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.
6400 Ivy Lane
Greenbelt, Maryland 20770
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
P A R T I C I P A N T S (Continued)
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
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
C O N T E N T S
Call to Order, Welcome and Introductions
Charge to the Food Advisory Committee
Richard Durst, Ph.D., Acting Chairman 6
Conflict of Interest Statement & Other
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,
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
Steven M. Gendel, Ph.D., FDA 218
C O N T E N T S (Continued)
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
Panel Discussion with Guest Speakers
Thresholds for Food Allergens - Questions 272
Richard Durst, Ph.D., Acting Chairman 414
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
have read that thoroughly. In my
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
DR. TEUBER: Good morning. My name is
Teuber, I am an allergist at UC-Davis.
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
DR. KELLY: I am Ciaran Kelly, and I am a
gastroenterologist at the Harvard Medical School in
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
DR. WASLIEN: I am Carol
Waslien. I am a
nutritional epidemiologist at the University of
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
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
CHAIRMAN DURST: Thank you very
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
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
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
government employees or regular Federal
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
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
to the discussions of today's and
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
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
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,
Dr. Steve Taylor, and
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
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
Regulatory Affairs at CFSAN, the FDA.
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.
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
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
for a meeting this morning.
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
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
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
from you here in terms of your expertise in
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
We are hoping that eventually thresholds
will provide another path to safety. This is the
beginning of the inquiry into thresholds, that is,
approaches that are outlined in the report.
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.
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
USE OF FOOD ALLERGENS THRESHOLDS
MS. COPP: I was hoping. Oh, well.
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.
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
or contains a major food allergen
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.
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
addressing the issue or the occurrence of
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
additive approval process that the food ingredient
does not cause an allergenic response that poses a
risk to human health.
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.
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
when residues of an allergenic food are
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.
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
The next speaker is Dr. Robert Wood,
at Johns Hopkins University School of
Medicine, who will give us an introduction to food
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.
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
of the food as opposed to a food
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.
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.
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
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
virtually impossible to determine a threshold
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.
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
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
DR. WOOD: There is a long list
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
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
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
Eighty to 90 percent of children will
outgrow those food allergens and not carry them
into adolescence or adulthood, whereas the peanuts,
fish and shellfish are significantly
more difficult to outgrow, less commonly outgrown,
and tend to persist into adulthood and actually
through the patient's entire lifespan.
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.
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
He is school age at this point.
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.
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
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
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
moving into more of a systemic reaction that we
would refer to as "anaphylaxis."
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.
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.
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
shellfish allergic. He was making efforts to avoid
shellfish, and he had been reaction-free for
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.
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
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
the United States each year due to fatal
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.
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
where you don't see these direct
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
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
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.
DR. WOOD: Now, the last category
want to mention is something that we will lump
together as gastrointestinal food hypersensitivity.
There are a variety of conditions that fall under
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
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
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
There are some other conditions,
enterocolitis syndrome and dietary protein
proctitis, that are much more common in very young
The importance of presenting these
different syndromes here is that some of these
syndromes are IgE mediated and some of them are not
mediated, some of them are very acute and some
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
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
proteins that identifying thresholds are going
to be much more difficult.
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
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,
developed hives within 2 minutes."
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
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
They are generally accurate when they are
negative. Although, they will
only be active when
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
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
interpret our tests in the context of the
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
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.
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,
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
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
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.
DR. WOOD: I think I pretty much mentioned
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
occurred. Even though there is a lot
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
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.
DR. WOOD: Now, whenever we are doing this
analysis, we try to break things into
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
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
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.
DR. WOOD: When we broke things
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
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
Now, why would that be the case?
be for two reasons. The biggest reason is that
cardiovascular reactions are not that common in
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
The other reason that we might have seen
the absence of cardiovascular reactions would be
that we were dealing with a relatively low-risk
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
When you look across the specific foods,
important point that came out of this is
that you can't say that one type of food allergy in
this kind of setting is more dangerous than
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.
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
association between their IgE level and
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
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
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
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.
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
It is picking out those that even though
scores said that they are not so allergic
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
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
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.
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
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
They are going to need some combination of
-- endoscopy, if it is a
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.
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
also helps to promote the outgrowing
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
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
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
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
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
there are a bunch of different options we
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
like Neocate and Elecare.
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.
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
CHAIRMAN DURST: Thank you, Dr. Wood.
Are there questions for discussion?
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
DR. WOOD: No. I mean, most of these kids
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
CHAIRMAN DURST: Yes.
MS. HALLORAN: Jean Halloran. Could you
say something about the process about growing
allergies? How does that work? What actually
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
That is where we think that strict
avoidance is likely to promote the outgrowing
and with a prolonged period of strict
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
ethical to perform? I guess my concern
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
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
people that have bad reactions.
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
is going to be and will always be these children
are much more reactive than the adults for most of
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
this is Dick Durst -- just points of
clarification. On your slides where you indicated
"wheat," now this is the IgE-mediated type allergy
as opposed to our discussion tomorrow on celiac
DR. WOOD: Yes, these results are entirely
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
capable of causing allergy in select
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
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
largely a clinical impression?
