. I'm not aware of any studies.
I will tell you from the fatality registry and the
fatality studies that have been published, there
have been a number of people who have died who had
only previously had mild reactions.
I'm not sure we are ever going to be able
to put people in neat, little boxes that says,
"You're a mild reactor, and you will always stay
there." This seems to move and nobody can predict
when or why.
CHAIRMAN DURST: Margaret.
DR. McBRIDE: Margaret
McBride. As I
375
listen to all of this, a couple of things come to
mind, and one is that we really are looking at
risk. No matter how you define the range of
sensitivity there is going to be an outlier or
there are going to be outliers of that very
sensitive end.
In a sense, that is what people have been
asking, What are we aiming for? We really know
that we can't set something that will be truly safe
for everyone.
The other things is, if understand again,
LOAELs, if we in fact we could test everyone, we
would get a LOAEL and we wouldn't need any safety
factor.
The safety factor is because we can't test
everyone and because we are assuming that we are
not testing the most sensitive individual. Does
anybody want to comment on that?
I mean, what we are trying to say is easy
to say. I would certainly agree that we don't have
the data to set a safety factor, but remember that
we are
setting a safety factor because we can't
376
test everyone or because, understandably, the most
sensitive people won't sign up for the testing.
We have a conundrum, but we still have
folks who need to read labels. I mean, I'm a
clinician, so it is easy for me to live with some
uncertainties because I'm forced to every day when
the data isn't available.
DR. BRITTAIN: Yes, this is Erica
Brittain. That brings up something that I keep
thinking about. There really isn't a safety
threshold overall so much as each person has their
own threshold.
This is a totally different way of
thinking about it. However, if you could label the
food by the quantity instead of saying yes/no it is
above some magic line, is that a solution, that
people would know their own tolerability?
DR. McBRIDE: It may change over time, you
know, maybe we need to look at yearly threshold
testing or something.
DR. MALEKI: Soheila Maleki. Exactly, as
Anne just
mentioned, you don't even know the
377
reactors much less the threshold levels for each
person changing. You can just choose a population
that you believe to be the most reactive and
determine what you best can determine.
Maybe technology will improve with time,
and you an do a lot better, or more people can be
tested in that way. Yes, that is a nice thought,
but I don't think most people know what their
thresholds would be.
CHAIRMAN DURST: Okay. Shall we move on?
(No verbal response.)
CHAIRMAN DURST: As far as the second one,
we touched on it a little bit the LOAELs and
NOAELs: "Is the initial objective response seen in
a clinical challenge study always an adverse effect
that poses a risk to human health?"
DR. TEUBER: I find this question a little
bit ambiguous. An objective response in one
person, so, yes, that particular response in many
of these studies has been an extremely severe
response, but not in the studies that were designed
as a true
threshold study.
378
They are just saying clinical challenge
study. Since so many of these studies were
diagnostic, there were so many people who reacted
on the first dose. Yes, it could be a
life-threatening reaction; but in the
well-performed threshold studies, the first
objective reactions have not been life threatening.
It could still be clinically significant. You
would want to account for that with the uncertainty
factor going down below that.
DR. MALEKI: Soheila Maleki. Just an
addition, the dosage again that Steve also
mentioned before, the dosage with a clinical
challenge study is very different than the dosage
that use for threshold doses. For a threshold, you
are obviously trying to determine a threshold.
With a clinical challenge, you want to have a
clinical reaction to say, yes, this person is
allergic.
Am I correct, Suzanne?
DR. TEUBER: Yes. They could have chosen
lower doses
to start with, but I think people are
379
now choosing far lower doses to start with, even in
diagnostic challenges. However, there had to be
something to start with in the literature, and that
is what we have.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: Marc Silverstein. If I
were to try to operationalize a question like that
for an epidemiologic study or a clinical study, the
words that I would be focused on is "always" and
"risk."
For me "always" might be 90 or 95 percent.
An attorney might say it is 50 percent or greater.
There would be some, "Well, what is always?" It
would be some large number. For us in the clinical
realm, we might say it is 80, 90, 95 percent.
