1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

FOOD ADVISORY COMMITTEE MEETING

Advice on CFSAN'S Draft Report:

Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food

Wednesday, July 13, 2005

8:30 A.M. to 5:50 P.M.

Greenbelt Marriott

6400 Ivy Lane

Grand Ballroom

Greenbelt, Maryland 20770

P A R T I C I P A N T S

FOOD ADVISORY COMMITTEE STANDING MEMBERS:

Richard A. Durst, Ph.D. - Acting Chairman

Jeffrey A. Barach, Ph.D. (Industry Representative)

Patrick S. Callery, Ph.D.

Dennis Gonsalves, Ph.D., M.S.

Jean M. Halloran (Consumer Representative)

Douglas C. Heimburger, M.D., M.S.

Margaret C. McBride, M.D.

Mark Nelson, Ph.D. (Industry Representative)

Carol I. Waslien Ghazaii, Ph.D., R.D.

TEMPORARY VOTING MEMBERS:

Petr Bocek, M.D., Ph.D.

Margaret Briley, Ph.D., R.D.

Erica Brittain, Ph.D.

Ciaran P. Kelly, M.D.

Soheila June Maleki, Ph.D.

David O. Oryang

Marc D. Silverstein, M.D.

Suzanne Teuber, M.D.

FOOD AND DRUG ADMINISTRATION:

Catherine Copp, J.D. - Senior Policy Advisor

Food and Drug Administration, CFSAN

Steven M. Gendel, Ph.D. - Senior Scientist

Food and Drug Administration

National Center for Food Safety and Technology

Rhonda Kane, M.S., R.D. - Consumer Officer

Food and Drug Administration, CFSAN

Michael M. Landa, J.D. - Deputy Director for Regulatory Affairs

Food and Drug Administration, CFSAN

Stefano Luccioli, M.D. - Senior Medical Advisor

Food and Drug Administration, CFSAN

Marcia Moore, Food Advisory Committee, Executive Secretary

Jenny Slaughter - Director

Food and Drug Administration Integrity and Ethics Staff

P A R T I C I P A N T S (Continued)

GUEST SPEAKERS:

Rene Crevel, Ph.D. - Senior Scientist

Unilever, Safety and Environmental Assurance Centre, United Kingdom

Susan Hefle, Ph.D. - Associate Professor and Co-Director

Food Allergy Research and Resource Program, University of Nebraska

Stefano Luccioli, M.D., - Senior Medical Advisor

CFSAN, FDA Assistant Professor, Georgetown University

Anne Munoz-Furlong

Director, Food Allergy & Anaphylaxis Network

Steve Taylor, Ph.D. - Maxcy Distinguished Professor & Director

Food Allergy Research and Resource Program, University of Nebraska

Robert Wood, M.D. - Professor

Johns Hopkins University School of Medicine

C O N T E N T S

PAGE

Call to Order, Welcome and Introductions

Charge to the Food Advisory Committee

Richard Durst, Ph.D., Acting Chairman 6

Conflict of Interest Statement & Other

Instructions

Jenny Slaughter, FDA 10

Welcome and Opening Statement

Michael M. Landa, Esq., CSAN, FDA 14

Use of Food allergen Thresholds

Catherine L. Copp, Esq., CFSAN, FDA 18

Introduction to Food Allergens

Robert Wood, M.D. 23

Patient Perspectives on Food Allergies

Anne Munoz-Furlong 72

Allergenicity: Analytical Methods

Susan Hefle, Ph.D. 99

Question and Answer Session 126

Oral Challenge Studies: Purpose, Design,

and Evaluation

Stefano Luccioli, M.D.

Senior Medical Advisor, CFSAN, FDA 133

Question and Answer Session 161

Threshold Modeling Approach

Rene Crevel, Ph.D. 170

Food Allergen Thresholds

Steve Taylor, Ph.D. 189

Overview of Approaches to Establishing

Thresholds: Allergens

Steven M. Gendel, Ph.D., FDA 218

C O N T E N T S (Continued)

PAGE

Public Comments:

Tracy Atagi 228

John Carroll 232

Diane Castiglione 242

Will Duensing 247

Martin J. Hahn, Esq. 250

Peggy Mockett 254

Kim Mudd 257

Kim Mulherin 260

Linda Webb 264

Jupiter Yeung 268

Committee Discussion:

Panel Discussion with Guest Speakers

Thresholds for Food Allergens - Questions 272

Adjournment

Richard Durst, Ph.D., Acting Chairman 414

P R O C E E D I N G S

CALL TO ORDER, WELCOME, AND INTRODUCTIONS

CHARGE TO THE FOOD ADVISORY COMMITTEE

CHAIRMAN DURST: I would like to call the

meeting to order.

Good morning. I am Dick Durst, professor

of chemistry in the Food Science and Technology

Department at Cornell University. I was asked to

chair this meeting over the next two and a half

days. I would like to make a few announcements

before we begin our meeting this morning.

I would appreciate it if everyone would

turn off their cell phones, unless they are

expecting a call of a super emergency nature. I

would also like to ask if the guest speakers could

make themselves available for the discussion this

afternoon, I would really appreciate it. We may

have some additional questions.

We have received a charge from the FDA to

give our evaluation of the draft report prepared by

the Threshold Working Group. I assume all of the

members have read that thoroughly. In my opinion,

I it was fascinating.

It was an excellent article and I commend

the Committee for coming up with it. It was very

educational. Not being an expert on food allergens

myself, it was extremely educational, and I was

able to follow it quite clearly.

Our charge is to evaluate this report to

determine whether the approaches that are presented

in there are the only ones or the better ones,

which of the ones that are in there might be the

most appropriate. This is the focus of our meeting

today, both on the food allergens and on gluten.

Let me also begin by asking the committee

members to introduce themselves. We will start

with Dr. Silverstein.

Marc, would you start it off?

DR. SILVERSTEIN: Good morning. My name

is Marc Silverstein, and I'm a general internist

and geriatrician at Baylor Health Care System in

Dallas.

DR. TEUBER: Good morning. My name is

Suzanne Teuber, I am an allergist at UC-Davis.

MR. ORYANG: Good morning. I am

David Oryang. I am a risk analyst and agricultural

engineer at the United States Department of

Agriculture, Animal and Plant Health Inspection

Service.

DR. KELLY: I am Ciaran Kelly, and I am a

gastroenterologist at the Harvard Medical School in

Boston.

DR. MALEKI: I am Soheila Maleki. I am a

scientist with the USDA.

DR. BRITTAIN: Erica Brittain, I am a

statistician at the National Institute of Allergy

and Infectious Disease.

DR. BRILEY: Margaret Briley, University

of Texas at Austin, nutritionist.

DR. BOCEK: Good morning. I am

Petr Bocek, medical officer in NIH's National

Institute of Allergy and Infectious Diseases.

MRS. MOORE: I am Marcia Moore. I am with

the FDA as the executive secretary of the Food

Advisory Committee.

DR. WASLIEN: I am Carol Waslien. I am a

nutritional epidemiologist at the University of

Hawaii.

DR. McBRIDE: I am Margaret McBride. I am

a child neurologist at Akron Children's Hospital.

DR. CALLERY: I am Patrick Callery, a

pharmaceutical scientist from West Virginia

University.

DR. GONSALVES: I am Dennis Gonsalves, a

scientist with USDA in Hawaii.

DR. HEIMBURGER: I am Doug Heimburger, a

physician and nutrition specialist at the

University of Alabama at Birmingham.

DR. BARACH: Jeff Barach with Food

Products Association, vice president for special

projects and regulatory affairs.

DR. NELSON: Mark Nelson with the Grocery

Manufacturers Association responsible for

regulatory and scientific policy.

MS. HALLORAN: Jean Halloran from the

Consumers Union where I am director of food policy

initiatives.

CHAIRMAN DURST: Thank you very much.

One other item is that we may have some of

our members leave early on Friday, depending on the

amount of time we can spend. What I propose is

that today and tomorrow that we anticipate having

to go perhaps till 6 o'clock so that we can be sure

that we have enough time for all of our

discussions.

Okay. Let me introduce our first speaker.

This will be Jenny Slaughter, director of Ethics

and Integrity Staff at the FDA, to describe the

"Conflict of Interest Statement" and other

instructions.

CONFLICT OF INTEREST STATEMENT

AND OTHER INSTRUCTIONS

MS. SLAUGHTER: Well, good morning and

welcome. The Food and Drug Administration is

convening today's meeting of the Food Advisory

Committee under the authority of the Federal

Advisory Committee Act of 1972.

With the exception of the industry

representatives, all members of the Committee are

special government employees or regular Federal

employees from other agencies subject to Federal

conflict of interest laws and regulations.