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
outcome is about 10 years down.
CHAIRMAN DURST: Marc.
DR. SILVERSTEIN: I have had some
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
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
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
policy in making regulatory decisions?
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
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.
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
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
safe from the perspective of that
patient's allergen --
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
CHAIRMAN DURST: All right. Seeing no
further hands in the air, I think we will thank
Wood. We are right on schedule. Thanks again.
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.
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.
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
physician referrals, so we know we are talking
about IgE-mediated responses when we are looking at
Our mission has four points: to increase
public awareness, provide advocacy and education,
and advance research on behalf of those with food
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
of these patients have families who
follow their restricted diet. The impact is
actually many times greater than the number of
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.
MS. MUNOZ-FURLONG: Talking about
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.
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
every single one of the major eight
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
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
Decisions about dining out and socializing
are made based on not a food preference, but is the
"Can the manager be trusted to give us
"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
allergy is real, and so decisions are made
about whether they can visit that individual or
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
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
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
their score for the quality of life.
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
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
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.
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
What we are already seeing with some of
the companies complying with FALCPA regulations is
are products on the market that are
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.
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
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.
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
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.
MS. MUN[MLM2]OZ-FURLONG: We can see this
in a study that was published in 2002 by
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.
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
This makes it very difficult for us to
educate consumers and the others who are reading
their behalf and telling them what to do
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?
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
consumers, "It is on the package only because
our legal counsel has advised us to put this on
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
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,
randomly to us, that some companies can
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
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
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
the allergen might be, only 74 percent
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.
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
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
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.
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
If we undermine the integrity of the
label this will potentially lead to more
allergic reactions as they take more risk, which is
going to increase the number of doctor visits;
hospital visits; and, potentially, fatalities.
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
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,
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.
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
both sides of this issue, the key here is
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
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.
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
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
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.
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
repeated that same study in 2002, and found
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.
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
CHAIRMAN DURST: Thank you.
Does the Committee have any questions?
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
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?
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
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
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
understand that you are frustrated and
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
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
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
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
CHAIRMAN DURST: I think we need to move
Our next speaker will be Susan Hefle,
professor and co-director of the Food
Allergy Research and Resource Program at the
University of Nebraska, who will be speaking on
"Allergenicity: Analytical Methods."
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
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.
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,
Taylor and I sat around and thought about
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
We want the data to be relevant. We want
the data to be useful. If the industry goes back
says, "I want to fix this, but what if I get
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
I don't think at this point there is any
change them right now. But, again, as
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.
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
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
Some testing of finished product on
certain occasions though is done, especially when
you can have
the product under full control. They
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
assessment. Some companies would like
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.
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.
DR. HEFLE: FDA works with AOAC and has
plan more validation studies with other
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
change equipment, to make modifications,
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.
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
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
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
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.
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
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
A case in point was the standard that was
used in the AOAC-RI-FDA study. It was peanut
by a major manufacturer. It is fine
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
There are several of these materials
available, and we could begin to talk about going
through some interlab trials with some of these, if
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
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
If you make many cookies in a home-size
oven or a
Suzy Homemaker or Easy-Bake Oven, it is
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
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.
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
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
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,
DR. HEFLE: Most kits for most allergens
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
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
Matrix effects, my lab has used all of the
ELISA-based test kits available on the market in
validations and tests. It is kind of my
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
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
too. Therefore, we don't usually see
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.
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
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
that, so you can't use it for this.
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
samples out there.
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.
DR. HEFLE: We cannot currently do
immediate monitoring in the food industry, though.
technology doesn't exist. It is getting
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
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
historically designed for allergen clean.
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
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.
DR. HEFLE: This is a study that we
completed and published in 2004 of some
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,
have been validated in interlab trials or
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
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
My lab uses an amino acid determination
Edman degradation, but we also use aqueous
extraction. We try to maximize that aqueous
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
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.
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
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
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.
think that is the end of my
presentation, and I thank you very much for your
CHAIRMAN DURST: Thank you.
Committee, do you have any questions or
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
to clean up, and they are still having
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
an allergen when it is directly added
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
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
DR. MALEKI: I see.
DR. NELSON: It is understanding your
what ingredients are going into the food;
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?
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
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
are evaluated at the company level first
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
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
They do tell the manufacturers to validate
or run their own in-house validations before they
the results. The manufacturers do tell
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
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
are that are made.
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
now. We will take a 10-minute break and
reconvene at 10:45.
(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.
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
design and conduct, and also spend a
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
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
However, in recent years, there has been a
lot of emphasis on using oral challenge studies to
minimal eliciting doses. This has
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
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
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
biomarkers to predict severity. This is
important, I think, factor when we are looking at
evaluating minimal eliciting doses.
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.