Then, risk to human health? Well, if the
outcomes of an allergic reaction could include
death among the spectrum of anaphylaxis, then we
might be thinking of risks that were weak risks.
Low risk would be clinically important risk.
In an epidemiologic study, we might say
even those
variables where the risk ratio was less
380
than two might be important, or we may say we are
going to consider large risks that might be risk
ratios of four or greater.
As I try to answer some of these
questions, other than an absolute no risk and
never, I would try to operationalize them in terms
of magnitude knowing that in the real world
clinicians and policymakers have to make some
decisions.
Having said that, my subjective
inclination would be to say I would think that
clinicians caring for patients and policymakers
would make assume that if a patient reacted
positively in a diagnostic challenge with objective
symptoms, that patient is at risk probably to the
point where they would translate it into a
recommendation for patient and the family with
regard to diet.
With regard to that, I would say it seems
to me that it is reasonable to say, yes, objective
symptoms would be tantamount to saying essentially
risk would be of sufficient frequency and
381
sufficient magnitude to answer this question yes.
That would be the way I might approach it.
CHAIRMAN DURST: Petr.
DR. BOCEK: Petr Bocek. I think the
remainder of the paragraph is actually looking at
the subjective response and the objective response.
I understand this first question as if you do a
challenge study and your stopping point would be
the initial objective response, it is asking, does
it always impose this risk to human health?
Well, my answer is no. Because if you do
a challenge study, a clinical challenge study, and
your endpoint is the first initial objective, most
of the time it is not life-threatening.
The data we have, how many people actually
die during the challenge study? It is usually
cutaneous manifestation, hives, or something like
that. To me that doesn't pose a risk to human
health. That is how I understand the question.
CHAIRMAN DURST: Yes.
DR. NELSON: Mark Nelson. Yes, I was
trying to
understand the question as well. It
382
struck me as ambiguous. I guess I have a question
of the clinicians. Is the objective of a clinical
challenge to try to get a response to see?
As Petr said, following on the subsequent
questions, I think my interpretation of the
questions it that they seem to be asking us whether
the clinical challenge approach is really the best
way to try to set a threshold as opposed to use it
as a diagnostic tool.
DR. TEUBER: Suzanne Teuber here. Again,
in interpreting this question, I am trying to
figure out if they mean should they be throwing out
the data of people who reacted on the first dose in
the diagnostic challenge studies; and, if so, we
know that they really have to have a lower LOAEL
level than that.
The next question is, Is it scientifically
sound to use this response to determine a LOAEL?
My answer to that would be no. Again, the question
is ambiguous of what was intended. Again, I would
throw out data on people who are first-dose
responders
because they really would probably react
383
at lower levels. Is that what it is asking?
CHAIRMAN DURST: Steve, would you be able
to address that ambiguity?
DR. GENDEL: Let me get back to you on
that.
CHAIRMAN DURST: I beg your pardon?
DR. GENDEL: Let me get back to you on
that.
(General laughter.)
CHAIRMAN DURST: Jean.
MS. HALLORAN: Yes. My reading was that
they were trying to get at how you interpret data
from clinical challenges where you've got LOAELs in
the absence of NOAELs. I think all of our experts
have said that if you only have a LOAEL and not a
NOAEL, then you don't know what the NOAEL is.
(General laughter.)
MS. HALLORAN: Then, the third question
for the safety-assessment approach, Is a proposed
uncertainty factor of tenfold sufficient and
appropriate to use in the absence of a NOAEL?
I
don't know what others think, but from
384
what I've heard it seems to me like the answer is
not necessarily. You just can't necessarily guess,
because there is no standardized procedure.
DR. HEIMBURGER: It would be much more
than tenfold.
MS. HALLORAN: Yes.
DR. HEIMBURGER: The difference between
the LOAEL and what you did and the NOAEL --
Doug Heimburger -- so I think the answer to that
question is no.
DR. MALEKI: Soheila Maleki. I think the
answer to the first three questions is no, no, no.
(General laughter.)