FDA has determined that members of this

Advisory Committee are in compliance with Federal

ethics and conflict of interest laws including, but

not limited to, 18 U.S.C. 208 and 21 U.S.C. 355 and

354.

Under 18 U.S.C., Section 208, applicable

to all government agencies, and 21 U.S.C. 355,

applicable to only FDA, Congress has authorized FDA

to grant waivers to special government employees

who have financial conflicts when it is determined

that the Agency's need for particular

interventional services outweighs the potential

conflict of interest.

Members who are special government

employees at today's meeting including special

government employees appointed as temporary voting

members, have been screened for potential financial

conflicts of interest of their own as well as those

of their spouse, minor child, and employer, which

are related to the discussions of today's and

tomorrow's and Friday's meeting regarding the "FDA

Draft Report: Approaches to Establish Thresholds

for Major Food Allergens and for Gluten in Foods."

These interests may include investments,

consulting, expert witness testimony, contracts,

grants, research and development agreements, public

speaking, writing, patents, royalties, and primary

employment.

In accordance with 18 U.S.C. 208(b)(3),

full waivers have been granted to the following

participants, Dr. Suzanne Teuber and Dr. Soheila

Maleki, please note that all of the interests in

the firms that could potentially be affected by the

Committee's decisions.

A copy of the written waiver statements

may be obtained by submitting a written request to

the Agency's Freedom of Information Office, Room

12A-30 of the Parklawn Building.

In addition, the following individuals are

participating as FDA's invited guest speakers,

July 13th: Dr. Rene Crevel, Dr. Susan Hefle,

Anne Mun [MLM1] oz-Furlong, Dr. Steve Taylor, and

Dr. Robert Wood.

The following individuals will be

participating as FDA invited guest speakers

tomorrow, July 14th: Dr. Pekka Collin,

Dr. Alessio Fasano, Dr. Donald Kasarda,

Dr. Cynthia Kupper, and Dr. Joseph Murray.

Lastly, I would like to report that

Dr. Jeffrey Barach and Dr. Mark Nelson are serving

as the industry representatives on the Committee at

today's meeting. They are acting on behalf of all

regulated industry.

Dr. Jeffrey Barach is employed by the

National Food Processors Association and

Dr. Mark Nelson is employed by the Grocery

Manufacturers of America.

A copy of this document will be placed on

the back table, if anybody wishes to take a look at

it. I thank you.

CHAIRMAN DURST: Thank you very much.

We will now go on to the welcome and opening

statement by Dr. Michael Landa, the deputy director

for Regulatory Affairs at CFSAN, the FDA.

Mike.

WELCOME AND OPENING STATEMENT

MR. LANDA: Thank you, Dr. Durst. You

will be pleased to learn that I don't have a

doctorate or an M.D. I'm just a plain, old J.D.

(General laughter.)

MR. LANDA: Thanks again. Good morning to

everyone. Welcome to the members of the committee,

to the guest speakers, to members of the public who

have joined us today, and to my fellow FDA

employees.

I would like to give a special thanks to

the Committee members for your willingness to take

time from busy schedules to help us with your

expertise for a meeting that will be several days

long. We are all here today, tomorrow and a fair

chunk of Friday.

Let me just add that Dr. Brackett had

hoped to be here this morning, but he wasn't able

to make it. I am hopeful that he will be here for

some portion of the meeting. He was called

downtown for a meeting this morning.

I am going to refer to a couple of points

on the food allergens, but the points I'm making

apply to celiac disease as well. It is just less

cumbersome to start with the food allergens. The

agenda has been making, I think, an opening

statement, of course I'm really not going to do

that.

There are just a few points I want to make

as you go into your inquiry today. The first is

virtually every FDA speaker makes at this kind of

proceeding which is what we do really is based on

science.

We talk about being a science-based

agency. It is the bedrock; it is the foundation.

In that context, I am going to paraphrase what may

be a rather obscure 19th century Senator, Karl

Shrews from Pennsylvania.

The paraphrase essentially is, Our science

correct or incorrect, when it is correct, help us

keep it correct; when it is incorrect, help us to

correct it. That is as much as anything else what

we want from you here in terms of your expertise in

the science.

If with respect to the threshold in the

Draft Report, we have gotten it right, we want to

know from you that we have gotten it right. We

want your help in keeping it right. If we have

gotten it wrong, we want your help in getting it

right. That includes, as you will hear, if we have

not considered an approach that we should have

considered, we want to know that from you.

The third point I will make is that

Americans suffer from food allergies, particularly

children. There is some evidence that the number

is increasing. If you add to that family members,

you really have tens of millions of folks who are

involved. At the moment their principle means of

protection really is exquisite attention to the

food label. That is their pathway to safety I

suppose.

We are hoping that eventually thresholds

will provide another path to safety. This is the

beginning of the inquiry into thresholds, that is,

the approaches that are outlined in the report. It

is the first step in a very important process.

The last point I will make is just that

this is as much as anything else for members of the

public, the docket is going to remain open until

about the middle of August.

If people have comments, based on what

they have heard today, for example, they should

feel free to submit those comments to the docket.

Again, it is until about, I don't remember the

precise date, but it is the middle of August.

In that connection, I should say we are

especially interested, as I think is always the

case, in data. In this case, data of the type

outlined in the report.

Thank you.

CHAIRMAN DURST: Thank you, Mike. Since

Mr. Landa didn't want me conferring a doctorate

degree on him, I will not do it with Catherine

Copp, who is the policy advisor at CFSAN, also the

FDA, who will discuss the use of food allergens

thresholds.

USE OF FOOD ALLERGENS THRESHOLDS

MS. COPP: I was hoping. Oh, well.

(General laughter.)

MS. COPP: Thank you, Dr. Durst.

Good morning. As you know, the focus of

this meeting today and tomorrow and the discussion

on Friday is the Draft Report of CFSAN's Threshold

Working Group: Approaches to Establish Thresholds

for Major Food Allergens and For Gluten in Food.

I have been asked to provide a context for

the Draft Report in terms of CFSAN's programmatic

efforts. This is one thing that if I were a real

doctor I could do. Lawyer's don't do this.

(Slide.)

MS. COPP: Last August, Congress enacted

the Food Allergen Labeling and Consumer Protection

Act, which we refer to in-house by the somewhat

awkward acronym "FALCPA."

This new law amends the Federal Food, Drug

and Cosmetic Act, the principle statute

administered by FDA by requiring that the label of

a food product that is or contains an ingredient

that bears or contains a major food allergen

declare the presence of the allergen as specified

in the law. In shorthand, the declaration is to be

in "consumer friendly" terms.

FALCPA defines a "major food allergen" as

one of the eight foods or food groups or a food

ingredient that contains protein derived from one

of these foods. Those are listed on the bottom of

this slide. By "food groups," I mean fish, tree

nuts and crustacean shellfish, which were

identified by Congress in the law.

(Slide.)

MS. COPP: The possible existence of

threshold levels for food allergens is an important

scientific issue, as Mr. Landa has pointed out,

associated with our implementation of FALCPA.

Although the law does not require FDA to

establish thresholds for any food allergen, there

are three possible ways, which are listed on this

slide, that such thresholds could be used to

implement the new law, these are: administering the

petition process provided for in FALCPA,

administering its notification process, and

addressing the issue or the occurrence of

cross-contact.

(Slide.)

MS. COPP: FALCPA provides two processes

by which an ingredient may be exempt from the

FALCPA labeling requirements, a petition process

and a notification process. I'm trying to read my

own slides (laughter). No, okay.

Under the petition process, an ingredient

may be exempt, if the petitioner demonstrates that

the ingredient does not cause an allergenic

response that poses a risk to human health.

Given this language for the petition

exemption standard, we believe it will be very

important for us to both understand food allergen

thresholds and to have a sound scientific framework

for evaluating the existence of such thresholds.

Under the notification process, an

ingredient may be exempt, if the notification

contains scientific evidence that demonstrates that

the ingredient does not contain allergenic protein,

or, if FDA has previously determined under the food

additive approval process that the food ingredient

does not cause an allergenic response that poses a

risk to human health.

(Slide.)

MS. COPP: Given this language for the

notification exemption standard, we also believe

that it will be very important for us to understand

food allergen thresholds and to have a sound

scientific framework for evaluating the existence

of such thresholds.

(Slide.)

Finally, the FALCPA directs FDA to prepare

and submit a report to Congress. This report will

focus principally on the issue of cross-contact of

foods with food allergens and is to describe the

types, current use of, and consumer preferences

with respect to so-called "advisory labeling."

Processed in a facility that also processes tree

nuts is an example of such labeling.

Cross-contact may occur during food

production when residues of an allergenic food are

present in the manufacturing environment and are

unintentionally incorporated into a food. Because

the food is not intended to contain the allergen,

it is not declared as an ingredient on the food's

label. In some cases, however, the potential

presence of the food allergen is declared by a

voluntary advisory statement.