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,
want to diagnose individuals with an
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
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
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
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
Individuals with asthma tend to have more
severe reactions and are probably the group most
representative of fatal reactions.
including these individuals, you may be missing not
only sensitive individuals but individuals who are
potentially very severe responders.
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
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
where dried milk or spray-dried egg are not
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
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
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
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
taste. Therefore, some researchers have preferred
to use capsules, since this basically bypasses the
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
both the researcher and the subject, but
they are used as well. However, I think the
preferred method and the easier method is to do a
separate placebo day.
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
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
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
Now, with choosing the starting dose, this
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
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
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
the X, 2X or 4X.
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.
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
in some studies this was not necessarily
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
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
challenge, or in cases where you are
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
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
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
would not react. Also, you could use if
66 is more than 59, you could also say, well, 95
percent confidence that 95 percent, 1 in 20, will
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.
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.
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
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
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
challenge be part of that analysis?
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?
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
open challenge and react. It is not
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
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
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
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
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.
DR. LUCCIOLI: This just is a hypothetical
dose curve adapted from Jonathan Hourihane, who has
nice research in this area, basically
just to show you how severity and sensitivity may
factor in. I don't really want to spend time on
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.
DR. LUCCIOLI: To just show you some of
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
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
effect. However, in infants, infants
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.
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
How should these be factored into the
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.
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
a subjective response or so forth. This
could also affect interpretation of these eliciting
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?
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.
DR. LUCCIOLI: What has been
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.
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
third of individuals reacted and had mild
reactions, a third had moderate, and a third had
severe. How do you factor in those severe
responses when you determine uncertainty or other
Also, potentiating mitigating factors are
important: anxiety/stress, medications, and so
forth. These can either potentiate the reaction or
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.
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.
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
CHAIRMAN DURST: Thank you very much.
Are there any questions from the
We will start here.
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
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
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
in terms of if they also have a
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
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
CHAIRMAN DURST: Suzanne.
DR. TEUBER: One of the aspects that we
are all very concerned about is which threshold to
when it may cause a subjective reaction.
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
studies that are being designed
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
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
The assumption, though, is that because of
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
To help the wide dissemination of the
report and presentation, I would like to suggest
that we in
our thinking we may say "subjective
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
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
populations differ in proportion or the sample
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
Of course, the selection of individuals
who are referred to a physician, who are referred
allergist, who are selected for an oral
challenge, food challenge, study would potentially
lead to erroneous inferences if there were
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
CHAIRMAN DURST: Are there any other
(No verbal response.)
CHAIRMAN DURST: If not, thank you very
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
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.
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
behind them; and then say something about
interpreting the results of applying these models.
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.
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
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.
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
they have experienced, the allergological
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.
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
instance, if you have a study with 29
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
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
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
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
as an objective for the food industry.
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
using the figure itself.
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.
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
study population reacting here.
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.
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
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
statistical distributions and calculated
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
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
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.
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
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.
DR. CREVEL: When you move away
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
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
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
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
There are people whose allergies are
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
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
outside. We are doing some work
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.
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
else does not protect everybody because of
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.
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,
lowest observed adverse effect level or
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
DR. BRITTAIN: That was a really
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
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.
mean, this is a big data gap at the
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
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
(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
of Nebraska, who will discuss Food
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
DR. TAYLOR: I think the National Academy
of Sciences outlined risk assessment approaches a
number of years ago, and I always like to start
slide, even though I'm not going to
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.
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
responses on different days to the same
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
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
DR. TAYLOR: I think there is another part
that we haven't heard quite enough about, and Rene
pointed it out in his presentation. It
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.
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
aids and historically haven't been
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
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.
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
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.
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.
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
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.
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
I will point out the fact that the results
of the First Threshold Conference have largely been
published in the peer reviewed, scientific
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
Dr. Wood reported this morning, recognize that most
diagnostic challenges start at 400 to 500
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
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
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.
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.
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
and we didn't reach consensus. We had
about 20 clinicians at this conference, and we did
not reach consensus on what threshold doses should
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.
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
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.
DR. TAYLOR: The Second Threshold
Conference was held in 2002 and was geared to
address the biggest concern we had from the first
that was a lack of a consensus protocol.
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
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.
DR. TAYLOR: We did have the Third
Threshold Conference where we tried to determine
what you do with the data once you collect it.
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
soybean-allergic individuals in the world
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
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.
DR. TAYLOR: Well, classical risk
involves determining the NOAEL for a
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?
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
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
allergic to the food that is under
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.
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
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
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
included a number of people from the most
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
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
congratulate them for that, because that
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.
DR. TAYLOR: This is for egg.
DR. TAYLOR: This is for milk.
DR. TAYLOR: We have got a lot of data
points. What are the uncertainty factors? Well,
adults, adolescents, children, infants.
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.
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
In many of these cases, the physicians
didn't determine the protein content of the
challenge materials, so you've got to make
guesses. There are uncertainties about
the challenge materials.
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.
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.
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
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
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.
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
subjective symptoms and the doses that
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