CHAIRMAN DURST: That was easy. I wish
they were all that easy.
(General laughter.)
CHAIRMAN DURST: Margaret.
DR. McBRIDE: Margaret McBride. Just
along the same lines, really the issue of the
increment, even if you are doing a threshold study,
is important.
CHAIRMAN DURST: Sure.
385
DR. McBRIDE: Probably that's something
that needs some standards.
DR. MALEKI: Soheila Maleki. I think the
better question would have been that instead of a
clinical challenge study to ask us about a
threshold dose study, and then all of these
questions would be relevant. In a clinical
challenge study where you usually use higher doses,
and again you don't know the NOAEL, then it is not
relevant to ask the question.
DR. HEIMBURGER: Doug Heimburger. The
overarching thing here is, Should data from
clinical challenge study be used to set these
levels?
DR. MALEKI: It is no.
DR. HEIMBURGER: The overarching answer is
no.
DR. MALEKI: Soheila Maleki again. If you
actually change that question to what I believe
might have been intended as some clinical
challenges for threshold dose studies, then you can
answer some
of these questions or address them.
386
Because most of the data that is in the
literature is clinical challenge studies, the
question was actually intended to see if --
(Simultaneous discussion.)
DR. HEIMBURGER: Should we answer the
question after changes those words and then
re-answer it?
(General laughter.)
DR. MALEKI: Actually, I think they might
have been to look at the literature. Since most of
the literature is on clinical challenges, they
wanted to know if they can use that data in order
to answer these questions. It is actually an
appropriate question, and the answer is again no.
DR. HEIMBURGER: No.
(General laughter.)
CHAIRMAN DURST: Yes.
DR. KELLY: Ciaran Kelly. I agree with
the second two numbers, but I would like to revisit the
first numbers. The question is, “Do objective responses
in clinical challenge studies always have an
adverse
event that poses risk to human health?”
I
387
agree absolutely with Petr, that these are not
life-threatening responses.
On the other hand, are they acceptable
responses? Would an individual experiencing this
response at a meal consider that they'd had a
healthy meal?
I think if you look at it in that way the
answer would be, yes, these are significant to risk
human health, if you have a broad sense of health
and well-being. Although, I agree that they are
not by any means a risk to life -- probably no risk
to life.
DR. BOCEK: Petr Bocek. They are asking
about clinical challenge, and I don't think anybody
is having a happy, healthy meal doing clinical
challenges.
(General laughter.)
DR. KELLY: Yes, but the question as I
understand it is -- Ciaran Kelly again -- if an
individual has that level of symptomatology, would
that be considered an allergic reaction in everyday
life? I think the answer to that is yes, I
388
believe.
CHAIRMAN DURST: Marc?
DR. SILVERSTEIN: Marc Silverstein. I
would like to just clarify. My thinking would be
that if clinicians would translate a positive
response to a clinical challenge or a food
challenge test into a recommendation for dietary
modification, that basically is affecting the
patient's care and that is affecting their health.
To me that is a simple-minded but very realistic
issue.
Does it mean that the patient will have a
risk of dying? Yes. How big of a risk? Maybe 10
or 15 or whatever percent is graded by the risk
ratio. What proportion of patients may have it?
Some proportion of the population. What would you
do as a clinician based on that?
If it is a sufficient threshold for
clinicians to change the management, I think it
would be a sufficient threshold for parents and
individuals to say that would affect what they
would like
to see in labeling. That is why I think
389
I couldn't say no.
DR. TEUBER: Suzanne Teuber. This is
again why I did not say no to that, either. I said
yes, if you have an objective response. You have
to remember there is an uncertainty factor, and I
don't know the right term to apply, but that
applies to that individual based on the multiple
factors that have been discussed: whether their
asthma is under control, time of year, time of day,
circadian rhythm, other medications, exercise. I
think if you have an objective response at a dose,
it certainly could pose a risk in another
circumstance with that same dose.
DR. GONSALVES: I think we are doing a lot
of talking here, but it seems like Dr. Taylor said
that he is convinced that if you go back and look
at the clinical data, you could get the NOAEL
response there.