We also believe that understanding food

allergen thresholds and developing a sound

scientific framework for evaluating the existence

of such thresholds may also be useful to us in

evaluating and addressing food allergen

cross-contact and the use of advisory labeling.

Thank you.

CHAIRMAN DURST: Thank you very much.

Does the Committee have any questions or

discussion of this presentation?

(No verbal response.)

CHAIRMAN DURST: If not, I think we will

proceed.

The next speaker is Dr. Robert Wood,

professor at Johns Hopkins University School of

Medicine, who will give us an introduction to food

allergens.

INTRODUCTION TO FOOD ALLERGENS

DR. WOOD: Thank you very much. It is a

pleasure to be here. What I was asked to do is to

provide an overview of food allergens and food

allergy leading into the discussion that is going

to go on over these next couple of days.

(Slide.)

DR. WOOD: The beginning of this, any talk

about food allergy really requires that we have

some common definition that we can all agree on.

This is something that is not as easy as it might

sound and often generates a lot of confusion. The

reality is that a lot of what is called food

allergy is really not food allergy and may fall

under more of a food intolerance category.

When we are talking about food allergy,

there are a couple of key ingredients. One of them

is that there is an immunologic component to the

reaction. The reaction is typically to the protein

component of the food as opposed to a food

intolerance that is more often related to the

carbohydrate component of the food. Importantly to

this meeting, exquisitely small amounts may cause a

reaction and that these reactions can be severe and

even life threatening.

(Slide.)

DR. WOOD: The pathophysiology of the

allergic response is sort of very schematically

diagramed here. What we are thinking about is a

process that begins with exposure and with most

allergy, probably all allergy, you have to have

some prior exposure to develop your sensitivity.

(Slide.)

DR. WOOD: There is a genetic

predisposition that makes some people particularly

more prone to develop allergy in general, whether

it be food allergy or respiratory allergy, than

others. There are some people who no

matter what, how, when and where they are exposed

they will never develop an allergy, and others who

with very trivial exposure may develop a severe

allergy.

If you are in this group who is

genetically predisposed, your immune system then

goes through a process we will refer to as

sensitization. Sensitization is most often

involving the production of IgE antibodies. We

will talk about this in a little bit more detail

about some different food allergy syndromes.

However, it is also important to note that

not every food allergy involves IgE and that there

may be differences in the types of reactions and

the doses of food required to induce a reaction in

those patients that have IgE versus

non-IgE-mediated food allergy.

Once you have become sensitized, then

reexposure to this food will lead to symptoms.

These symptoms may be abrupt, they may occur within

seconds of eating the food, or they may be very

low-grade and chronic. This is another concept

that we will come back and talk to a little bit.

With some patients it will be very easy to

determine a threshold, and in some patients it will

be virtually impossible to determine a threshold

because their symptoms will not appear in a

challenge test. They may take days or weeks of

chronic exposure and then develop very significant

disease based on that chronic exposure.

(Slide.)

DR. WOODS: The prevalence of food allergy

is substantial. The numbers that we would be most

comfortable with would be 5 to 7 percent of young

children; 2 to 3 percent of adolescents and adults;

at least 10 or 11 million Americans affected.

We do believe that the prevalence is

rising. We don't believe that this is specific to

food allergy. There has been a substantial rise in

asthma and other allergic diseases as well as food

allergy.

Now, the reason that these numbers change

between childhood and adolescence and adulthood is

because a large proportion of food allergy is

outgrown over the first five to seven years of

life.

(Slide.)

DR. WOOD: There is a long list of

potential food allergens out there. At least 200

foods have been identified and characterized as

truly food allergens, but there is a relatively

shorter list that are focused upon because they are

responsible for the vast majority of food allergy

that occurs.

The list on the left-hand side

representing what is most common in young children:

milk, egg, peanut, soy, wheat, and tree nuts.

Then, the list shifts a little bit as you get into

older children, adolescents and adults and is

dominated by peanuts, tree nuts, fish, and

shellfish.

The reason that this list changes from

childhood to adulthood is because four of these

most common food allergens in your children --

milk, egg, soy, and wheat -- are typically

outgrown.

Eighty to 90 percent of children will

outgrow those food allergens and not carry them

into adolescence or adulthood, whereas the peanuts,

tree nuts, fish and shellfish are significantly

more difficult to outgrow, less commonly outgrown,

and tend to persist into adulthood and actually

through the patient's entire lifespan.

(Slide.)

DR. WOOD: Now, the signs and symptoms of

food allergy are highly varied. They may be

chronic and low grade as I mentioned, they may be

acute and life threatening. What I want to run

through in the next couple of minutes are just some

examples of allergic reactions that will point out

a number of things about not only the kinds of

reactions, but the exquisitely small amounts of

food that induce these reactions we are going to

show you, and the sort of day-to-day issues that

patients with food allergy are facing.

(Slide.)

DR. WOOD: The first couple of patients I

am going to show you have urticaria or hives. This

is a total body hive reaction that this boy is

experiencing, a patient I have known since he was

an infant.

He is school age at this point. This

reaction occurred when he was in the grade school

cafeteria, was being teased about this food

allergy, another child blew a straw full of milk

across the table into his face, and he had this

really significant reaction.

(Slide.)

DR. WOOD: This baby here was identified

with milk allergy in the first few weeks of life.

There are some children who don't show up with food

allergy until they are two or three or four years

old, while there are others who are really

demonstrating food allergy in the first days of

life.

This was a baby who was so allergic that

he would react very acutely if his mother, who was

breast feeding him, ingested any milk protein. She

was on a very strict avoidance diet after we

identified his milk allergy, but on the occasion of

her birthday ate a piece of cheesecake, breastfed

him an hour and a half later, and he had this acute

hive reaction.

(Slide.)

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."

(Slide.)

DR. WOOD: Now, this is a patient here who

is having an anaphylactic reaction. When you look

at her back here, it looks just like hives. When

you see her front, though, she is having swelling

and breathing difficulty.

(Slide.)

DR. WOOD: This is a patient who was

having a reaction in the midst of a food challenge

-- not in the midst of it, after her first tiny

dose of egg protein, she went into this very

severe, anaphylactic reaction.

(Slide.)

DR. WOOD: This boy here is someone who is

having a dramatic episode of swelling. His

reaction occurred. Most patients, we should say,

who are having severe reactions know about their

food allergy and are making efforts to avoid it.

He was shellfish allergic -- he is

shellfish allergic. He was making efforts to avoid

shellfish, and he had been reaction-free for

several years.

Then, on another birthday occasion, he ate

chicken in a restaurant and the chicken had been

fried in the same oil as shrimp had been fried.

With that cross-contact, this severe reaction.

(Slide.)

DR. WOOD: Anaphylactic reactions are

defined as a systemic allergic reaction,

involvement of multiple organ systems. These have

an abrupt onset typically. They are related to IgE

antibodies.

You can identify these by doing a skin

test or a blood test looking for IgE. The

manifestations are not always severe. There is an

impression that all anaphylaxis is

life-threatening. Some episodes are relatively

mild, but others progress rapidly to

life-threatening or fatal reactions.

We think that there are at least 150

deaths in the United States each year due to fatal

food-induced anaphylaxis. That number is probably

a substantial underestimation, but we would be very

comfortable saying that it is well identified of

100 to 150 deaths per year.

There are different types of reactions:

some are single phase and some have two phases,

where a patient may look better and then two or

three or four hours later have an even more severe

reaction than they had initially, some of those

lead to the worst outcomes.

(Slide.)

DR. WOOD: This is a patient with one of

the more chronic forms of food allergies, the

patient with severe itching due to his eczema. In

Eczema, a food allergy is often underappreciated

because there is not an obvious cause and effect.

This is one where it is more of a

low-grade, chronic reaction. Hence, this is much

harder for a patient or a family member to identify

that, yes, he ate this food and he is more itchy

now, rather it is really more of a low-grade

reaction where you don't see these direct

relationships between ingestion of the food and the

outcome being their eczema or atopic dermatitis.

It is also a condition where food allergy

is underappreciated by physicians and where

patients may be treated with a variety of different

creams and lotions and only later on find out that

it was really a food allergy that was driving the

eczema.

Overall, 40 to 50 percent of patients with

severe atopic dermatitis and 20 or 25 percent with

less severe cases have an underlying food allergy.

The same list of foods: egg allergy being

most common, followed by milk, peanuts, soy, wheat,

and fish. These six foods account for the vast

majority of food sensitivities seen in atopic

dermatitis.

From our standpoint, it makes it

relatively easy to screen patients and find which

of them are allergic by testing for a relatively

short list of foods.