It seems to me that one would want to go
back and put this on a more scientific basis, once
you go back and look at those data and see where
you come to
your NOAEL reactions.
390
DR. TEUBER: Suzanne Teuber here again.
Again, this would be going back to clinical data
that was mainly on diagnostic challenges in
populations that do not reflect all of the
extremely sensitive people that folks are most
concerned about, whereas the threshold studies have
been really trying to recruit these extremely
sensitive people.
The NOAEL data that might be obtained from
funding, say, the Johns Hopkins group and the
Mount Sinai group to go back might not give the
levels that you would get from a new prospective
challenge study that is really recruiting these
people.
CHAIRMAN DURST: I think we have kind of
moved into the third question there with some of
these comments concerning the thresholds
established for the major food allergens, so I
guess we will continue on along those lines.
"Is it scientifically sound to use the
threshold established for a single food allergen as
a threshold
for all major food allergens?"
391
Suzanne?
DR. TEUBER: Suzanne Teuber. I would say
no, because we have the examples from soy, at least
from the data that we have, that the thresholds are
higher. It is actually again very, very difficult
to obtain people with lasting soy allergy.
CHAIRMAN DURST: Does anybody disagree or
support that?
Soheila?
DR. MALEKI: Soheila Maleki. I don't know
if I would say I agree or disagree, because I'm not
a clinician, but I actually have a question to add
to that, to anybody that can answer it.
Is there a particular food -- again, like
they say, for example, peanut -- that is the most
sensitizing, that if you picked that, you would
pretty much cover the thresholds for the rest,
Suzanne, or somebody that might want to answer
that?
CHAIRMAN DURST: David?
MR. ORYANG: It would seem from the safety
perspective, the public health perspective, it says
392
here, "In the absence of specific data," okay. Is
it scientifically sound to use a threshold
established for a single food allergen?
Yes, if you get the one that more people
react to or react most adversely to and use that as
a safety factor, you know that the other ones that
people don't react as much to will be covered.
Wow, I see all of these looks.
(General laughter.)
CHAIRMAN DURST: Okay. Mark?
DR. NELSON: This is Mark Nelson. I guess
the concern I have is that to use a single number,
one wouldn't be basing it on the science because we
do have some evidence that there are different
thresholds or different sensitivities for the other
allergens.
Also, then, objectively from a policy
standpoint, if you are going to label everything in
terms of the most sensitive or the most adverse
allergen, then you are going to be ending up
labeling incredible parts of the food supply, which
would
hamper the choices of the allergic
393
population.
MR. ORYANG: David Oryang. I would add to
that and say, yes, in the absence of specific data
and if the allergen has data and it can be
compared.
I mean, if you know what to apply to a
specific allergen, then I think you use what is
applicable because you have the data. However, if
you don't have the data, and you know that people
react to it, where do you set the level? Maybe you
tie it to something that you believe is rather
similar or more reactive, and you know that you've
covered it in the absence of data.
CHAIRMAN DURST: Okay.
DR. KELLY: Ciaran Kelly. I have two
difficulties with this approach. The first is
exactly what Mark mentioned, and that is, that
would be setting an unnecessarily low level. For
example, soy would have to be reduced to the level
of some far more generally allergenic compound such
as tree nuts or peanuts, that's the first.
The second is there is a fallacious
394
assumption here that somehow you can know which is
the most allergic without knowing the level, the
threshold level, for each. In order to choose the
most allergic, you have to know which is the most
allergic.
(General laughter.)
DR. KELLY: Basically, when you work
through it, you can't do it.
CHAIRMAN DURST: Marc?
DR. SILVERSTEIN: Mark Silverstein. We
often use epidemiologic studies to make inferences
about individuals. We may make an inference based
on the prevalence in a population or the severity
of a condition in a population about what that may
have as an impact for individuals.
However, that usually assumes homogeneity
in the population when we are going from population
data to individual data; and, similarly, going from
specific allergen, we are basically assuming some
homogeneity in the response.
I think we have enough evidence from other
areas to
say that it is this homogeneity assumption
395
that we are uncomfortable with. I think there is
reason to believe, because we have some insight
into the nature of allergic responses, how variable
it is across allergens and individuals, that maybe
the assumptions going from allergens to rather
specific allergens wouldn't be valid; and,
similarly, going from population studies to
individual studies might not be met.
CHAIRMAN DURST: Dick Durst. I would just
like to comment that to me this approach is very
arbitrary. To me it is similar to the statutory
approach. It seems to be a one-size-fits-all type
of approach.
I think we have probably in the literature
enough data to see that is not really a realistic
way of going about it. We certainly need more data
to nail these thresholds down. From what's out
there even now, I think it is not the best approach
to use.
Marc? Oh, I'm sorry, either Marc or Mark.
DR. SILVERSTEIN: I was just going to ask,
Is
Catherine Copp likely be here tomorrow?
396
MRS. MOORE: Yes. Yes, she is here right
now.
DR. SILVERSTEIN: Oh, she is? May I ask
her a question. What I found was interesting was
the paradigm for the statutory approach under an
exemption would say "Demonstrates that ingredient
'does not cause an allergic response that poses a
risk to human health.'"
I was wondering whether there is some
regulatory precedence for what degree of risk,
either in terms of severity or proportion of
population affected that operationalizes that: no
fatalities, no hospitalizations, or is just less
than some amount in a population? Are there
precedents? What would you use to accept a
position that said that there would be no risk?
MS. COPP: Well, I think in a way
Steve Gendel answered your question when it was
posed in a more general way, and that is, we are
asking you to give us guidance on how to, for lack
of a better term, do risk assessment evaluation,
lower case
risk assessment.
397
I'm sorry, I didn't put my name on the
record, Catherine Copp. It seems to be a problem
with all of us this late.
(General laughter.)
MS. COPP: In terms of applying what is
the statutory standard, that would involve risk
management, which could involve and likely involve
more factors than simply the scientific
information, so that is one piece of the answer.
The other piece is in implementing this
statute we would seek to implement Congress'
intention. I'm not in a position -- I am not
counsel to the Center anymore, I was, some of you
know that. We need to think about that along with
what does that statutory language mean.
There are, just as a general rule -- and
we have counsel here but I don't think he is going
to answer the question any more than I am -- the
general tools that we use for statutory
construction would be available to us. I know that
is not a specific answer, but that is really
because we
are not there really yet.
398
Do you want to ask a follow-up and see if
I can avoid that one, too?
(General laughter.)
DR. SILVERSTEIN: No, I would just like to
reserve the right to ask a follow-up. I need time
to think about this.
(General laughter.)
DR. SILVERSTEIN: I guess I will make the
inference that there isn't a lot of guidance in
terms of high the risk might be or the nature of
that risk?
MS. COPP: To the extent that there is
guidance, maybe I can answer it this way. To the
extent that there is guidance, I think as a
scientist you would not find it very specific. Is
that a fair response?
CHAIRMAN DURST: Mark, I think you had
your hand up?
DR. NELSON: I just wanted to respond to
your comment, Mr. Chairman, about the arbitrariness
of the statutory approach, and to some extent it
is. It is based on the scientific expertise of
the
399
U.S. Congress.
(General laughter.)
DR. NELSON: I think also as pointed out
here and I think the results of the Threshold
Working Group's report this would give us a
starting point to deal with some of the allergens
potentially as we gather information, gather more
data to deal with the others. I think it is a
starting point from an operational and a policy
standpoint.
DR. KELLY: A related question. To my
mind, the statutory approach isn't so much an
approach as almost a loophole or a back door method
to set a relatively arbitrary threshold.
My impression is that the intent was to
say since there is no negligible allergen present
in the oils and since they are widely used, that
you could continue using them, not to say that the
level that might be present inadvertently in some
is safe.
That is another approach that hasn't been
discussed,
and that is to take foods which are
400
currently well tolerated by individuals with
allergies and determine what the levels of
contaminating allergens are and use that
information as a mechanism to approach what are
currently well-tolerated levels.