(Slide.)

DR. WOOD: Now, the last category that I

want to mention is something that we will lump

together as gastrointestinal food hypersensitivity.

There are a variety of conditions that fall under

this umbrella.

There are some that are in the immediate

hypersensitivity category. This would be part,

say, of an anaphylactic reaction where someone ate

food, broke out in hives, had vomiting, diarrhea,

abdominal pain, or other gastrointestinal symptoms.

There is another condition called "oral

allergy syndrome" where patients have reactions

that are confined to their mouth or throat or lips,

particularly related to fresh fruits and

vegetables.

There is another group of conditions that

are lumped under a category of eosinophilic

disorders of the GI tract. There is a specific

condition, eosinophilic esophagitis, where only the

esophagus is involved. As most people in the

audience know, the eosinophil is a type of white

blood cell that is most affiliated with allergic

reactions.

If you take someone who is having a bad

hay fever day outside today and look at their nasal

secretions, their nasal secretions will be loaded

with eosinophils. If you take someone that is

having difficult asthma, their bronchial mucosa

will be loaded with eosinophils.

By the same token, if you have allergic

eosinophilic esophagitis, the lining of your

esophagus is loaded with eosinophils. It may be

isolated to the stomach, it may be more diffuse

where we would call it "allergic eosinophilic

gastroenteritis." This is somebody who may have

disease anywhere in their GI tract, and oftentimes

very diffusely.

There are some other conditions,

enterocolitis syndrome and dietary protein

proctitis, that are much more common in very young

babies.

The importance of presenting these

different syndromes here is that some of these

syndromes are IgE mediated and some of them are not

IgE mediated, some of them are very acute and some

of them are very chronic.

It turns out that those syndromes that are

more chronic and low-grade that don't present with

any acute symptoms, don't present with any clear

cause and effect of eating the food and having

increased gastrointestinal symptoms are going to

be, potentially, the most difficult for this

Committee to grasp. That is because these patients

are often reacting to remarkably small exposures.

I will come back at the end to sort of

give a couple of examples of the dilemma that kind

of patient is going to present to us as we really

try to figure out what is safe and what is not

safe.

It also turns out in the same vein that

the non-IgE conditions in general are probably

going to be most difficult to deal with, both

because they often don't have the acute IgE-type

symptoms, and because they are predominantly

mediated by a different part of your immune system

that can recognize even smaller degrees of these

food proteins that identifying thresholds are going

to be much more difficult.

(Slide.)

DR. WOOD: Now, when we are trying to

approach a patient with a food allergy, one of the

real difficulties is making an accurate diagnosis.

The diagnosis, as in most everything we do, begins

with a history, talking about the foods they

suspect are causing problems, whether we think the

symptoms are consistent with food allergy, whether

this is something that may not be food allergy at

all, or whether it may be a food intolerance rather

than an allergy. We are going to be interested in

the timing of the symptoms and the reproducibility

of reactions.

It turns out that when you do a very

careful history, most of the time it is wrong. It

will be correct in the acute reactions, where you

have a patient who comes in and says, "I fed him

scrambled eggs for the first time last week, and he

had hives all over."

"She took her first bite of peanut butter,

and developed hives within 2 minutes."

It is very likely that the history will be

born out when you do further testing. However,

when you look at the bulk of patients with food

allergies, many of them will have these more

chronic conditions like eczema or the

gastrointestinal disorders. When you are looking

at those patients, you will only verify the history

when you do further testing about a third of the

time.

(Slide.)

DR. WOOD: The next set of tests we do

after taking a history would typically either be

skin testing or serologic testing. A RAST test,

"radioallergosorbent test," is the most common

serologic test that is used.

These tests have some value and they also

have some problems. The problems they have is that

there is a relatively high rate of false-positive

tests. They do not have a terribly good positive

predictive accuracy.

They are generally accurate when they are

negative. Although, they will only be active when

they are negative when you are convinced this

patient has an IgE-mediated condition, because both

of these tests rely on the presence of IgE

antibodies to identify the specific food allergy.

An example would be if a patient develops

hives or anaphylaxis, which typically are

IgE-mediated, and they suspect that it is a certain

food. If you get a positive test back, it is very

likely that they have that allergy. If you get a

negative test back, then you need to keep looking.

It was not likely that food that caused that

reaction.

However, if you have a patient with

something like the allergic eosinophilic

gastroenteritis where there may not always be IgE

antibodies, you cannot stop with a negative test

and say, "We've proven you don't have food

allergy." That is something that happens all the

time, but it is often going to lead to a

misdiagnosis and mismanagement of that patient.

The bottom line is that we need to

carefully interpret our tests in the context of the

overall clinical picture, and that we need to rely

on oral challenge tests as the more accurate tests,

so that we will say that they are not completely

definitive. They are more definitive but not

completely definitive.

Again, they are going to be less

definitive in the patients that have more delayed

type reactions or more chronic conditions where

they won't react in that four-hour observation

period of your food challenge.

(Slide.)

DR. WOOD: You are going to hear more

about food challenges this afternoon, but I will

just mention a couple of issues here in terms of

the way that they can be done. They can be broken

down as open challenges where both the patient and

the person administering the challenge knows what

is being given.

A single-blind challenge is where the

patient is blinded but the person administering the

challenge knows the food that is being

administered, whereas a double-blind,

placebo-controlled challenge is regarded as the

most accurate test because it eliminates the bias

that may occur on the part of both the patient, who

may be feeling a great deal of anxiety about this

food challenge, or on the part of the observer, who

may have their own biases about this patient's

allergy and might overinterpret or underinterpret

symptoms.

We would say that these are going to be

the most accurate tests for the diagnosis of food

allergy. We would use them, if the history and lab

results don't provide a clear diagnosis. That is

often the case, again, when we have both a history

that may not be accurate and laboratory tests that

may not be completely accurate.

Then, we also do them very commonly to

determine when an allergy has been outgrown. This

would be a patient who has been known to be

allergic to a food, and we would be monitoring them

with some regularity in determining at some point

that it is worth trying to retry that food.

We would typically do it in a controlled

setting, just because even in some patients you

don't expect to react at all there may be

significant reaction. Consequently, we have to do

these with considerable caution.

(Slide.)

DR. WOOD: I think I pretty much mentioned

this.

(Slide.)

DR. WOOD: Now, they asked me to mention,

briefly, a study that we published last year

looking at the risk of oral food challenges. What

we have presented in this paper were results on

almost 600 challenges, 253 of which were failed

challenges. The patients reacted in the challenge,

so that is where we can look at the risk. The

other 57 percent, the patients had no symptoms, so

it was a risk-free challenge once they might have

gotten over the anxiety of being there.

We collected a lot of information on

demographics, other atopic disease, symptoms during

challenges, treatment needed, doses at which

reactions occurred. Even though there is a lot

said about safety of food challenges, there has

been very little published before this paper on

what really occurs.

Now, I'm going to say this again a couple

of times looking at the data, but I will say it up

front here, that these results are not

representative of the general population of food

allergy.

These patients that are being challenged

in this either had an unclear diagnosis, so it

wasn't a dramatic kind of situation, or they were

thought to have potentially outgrown their allergy

and were being challenged to potentially prove that

their allergy was gone.

We are really looking at very low-risk

population, and it is not representative of the

whole population of food allergy patients that are

out there. Again, I will say this a couple more

times looking at the specific data.

(Slide.)

DR. WOOD: Now, whenever we are doing this

sort of analysis, we try to break things into

categories. One of the tough categories to decide

is how do you rate reactions. You will see in the

literature some different definitions that have

been used.

We chose to create our own for a series of

studies that we were doing, and talked about mild

reactions that were skin and/or oral symptoms only.

Oral symptoms is just at itching or they will often

have an obvious hive-like reaction in their mouth

or pharynx when they are having one of these

localized reactions.

A "moderate reaction" was described as

upper respiratory and or GI symptoms only or any

three systems. When we are talking about systems,

we broke that into: skin, GI, upper respiratory,

lower respiratory and cardiovascular.

Then, severe reactions were those that

were that were potentially life threatening, where

they have lower respiratory and/or cardiovascular

symptoms or any four systems were involved.

(Slide.)

DR. WOOD: When we broke things down into

these different systems which were involved in

which challenges, you will see here that when we

look at this column on the right here, which is the

total in this paper we reported on milk, egg,

peanut, soy and wheat.

The greatest number of failed challenges

was to milk, 90; 56 to egg; 71 to peanut; 21 to

soy; 15 to wheat; for a total of 253. You will see

that skin manifestations were most common, 78

percent.

This is actually similar to what we have

seen and what is in the literature in terms of

reactions that happen out in the real world.

Eighty percent of food reactions, 80 percent of

anaphylactic reactions involve the skin, but about

20 percent do not.