That is an approach that perhaps hasn't
received sufficient consideration because that is
an approach, for example, that we will be hearing
about tomorrow in relationship to celiac disease.
It is an approach that has been taking patients who
are currently taking foods with trace levels of
gluten but are doing very well clinically.
CHAIRMAN DURST: Soheila?
DR. MALEKI: Soheila Maleki. I kind of
want to -- well, it maybe semi-controversial --
follow up what Marc, too, said. Yes, it may seem
like a box, kind of loophole type of thing again.
Actually, I posed the question originally, but I
never made any comments on this.
Anne, if you have any comments on this,
well, feel free to make them because I don't want
to speak
for the consumer.
401
However, I do know that consumers know
there is, for example, milk in this product, I
don't care how long you tell them it is they are
never going to eat it, if it is labeled that way.
I don't really see a harm in picking the
lowest maybe for now. For example, right now the
thresholds for peanut are being worked on, so I
don't really see the harm in picking the lowest and
using that as a guidelines just to start with until
we have better methods.
If you tell a consumer, I mean, "Yes, it
has caseine" or don't label it at a higher label,
it doesn't matter because they are still not going
to eat a product that has that. They would much
rather know it is at the lowest possible level and
avoid it than to not label it because it is going
to limit their choices. They wouldn't have eaten
it in the first place anyway. They just want to
know that it is in there, if that makes any sense.
MS. MUNOZ-FURLONG: Right.
DR. MALEKI: It would be preferable to
just have
the lowest possible limit you have and
402
then say --
DR. BRITTAIN: Do you mean the limit of
detection? Is that what you mean?
DR. MALEKI: Like, right now we know
peanuts -- Soheila Maleki -- and, again, whether
you want to consider the most severe food or the
more prevalent food, that is a question that comes
up.
In this case, threshold levels for one of
the most severe food allergic reactions, which is
peanuts, is being determined. We are pretty close
to that. Could that actually be used for other
foods?
I know it seems like a cookie-cutter type
of choice, but, on the other hand, I wonder if the
food-allergic consumer wouldn't much rather have
that than wait around for another 8 to 10 years
until they figure out what the thresholds for the
other foods are. That is just a comment.
CHAIRMAN DURST: Jean?
MS. HALLORAN: Actually, this is a
question
for FDA, but I'm not sure FDA has the
403
option to wait around for 8 or 10 years. I think
it has to put out rules in the interim.
Their final question here is if you don't
use peanut as your threshold for other categories
like soy where you don't have much data, is there a
more appropriate method to use? That is their
final question to us. I am having a hard time
thinking of a better alternative, so I agree with
Dr. Maleki. DR. MALEKI: Soheila Maleki.
I agree. Again, we have pretty much, just based on
discussion that has come out said you can't really
set a method because you don't have the data. You
can't do modeling because you don't really have the
data. Right now, Dr. Hefle and Taylor are working
on organizing a group or have already started doing
the first real valid threshold dose studies that
are happening. This is data that is going to be
available, hopefully, soon.
At least it is something to go on versus
waiting around like she said, because there is no
funding, it takes a year, it takes $200,000 or so
to do
it. Do we really want to wait for that
to
404
happen?
CHAIRMAN DURST: Dick Durst. That is
certainly erring on the side of security and
safety. The other side of the coin, though, is now
you are going to be limiting people's abilities to
get foods that would be perfectly safe for them,
but it has now fallen into this threshold level
that, you know, says, "Oh, no, if there is
something in there, don't touch it."
I'm not sure, maybe a person with an
allergy would rather not have to try and have
access to some of these other foods, if there is
even the slightest chance of an allergen being
present.
DR. MALEKI: If I can answer that real
quick. As of now the detection kits that can
detect, for example, a product like this, that says
there is soy product in this candy bar or whatever,
that kit can detect a very, very low limit. The
industry is already labeling that as "may contain."
They are already not going to eat that product.
Do you see what I'm saying? As
far as the
405
level of detection of the kit is below what they
would touch anyway. I don't know if it would limit
their choices. I think they would rather know.
DR. NELSON: This is Mark Nelson. I
don't think that is an accurate generalization
about the label.
DR. MALEKI: Okay. Go ahead.
DR. NELSON: No, I was just going to say I
don't think that is an accurate generalization
about the label.
DR. MALEKI: I'm sorry? I don't
understand.
DR. NELSON: Just because a kit detects
it, depending on the sensitivity of the kit, it may
not necessarily be labeled if it is below a certain
level.
DR. MALEKI: Soheila Maleki. Can you
comment on that a little further? What do you mean
by that?
DR. NELSON: I think it refers to the rule
of thumb that Steve Taylor was talking about
earlier,
that a lot of the industry has been using
406
in the absence of specific regulation.
DR. WASLIEN: Which is what?
DR. NELSON: It depends on the company,
what they use. Some of them use 10, some of them
use 5.
DR. WASLIEN: Okay.
CHAIRMAN DURST: Okay.
DR. MALEKI: Soheila Maleki. I agree with
you, but the level still is pretty low is it is
higher than 10 parts per million or 2 parts per
million.
DR. NELSON: Yes, it is.
DR. MALEKI: We are not talking -- it is
not like the ingredient is there.
DR. NELSON: Right.
DR. MALEKI: All the "may contains" now
will be based on new label rules that will say
"contains." It is no longer to be "may contain."
DR. NELSON: Exactly, but there is an
ingredients label.
CHAIRMAN DURST: Okay.
Jeff?
407
DR. BARACH: Jeff Barach. I do agree with
the Chair and his comment about the fact that if
the level is set at the lowest possible level for
all allergens that we will see a proliferation of
labels that do contain information on allergens,
and that will limit the food choices for the
allergenic population.
To get to the last part of the question
that was brought up earlier, is there a more
appropriate method to use? I don't really
subscribe to that method, but if we are forced into
a box and we have to choose that type of method, I
would say that there is a possibility of grouping
some of these allergens together. That may be to
an advantage.
The levels of, say for instance, soy and
wheat are much higher than perhaps for peanut
protein, so there may be some opportunity to group,
say for instance, nuts, peanuts and soy and wheat
together to set levels rather than choose the
lowest for everything, which would cause a lot of
problems.
408
CHAIRMAN DURST: Okay.
DR. MALEKI: Just real quick. Soheila
Maleki. Again, it is in the absence of data, so
you can't group things together when there is no
data for the rest of the groups. Of course, that
is assuming you want an answer soon.
CHAIRMAN DURST: Okay. I would just like
to suggest the Chair has arbitrarily set 6 o'clock
as our deadline, so why don't we just quickly
discuss, we have 15 minutes left to discuss the
last part, which we touched on already, these
highly refined oils. Would anyone like to make
some comments on the questions in there?
Petr?
DR. BOCEK: Petr Bocek. Well, we know
that there are allergens which the epitopes are
confirmational. They are epitopes which are
linear. Some preliminary data from Hugh Sampson's
lab are showing that people who are allergic to the
linear epitopes are actually more prone to the more
severe reactions.
I
don't really know what the construction
409
entails, but I would be really concerned about the
denaturing of the protein and losing some of the
epitopes which would be allergenic in the protein
in the oils. That may be a reason that just the
level of the protein and the allergenicity of the
extracted oil may not be very well correlated. I
would have a problem with that.
CHAIRMAN DURST: Anyone else on that
topic? That was a good point.
DR. WASLIEN: You know, there is also the
question of oil level itself influencing the
absorption of allergens. If you are using
high-extraction oils as a standard, you are sort of
giving yourself an added safety factor, not safety
but a protective factor for setting limits or too
high a limit because of that oil protection or oil
interference with absorption. You may be using
protection when I shouldn't be using protection,
but that factors in there, too.
DR. MALEKI: Soheila Maleki. I would like to refer that to one of the panel members, either Steve or Sue, which have done
studies with oil, or do you have anything to say
410
with that as far as can the oils be used, the
protein level in the oil being used, to determine
the thresholds?