Oral symptoms occurred in about a quarter,

upper respiratory in a quarter, lower respiratory

in about a third, GI in 43 percent. We,

thankfully, had no cardiovascular reactions in this

population.

Now, why would that be the case? It would

be for two reasons. The biggest reason is that

cardiovascular reactions are not that common in

children.

The cardiovascular system of a child is

really sturdy enough to put up with the insult of

an allergic reaction without necessarily becoming

involved. Cardiovascular reactions are much more

common in adults, and this population was entirely

childhood.

The other reason that we might have seen

the absence of cardiovascular reactions would be

that we were dealing with a relatively low-risk

population.

When we break it down into those three

severity classifications -- mild, moderate and

severe -- you will see that the numbers are

relatively similar for each food. When we look at

the total category, they broke pretty close to a

third in mild, a third in moderate, and a third in

severe.

When you look across the specific foods,

the most important point that came out of this is

that you can't say that one type of food allergy in

this kind of setting is more dangerous than

another.

It turned out that the greatest number of

severe reactions occurred with egg challenges.

This was important information we thought to get

out to get out to people doing challenges.

A lot of allergists will say, "I'm going

refer you, Dr. Wood, all of my peanut challenges.

I'm not touching a peanut challenge because they

are really dangerous. However, I will do egg and

milk challenges out in my office any time."

The message there is that really all of

these foods have a potential to have severe

reactions and need to be done in a setting where

you are really equipped to deal with that potential

for a severe reaction.

(Slide.)

DR. WOOD: When we looked at the RAST test

score or the median IgE level for these different

challenge results, we found that there was really

no strong association between their IgE level and

the reaction severity.

Now, this is an example of where this

population is not a good one to look at for this

data. The reason is that we were essentially only

challenging people that had relatively or very low

levels.

We were not challenging people with very

high levels where they were extremely likely to

fail the challenge. There is no reason in most

instances to prove that they are allergic. When

you know with, say, 99 percent certainty that they

are allergic, we would not put that patient through

a challenge.

Consequently, if you went out in the real

world where the RAST test levels range anywhere

from zero to 100, you would typically see

escalating reaction severity with levels that are

higher. We have that data for peanut allergy where

the group of patients that had levels at 100 did

have more severe reactions when they had accidental

exposures.

(Slide.)

DR. WOOD: Then, I think the last thing to

present from this study is whether reaction

severity was correlated or related to the percent

of food ingested in these challenges. It turns

out, if anything, it is inversely correlated. The

more severe reactions, and none of these were

statistically significantly, but if you look at the

general trends, you will see here that the more

severe reactions occurred with milk and eggs.

As you can see, the severe reaction for

milk is 15 percent and 30 percent for eggs. When

you look at the total group here, 50 percent, 45

percent and 30 percent.

(Slide.)

DR. WOOD: What is the reason this

happens? Does this make any sense at all? Do you

have your more severe reactions with smaller

exposures? The reason we think it happens is

because it is just identifying the more reactive

patients.

It is picking out those that even though

our test scores said that they are not so allergic

that they should do this, it is picking out those

that react more abruptly and have more severe

symptoms early in the challenge just because they

were higher risk patients.

Now, we have come up in our studies about

some decision making about when we would do food

challenges. This is purely for clinical purposes.

These are for those reasons of when we are trying

to decide if they are truly allergic or when we

think that the food allergy might have been

outgrown.

What we would say is that we would do food

challenges based on their history of reactions. If

they have reacted recently, we wouldn't feel the

need to do a food challenge.

We would base it on their laboratory

testing, the skin testing and the RAST testing.

Then he would base it on the importance of the food

to the diet. There are some foods that are

obviously much more important to the diet.

A family may never care whether that child

ever eats a pea again the rest of their life. They

may elect to never have a pea challenge done, but

they may be jumping to do a milk or what challenge

at the first opportunity, because milk or wheat

back in the diet would make such a dramatic

difference in their day-to-day life.

Then, we have come up with some

recommendations based on RAST testing of when we

would recommend doing challenges. These cutoffs

for milk, egg and peanut are all where we found a

greater than 50 percent chance of passing the

challenge, if you have levels below that range.

For other foods, it has been harder to determine

cutoffs, and we would challenge at higher levels

for things like wheat and soy.

(Slide.)

DR. WOOD: Just to go through an algorithm

of how we approach diagnosis, then, because it does

impact on the discussions that are going to happen

here, we would first take our history.

Based on the history, we would make some

distinction whether we think this is consistent

with an IgE type reaction or whether we think that

it is consistent with a non-IgE type reaction.

If it is IgE-mediated in all likelihood,

then a skin test or a RAST test will help identify

whether that food that was suspected to cause a

reaction probably did or probably didn't.

If the test is negative, because the

negative predictive accuracy is so high, we would

feel that you could stop worrying about that food

at that time. If the skin test is positive,

because there are false-positive tests that occur,

we need to do something more.

We might do a trial on an elimination

diet; we might do a food challenge in one order or

the other; and based on all of that information, we

would arrive on the specific elimination diet

recommended for that patient.

If it falls into a non-IgE category, the

situation is much more difficult because we can't

rely on a simple screening test to weed out those

patients.

They are going to need some combination of

challenges -- endoscopy, if it is a

gastrointestinal symptom; elimination diets,

rechallenges, maybe a reendoscopy -- so there is a

much more difficult plan on this side of the screen

to sort out those patients.

(Slide.)

DR. WOOD: Now, I'm going to finish here

with a couple of conclusions and present a couple

of dilemmas. The conclusions are that food allergy

is very common. This is a remarkably worthwhile

initiative that is going on here, and that right

now avoidance is the only treatment plan.

We really hope in the next 5 or 10 years

that there are going to be other treatments for

food allergy. It may be enough so that even if

they don't cure the disease, that they will elevate

the threshold to a point that we don't even need to

have these meetings, that small exposures won't

even be relevant. We are not even close to their

yet, so avoidance is the only option.

Strict avoidance is essential to prevent

reactions obviously, but we also think that in many

patients it also helps to promote the outgrowing

process.

Here is where we may have very different

thresholds. We may have a threshold that this

child, say, with milk allergy -- they know for a

fact that they can eat this bread that has whey as

the tenth ingredient and never have a symptom.

They are perfectly fine with it.

What we have found that getting that bread

on a regular basis may keep their immune system

more revved up to maintain the allergy so this

thing that is way below their threshold for

reacting acutely may still drive the immune system

to maintain the allergy and prevent them from

outgrowing the allergy.

The next conclusion is that food

challenges are a useful means to diagnose food

allergy and a useful means to determine threshold

doses. There are going to be some limitations of

challenges, and one of them is that as opposed to

the study that I presented that Dr. Perry did with

me, you have to include in a threshold type study

the most allergic patients.

Doing the kind of patients that we are

studying on the lower end of the spectrum has

nothing to do with thresholds. It is irrelevant

data. You can't go to my study and say, "This

looks like a threshold because we are not including

in those kinds of studies those highly allergic

patients."

The greater dilemma, and this one is

solvable, there are plenty of real allergic

patients out there. They won't necessarily want to

undergo these studies, because it is not a pleasant

thing to have allergic reactions, but that part is

potentially solvable.

The more difficult thing is a

determination of the threshold doses that I

mentioned for the chronic allergic conditions,

especially those that are not IgE mediated probably

isn't possible.

To give a couple of examples, if we take,

say, milk allergy, the most common food allergy of

all, and we are talking about an infant who is on a

formula, there are a bunch of different options we

could have. Some of them can have soy, but some of

them are also allergic to soy.

Some would go on to a formula like

Alimentum or Nutramigen, which is a formula where

the milk protein has hydrolyzed to a small enough

fragment that in 98 or 99 percent of kids with milk

allergy. It completely solves the problem. They

don't react at all to that level or that type of

protein that remains in that formula.

That other 2 percent, though, may react

severely to that. They are typically the patients

with the gastrointestinal disease. They are

typically very sick; they are typically not

growing; they are typically malnourished.

They are a group of patients who aren't at

risk for the acute dangerous reactions, but they

may be at very high risk for chronic disease from

their food allergy.

Those patients will typically respond

dramatically to a formula that is based in a single

amino acids as a protein source, and that is a

formula like Neocate and Elecare.

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

your attention.

CHAIRMAN DURST: Thank you, Dr. Wood.

Are there questions for discussion?

Suzanne.

QUESTION-AND-ANSWER SESSION

DR. TEUBER: This is Suzanne Teuber. I

had a question about your patients with the Neocate

sensitivity in terms of what the company reported

for the soy lecithin, did they have any values that

you could report back as to a chronic ingestion

threshold?

DR. WOOD: No. I mean, most of these kids

it is most likely the soy lecithin. SHS doesn't

have that data on the protein content of their soy

lecithin. They say it is zero. These kids when

they were switched to Neocate One Plus, which has

no soy lecithin, their disease went away. We have

to assume that there was enough there to drive that

process.

CHAIRMAN DURST: Yes.

MS. HALLORAN: Jean Halloran. Could you

say something about the process about growing

allergies? How does that work? What actually

happens?

DR. WOOD: Well, that is a very good

question. There are a number of things that we

don't understand too well. However, what we think

is that in the majority of patients we think that

outgrowing is most related to the immune system

gradually forgetting about that concern that it

earlier had.

That is where we think that strict

avoidance is likely to promote the outgrowing

process, and with a prolonged period of strict

avoidance for many of these foods, the immune

system has a memory that isn't long enough to

maintain the allergy and that it will gradually

wane and then full tolerance will be accomplished.

There are probably lots of other mechanisms going

on immunologically that are not well understood.

The other question with this that we have

no great explanations for, lots of theories but no

great explanations, is why you can take a food

allergy like milk, which in early infancy can be

every bit as severe as a peanut allergy, and have

most kids outgrow that allergy, while very few kids

outgrow the peanut allergies. There is something

very different about the immunologic memory of one

food allergen versus another.

CHAIRMAN DURST: Yes.

DR. KELLY: Ciaran Kelly. I wanted to

come back to the issue of challenging individuals

with severe allergies as a method for determining a

threshold. I would like to hear your comments as

regards the feasibility and safety and whether that

would be ethical to perform? I guess my concern is

that once the threshold is crossed, whatever that

threshold might be, isn't there a potential for

severe allergic reaction?

DR. KELLY: Yes. Absolutely. There have

been threshold studies done for the biggie, peanut,

with very allergic people so it is doable. Now,

what we can say about this is that these studies

won't be done in children. It is not going to

happen.

That automatically limits your population

of people, because when you go out and try to find

your group of milk-allergic adults to do these

studies on, you are limited.

Now, they do tend to be more severe

reactors. From that standpoint, you have some

patients out there, but there is no IRB that is

going to let us do this in children. There has to

be demonstrated benefit to do a study with risk.

The safety element is one that we are

comfortable with, recognizing that you need to have

emergency management available to you because there

will be people that have bad reactions.

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

these foods.

For peanut allergy it is going to be the

simplest, because allergy tends to persist. We

think that people usually hit their peak level of

severity as an adolescent or young adult, so that

would be fairly easy to solve.

However, when you look at the others like

milk and egg and soy and wheat, you are by and

large going to have the highest level of reactivity

in your first couple of years of life.

When we think about those allergies, we

usually think of growing into the allergy for one

or two or three years where they are becoming more

and more allergic, and then they are becoming less

and less allergic over the next one or two or three

or four or five years as they outgrow the allergy.

It is a moving target at all points, but the most

severe reactivity is likely to be early on.

CHAIRMAN DURST: Dr. Wood, I have a

question -- this is Dick Durst -- just points of

clarification. On your slides where you indicated

"wheat," now this is the IgE-mediated type allergy

as opposed to our discussion tomorrow on celiac

disease?

DR. WOOD: Yes, these results are entirely

IgE.

CHAIRMAN DURST: Okay. Do other grains

cause the IgE type reaction as the wheat?

DR. WOOD: Yes, our study there, about 600

challenges, came out of about 3,000 food challenges

that we have done. There were five most common

foods that I had enough data to make some

conclusions that we were comfortable with. All of

the grains cause allergic reactions.

It turns out that wheat and rye are very

cross reactive from an IgE-mediated allergy

standpoint, and that most patients allergic to

wheat are also allergic to rye; it turns out that

about half are allergic to barley; and 10 to 20

percent are allergic to oat. Beyond those grains,

all of the other grains and grain substitutes are

clearly capable of causing allergy in select

patients.

CHAIRMAN DURST: Thank you. One other

question as far as clarification at least for my

mind. One of your slides with the food challenge

decision making had the units in caps "KU/L." I

don't know if you defined that? I was curious.

DR. WOOD: Yes. It stands for "kilo unit"

of IgE in a specific assay that Pharmacia has

developed called an immunoCAP RAST. It all goes

back to this one technology that is thought to be

the most accurate quantitative measure of specific

IgE, and the results are represented in that kilo

unit of IgE, the specific IgE antibody per liter of

serum.

CHAIRMAN DURST: Thank you.

There is another question?

DR. KELLY: I have one other question.

Dr. Wood, you made a very important comment about

the potential for continued subclinical exposure to

allergens perpetuating an allergic response. How

well accepted and how well documented is that, or

is that largely a clinical impression?

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

experience --

CHAIRMAN DURST: Identify yourself.

DR. SILVERSTEIN: Marc Silverstein, Baylor

Health Care System in Dallas. I have had some

experience in studying the epidemiology of asthma

and anaphylaxis. In both of those conditions, your

findings are very much dependent upon your

diagnostic criteria.

In clinical medicine, we have diagnostic

criteria. You have described the criteria for food

allergy, which would involve components of:

history, physical exam, laboratory tests, food

challenge, and response to clinical management with

elimination diets.

Are there standardized criteria that you

would see moving the diagnostic criteria that you

would use from clinical practice to investigation

and publication in peer review literature and/or

perhaps the policy in making regulatory decisions?

I am interested in, Is there a set of

standardized criteria that professional

organizations or clinicians would use for

investigation or for recommending policy? I

understand there is some recent work on definitions

and standards for anaphylaxis?

DR. WOOD: The definitions for

IgE-mediated food allergy are pretty clear and it

is pretty well accepted that it is if you have a

history that is consistent, you have a positive

allergy test, and you either fail a challenge test

or pass a challenge with a dose that is generally

accepted to indicate full tolerance. It is fairly

straightforward and well accepted in the peer

review literature.

It is much more difficult on the group of

patients with, say, eosinophilic gastroenteritis

where they don't necessarily have IgE. You require

a histologic diagnosis to identify the condition,

and then figuring out whether they have food

allergy driving the process exclusively, partially

or not at all is a much more difficult process.

It is doable, but you have to eliminate

foods, rebiopsy, reintroduce foods, and rebiopsy.

There are studies that have done that, but it is so

much more difficult to do that there is much less

of an acceptance of an absolute diagnostic

criteria, much, much less.

It is being looked at. This is a form of

allergy that is clearly either happening much more

often or being identified much more often or both,

so that the potential is there, but it is much

further away from a definition that is well agreed

upon.

CHAIRMAN DURST: Yes.

DR. BRITTAIN: This is Erica Brittain. I

have a clarification question on the food

challenge. How is the placebo control implemented?

DR. WOOD: I think you are going to hear a

lot more about food challenges this afternoon, but

the idea, and it is going to vary depending on the

age of the patient and what they can do, but the

idea that it needs to be well disguised and

obviously safe from the perspective of that

patient's allergen --

(Simultaneous discussion.)

DR. BRITTAIN: But --

DR. WOOD: Go ahead.

DR. BRITTAIN: I'm sorry. Is it by a

dose? Is a particular dose placebo, or does a

patient get all placebo?

DR. WOOD: Yes. I'm sorry I

misunderstood. The normal way the challenge is

done is to have a separate challenge for the

placebo and for the actual food being studied. The

usual way it is done is that the patient would come

in and have a day doing a placebo challenge and

come in and have a day doing the food challenge.

Challenges can be done in a matter of a

couple of hours in some situations, but to do

highly allergic people in a placebo-controlled

manner would usually take 8 or 10 hours for each

day.

CHAIRMAN DURST: All right. Seeing no

further hands in the air, I think we will thank

Dr. Wood. We are right on schedule. Thanks again.

Our next speaker will be

Anne Munoz-Furlong, who is director of the

Food Allergy and Anaphylaxis Network, who will

discuss patient perspectives on food allergies.

PATIENT PERSPECTIVES ON FOOD ALLERGIES

MS. MUNOZ-FURLONG: Thank you. I would

like to thank the organizers of the meeting for the

opportunity to be here.

(Slide.)

MS. MUNOZ-FURLONG: What I would like to

do is in that time that I have been allotted is

give you a sense of who this food allergic consumer

is; the food allergen labeling from their

perspective; and then, most importantly, their way

of looking at threshold levels for food allergens.

(Slide.)

MS. MUNOZ-FURLONG: By way of background,

the Food Allergy & Anaphylaxis Network or "FAAN" is

a non-profit organization. We were established in

1991 and have 27,000 members, almost 28,000

members. Eighty percent of these people come to us

from physician referrals, so we know we are talking

about IgE-mediated responses when we are looking at

our membership.

Our mission has four points: to increase

public awareness, provide advocacy and education,

and advance research on behalf of those with food

allergy.