DR. TAYLOR: (No microphone.) Since I
have absolutely zero confidence in the protein
levels that have been published in oil, I wouldn't
presume to use this approach to write regulatory
standards.
(General laughter.)
DR. MALEKI: Steve, I knew I'd get an
answer out of you on that one.
DR. TAYLOR: (No microphone.) It's late
in the day.
CHAIRMAN DURST: Yes. Dick Durst. As
Petr said, I think that would probably give an
erroneously high threshold because of the fact that
you are looking at total protein, and it may be
that a lot of it has been denatured to the point
where you still detect it as a protein, but it does
not have the allergenic effect any longer. I think
that was a good point.
Yes?
411
DR. KELLY: Ciaran Kelly. Could that
problem be overcome or reduced by using an enzyme
immunoassay for detection? Have any studies like
that been done, or has it always been totally
protein?
MS. MUNOZ-FURLONG: (No microphone.) No,
no study has been done using ELISA. I don't trust
those either for oil substances, using it in
not-risk kind of situations. I don't trust the
data any more if you have the ELISA test. IgE
levels have been used in some cases, too.
DR. KELLY: Are there any circumstances
where antigenic activity was identified in these
oils.
MS. MUNOZ-FURLONG: Yes.
DR. TAYLOR: (No microphone.) Yes, there
are --
MRS. MOORE: Excuse me. If you don't talk
into a mike, it might not make it into the
transcript, so I'm going to have to ask you to go
ahead and repeat, because we've gotten in trouble
for that in
the past.
412
(General laughter.)
MRS. MOORE: Just summarize what you just
said.
DR. TAYLOR: Traces of IgE-binding
proteins, allergens, are present in oils, that is
for sure. The problem is there is so little
protein there and it is so hard to extract it out
of the oil into an aqueous environment so that you
can use aqueous testing systems.
The results are probably somewhat below
the lower limit of sensitivity of the testing
systems that have been used. Frankly, I don't yet
trust any of the data that exists on protein levels
of oil.
That opinion is the same as the European
Food Safety Authority's expert panel in reviewing
data on soybean oil and peanut oil. They said they
trusted the clinical data that was done, but they
didn't trust the protein data. They are making the
industry in Europe go back and develop actually a
better protein method, which I hope they will be
successful.
413
DR. NELSON: Steve -- this is Mark Nelson
-- there is data from a clinical standpoint about
soy oil and its reactivity?
DR. TAYLOR: No. We finished the soy oil
clinical challenge trial using that famous 29
subjects.
(General laughter.)
DR. TAYLOR: None of them reacted to
highly refined soybean oil. We took 30 soybean
oils from 30 different facilities around the world,
and we tested them for protein.
We made an oil challenge vehicle out of
the three oils that tested highest for protein
using the method that I don't trust, but it was as
good as we could do.
Highly refined peanut oil has been
suggested. Jonathan Hourihane did a study with 58
people, there have been at least another 20 or 30
challenges in other trials, and nobody has ever
reacted to peanut oil in any of these controlled
clinical challenge trials.
Usually, with cumulative doses up to 15 or
414
16 milliliters of oil, which would be equivalent to
about the maximum amount you would likely get in a
meal.
I think the oils are safe, but if you ask
me how much protein is in them, I've got to dance
around that. At the moment, I don't think anybody
quite knows. It's not enough to provoke a
reaction, but there is some there.
CHAIRMAN DURST: Well, the Chair is
feeling generous and tired.
(General laughter.)
CHAIRMAN DURST: Unless Marcia has some
final comments--? No?
MRS. MOORE: No.
CHAIRMAN DURST: Well, I would like to
thank everybody for participating today. I think
we start at 8:30 tomorrow morning. Thanks to all
of the speakers for their contributions also.
(Whereupon, at 5:50 p.m., the meeting was
adjourned, to reconvene at this same place on
Thursday, July 14, 2005, at 8:30 a.m.)
- - -