(Slide.)

MS. MUNOZ-FURLONG: Now, as Dr. Wood said,

food allergy is believed to affect about 11 million

Americans or 4 percent of the population; fish and

shellfish allergy, 2.3 percent or 6.5 million;

individuals in peanut and tree nut, 3 million.

Consequently, between these four foods we

are talking about almost 10 million Americans.

These are the four foods, as was presented earlier,

that are lifetime allergies and also are believed

to cause the majority of the severe or fatal

reactions in this country.

The other point I want to make here is

that although we are talking about 11 million

patients, our data shows us over and over again

that most of these patients have families who

follow their restricted diet. The impact is

actually many times greater than the number of

patients.

(Slide.)

MS. MUNOZ-FURLONG: When we look at

shellfish allergy, this is looking at data that we

published about a year ago now. Te prevalence of

shellfish, we found about 2 percent of the

population or 6 million Americans.

The key foods responsible for the majority

of these reactions in rank order are: shrimp, crab,

lobster, and clam. For fish allergy, .4 percent of

the population: salmon, tuna, catfish, and cod

being the primary fish that cause reactions.

However, if you look at these a different

way, these foods, especially shrimp or salmon, are

available on almost every menu that you are going

to look at in a restaurant or food service

establishment. Therefore, the risk for these

individuals is constant.

(Slide.)

MS. MUNOZ-FURLONG: Talking about tree

nuts, and these most of you already know, are not

peanuts; they are different. Most people with a

peanut allergy avoid tree nuts as a precaution but

not because they are allergic to them. About

20 percent of the 20 peanut allergic population is

allergic to tree nuts as well.

When we are talking about tree nuts, it

affects about 1.5 million Americans. Again,

looking at data from our patient registry of 5,000

patients, we find that walnut, cashew, almond and

pecan are the leading cause of tree-nut-allergic

reactions in this country.

(Slide.)

MS. MUNOZ-FURLONG: What does it mean to

have food allergies? It is vigilant label reading.

You have got to read labels not just for food

ingredients but anything coming into the home.

Bath products can have tree nuts, milk or eggs in

them, for example.

Pet food, if you have ever looked at the

ingredient statement on a pet food, it can have

almost every single one of the major eight

allergens.

That is something you have to worry about,

especially if you have a toddler who will pick up

food from the floor or anyplace else they can get

it. Also, medications have been known to have

allergens in them, particularly milk.

It is not just a question of label reading

for food; it is for anything. Trace amounts can

cause an allergic reaction, and that has been

proven over and over again.

Just one bite can cause a reaction.

Therefore, we can't tell by looking at someone how

allergic they are going to be or what their

tolerance will be to that food.

Currently, as Dr. Woods said, the only

cure now is a dose of epinephrine, if the patient

has a history of severe reaction. The onus is on

the patient or the family to read the label and

avoid the allergen and then be quickly prepared to

handle an allergic reaction, if they have made a

mistake or accidentally ingested the food to which

they are allergic.

(Slide.)

MS. MUNOZ-FURLONG: Because there is no

cure, decisions about any part of the person's life

are centered around food allergy. This is what

makes food allergy so stressful on the family and

on the patients.

Whereas with other allergies you have

seasonal components and you might have an easy

spring but fall is the bad season or if you are

allergic to cats or dogs you can avoid those, with

a food allergy every decision every single day is

affected by your food allergy.

Food shopping can take two to three to

hours just from reading labels. Cooking, if the

family is bringing the allergen into the home, they

then have to prepare two meals, the

non-allergen-containing meal and then the

allergen-containing meal, and take precautions to

avoid cross-contact.

Decisions about dining out and socializing

are made based on not a food preference, but is the

food safe.

"Can the manager be trusted to give us

accurate information?"

"Can the person we are visiting be trusted

not to slip some of the allergen into the food?"

Then, the decision is made to move forward

based on the answers to those questions.

Even what school or childcare the

individual will be sending their food allergic

child to are going to first be centered on food

safety from a food allergy perspective.

Vacation and travel where you and I might

decide whether we want to go someplace warm or go

skiing in the winter, these families have to think

first about food.

"Can we ship food there?"

"Is there a safe place?"

"Can we rent a room with a kitchenette and

make some of the meals so that we can maintain some

level of safety?"

Even family relationships, there is always

somebody in the family that does not believe the

food allergy is real, and so decisions are made

about whether they can visit that individual or

not.

(Slide.)

MS. MUNOZ-FURLONG: As a result of all of

this, it has a tremendous impact on quality of

life. We published a study several years ago

looking at the impact of food allergy on quality of

life.

What we found is that families who have a

food-allergic child score lower on their perception

of whether their child has good health or not, the

emotional health and family activities than the

general population.

Certainly, they scored lower or worse than

families who are looking at or dealing with other

chronic diseases such as diabetes, juvenile,

rheumatoid arthritis and attention deficit

disorder, for example.

We also looked at some of the other

influences. If the individual has a food allergy

and asthma or atopic dermatitis, that further

lowers their score for the quality of life.

If a family has a child with two or more

food allergies, that group scored much lower in 9

out of 12 scales compared to those who only have

one or two food allergies that they are dealing

with.

When we look at our patient population at

FAAN, we see that it is not uncommon for our

members to report a child with a milk, egg and

peanut allergy simultaneously. You can imagine

eliminating those three foods and how it compares

to the impact on the quality of life for the entire

family.

(Slide.)

MS. MUNOZ-FURLONG: This is how, again

looking at the same data, you can see here in blue

is "General health" perception. Food allergy lower

than the normal for asthma, attention deficit

disorder and some of these other symptom scores.

Now, in talking about label reading, which

is really the cornerstone of managing a food

allergy. Here is what goes on.

(Slide.)

MS. MUNOZ-FURLONG: The person with a food

allergy is told by the physician, as you heard

earlier from Dr. Wood, "You have an allergy, avoid

the food." Zero tolerance. They must live in a

black-and-white world. If you are allergic, you

don't eat that product.

If the allergen is listed on the label or

the label says "Contains allergen," they are not

going to eat that product because they are trying

to avoid a reaction. As a result, they expect

ingredient labels to be consistent and, most of

all, reliable because this is what they are basing

the decision about food on. It will affect their

health and safety.

When they see the same product with

different ingredient statements, it makes them very

confused and frustrated and sometimes very nervous

because they, again, are looking for consistency in

labeling.

What we are already seeing with some of

the companies complying with FALCPA regulations is

that there are products on the market that are

pre-FALCPA and FALCPA compliant with different

ingredient information regarding allergens.

Already we are getting calls from our members.

"Which one of these labels is correct?"

"What if I hadn't picked up that second

label? How would I have known?"

This is what we are heading into as we

start to change these labels.

(Slide.)

MS. MUNOZ-FURLONG: The challenge for

food-allergic individuals is that the patients are

told to strictly avoid the allergen, there is zero

tolerance or be prepared to handle an allergic

reaction. Once a reaction begins, we don't know

how severe that is going to be.

They are not aware that there are

scientific names to foods when they are newly

diagnosed. This is something FAAN spends a lot of

time doing. It will get better as FALCPA is

implemented because labels will have simple

ingredient terms on them.

We have to remember it is not just the

patient or the patient's family reading the label,

but it is the teacher, the scout leader, the

friends and family members. The impact for any

labeling decisions are going to be quite broad.

(Slide.)

MS. MUNOZ-FURLONG: Allergens can appear

in unexpected places. This is just one slide of a

number of examples that we have for "Common Foods

in Unexpected Places." Every one of these examples

have caused an allergic reaction to one of our

members, because they were not expecting to find

the allergen.

Just to give you an example, if you have a

milk allergy, you would not have expected that

barbecue-flavored potato crisps might have milk in

them, and you might not have read that label, or

that canned tuna might have soy in it. Therefore,

it is not as easy as avoid the food, you've got to

be looking for unexpected sources.

(Slide.)

MS. MUN [MLM2] OZ-FURLONG: We can see this

reflected in a study that was published in 2002 by

Joshi, et al. They took some food-allergic

individuals, gave them products that were on the

market, and asked them to read the label for the

food they were trying to avoid.

You can see here that families avoiding

milk, only 7 percent were able to accurately

identify milk on the labels that were presented to

them; for soy, they did a little better at 22

percent; but peanut, only 54 percent got the label

reading correct, and most of this was because of

confusion about allergen labeling information.

(Slide.)

MS. MUNOZ-FURLONG: The problem with

allergen labeling information, there are no

guidelines or standards for use. This is

completely voluntary. As a result, every company

has their own decision tree and algorithm and

wording for what terms they will use and under what

conditions.

This makes it very difficult for us to

educate consumers and the others who are reading

labels on their behalf and telling them what to do

and what these mean.

The proliferation of "may contain"

labeling has really caused us some problems. Just

to give you a sense of what is going on, we had one

volunteer go out in the Northern Virginia area to

one grocery store and look at products from

cookies, crackers, candy and bakery. We were

trying to follow the model of a previous FDA study.

She came back with 28 different versions

of "may contain" statements. From the consumer's

perspective, what does that mean? Can they be

trusted, or should we ignore them?

(Slide.)

MS. MUNOZ-FURLONG: The current

environment because of this, there are some

physicians that advise their patients to ignore

precautionary labeling, because it is everywhere

and there wouldn't be any food for them to eat.

There are others who tell them, "Heed the

warning and avoid those foods."

Then, there are some companies who tell

the consumers, "It is on the package only because

our legal counsel has advised us to put this on

there."

Then, there are others that say, "You have

to trust that wording and not go near the product."

How does a consumer determine which is

which?

We are also seeing advisory statements for

peanut allergy only. The way the consumer

interprets these statements is that they are

shortcuts to label reading.

If they see "contains peanuts" or "may

contain peanut," they may not read the rest of the

ingredient declaration if they are looking for milk

or soy, because they think that the company

understands food allergy and would have listed all

of the allergens on there.

As a result of all of this, consumers are

confused and frustrated. Particularly what is

going on as their food choices are further

minimized is that there is risk taking behavior by

parents of kids with food allergies who decide,

seemingly randomly to us, that some companies can

be trusted and others not, so they will ignore "may

contain" on the companies they trust.

Then, the teenagers, our highest-risk

population for a severe reaction, want to be like

everyone else are reporting that they are ignoring

"may contain" statements, because it is on so many

foods they have eaten the food and not had a

reaction, so they don't really believe that these

are true.

(Slide.)

MS. MUNOZ-FURLONG: This is one of the

labeling studies that we conducted with our FAAN

members during a spring meeting a year or two ago.

We asked a question. They were supposed to answer,

"I would never purchase a product that says it

contains" whatever the "allergen" is. You can see

that almost 100 percent of them would avoid a

contain statement.

However, as you go from very specific to

black-and-white to vague "packaged in a facility

that also produces," say, peanuts or nuts or

whatever the allergen might be, only 74 percent

would avoid purchasing that product.

Consequently, 25 percent of the allergic

consumers are going to purchase products where they

don't really understand the precautionary labeling.

If the company is putting this on here because of

some risk, we've got a miscommunication or a

communication gap going on.

(Slide.)

MS. MUNOZ-FURLONG: Let's talk about

thresholds, then. Again, from the consumer's

perspective, their physicians advise, as you heard

from Dr. Wood, is strict avoidance or a reaction

may occur and you will not outgrow this allergen.

They are very motivated to try to strictly avoid

that food.

When we talk about thresholds to our

members, and these tend to be the most motivated

and well-educated of the food allergy population,

this is what we consistently get back. They

believe that threshold levels may put their

children at risk because their child is so

allergic.

They also wonder whether the threshold

levels, the whole discussion is based on the

industry or the government trying to figure out a

way not to have to clean or label for allergens.

Again, they are wary that this might be a loophole

that is trying to be directed at them.

(Slide.)

MS. MUNOZ-FURLONG: The catch 22 here,

from where we are at FAAN, is that we understand

that if we label for all allergens at all levels it

will further restrict diets. If we further

restrict the diet, we are going to increase

frustration which will yield risk taking.

It is going to undermine the integrity of

the ingredient label. As I showed already with

"may contain," we are already seeing that. They

believe "contains." However, if we put "contains"

on everything and they eat it and don't have a

reaction, we are going to diminish the validity of

that statement.

If we undermine the integrity of the

ingredient label this will potentially lead to more

allergic reactions as they take more risk, which is

going to increase the number of doctor visits;

hospital visits; and, potentially, fatalities.

(Slide.)

MS. MUNOZ-FURLONG: Here is an example of

what can go on and what we see as what we may all

be facing. This is a report that came to us from

one of our members who had a soy-allergic child who

had safely eaten soy lecithin in the past. Most of

our members, although we tell them to read the

ingredient declaration on products every time they

purchase them, become brand dependent and stop

reading the ingredient label. That is exactly what

happened here.

This was a product that the child had

safely eaten in the past. The mother did not read

the label, gave it to the child, he started eating

it. She then started reading the label and saw

that it now says "contains soy." She got very

nervous and screamed that it contained soy and

asked the child to spit the food out.

Immediately, he started having itching,

leading to hives, and a feeling of impending doom.

The mother gave him medication and thought she was

having a full-blown reaction.

The question we have to ask ourselves, Was

this a reaction, or was it a panic attack? She

called the manufacturer and was told that the

"contains soy" is because it contains soy lecithin.

Therefore, the ingredients hadn't really changed

from the product that they had safely eaten before.

From our perspective, we do not want to

see consumers or their families subjected to this

kind of fear. Because what you don't realize is

that once this reaction is taken care of, it takes

a long time for the family to trust again. We do

have reports of children developing eating

disorders and just being very cautious about being

around other people once they have had a reaction.

(Slide.)

MS. MUNOZ-FURLONG: From the consumer's

perspective, if we are looking at developing a

threshold level, and as I said there are pros and

cons to both sides of this issue, the key here is

we have got to do a good job of education. We have

got to educate physicians and registered dieticians

so that they can counsel patients accurately.

As you saw, we have done no training for

"may contain." We have got some doctors that say,

"Just ignore it." We can't afford to do that with

threshold levels.

We also have to educate patients and their

families and assure them that the food is still

safe and that they can trust the information on the

label. We also have to do outreach to the food

industry so that they can answer the queries from

food-allergic consumers in a way that will give

them confidence instead of make them nervous or

suspicious about whether they can trust the

information on the label.

(Slide.)

MS. MUNOZ-FURLONG: In summary,

food-allergic consumers want as many food choices

as safely possible. This is really why we are here

and why we are seeing some of this behavior with

advisory statements.

They want to open the diet. The children

want to be like everyone else, and they want the

least amount of restrictions, but they need to be

safe.

The consumer needs to understand the

information on the ingredient statement. They need

most of all to trust that that information is

reliable and it is going to be consistent from one

product to the other. They also need a minimal

number of precautionary allergen statements and a

guideline so that they understand what these

statements mean and what they should do as a result

when they see these on products.

(Slide.)

MS. MUNOZ-FURLONG: In conclusion, the

current labeling and manufacturing practices

present enormous challenges to food-allergic

consumers. As Dr. Wood said, the number of these

patients is increasing.

To give you an example, we conducted a

prevalence study of peanut and tree nut allergy in

1997, repeated that same study in 2002, and found

that in that five-year period the number of

children with peanut allergy had doubled. We don't

know how it is continuing to trend, but reports are

that it is still increasing.

(Slide.)

MS. MUNOZ-FURLONG: The bottom line is

above all we must protect the integrity of the

ingredient information. Because from the

food-allergic consumer's perspective, they depend

on this information to avoid an allergic reaction

and, most of all, to maintain their health and

safety. We already have data showing that food

allergy impacts the quality of life. We don't want

to further diminish their quality of life.

With that, I will end here and open for

questions.

CHAIRMAN DURST: Thank you.

Does the Committee have any questions?

Yes.

MS. HALLORAN: I mean, obviously a person

can survive without ever having to buy any packaged

food. I am wondering in terms of the kinds of

things you were talking about -- teenager's

preferences, the needs of a busy mother, et cetera

-- are there particular categories of food that are

prepared and packaged that are most sort of

important and essential in our modern life? I

mean, would it be bread or breakfast cereal or--?

MS. MUNOZ-FURLONG: If they ate

vegetables, they would be fine. How many kids want

to eat vegetables?

(General laughter.)

MS. MUNOZ-FURLONG: I think it really goes

back to quality of life. Children want to be like

everyone else, and they will do everything they can

to fit that mold.

I have a daughter that was diagnosed with

milk allergy and egg allergy when she was an

infant. I will tell you that I did everything I

could to make sure that she felt like her friends.

It is not just the patient or the child,

it is also the family wanting to not have their

child isolated or feel stigmatized because of the

allergy.

If everyone else is having breakfast in a

box, that is what these kids want. What we want is

to make sure that those labels are accurate, if the

family makes that decision.

Granted, there are some families that are

very cautious and will only make food from home,

make it from scratch. However, as the child gets

older and is out with friends, that is just not

doable.

MS. HALLORAN: Are there any particular

categories of foods?

MS. MUNOZ-FURLONG: No. As you saw in

that slide, "Common Foods In Unexpected Places," we

are seeing allergens everywhere. We have just got

to make sure that all of the labels are correct and

can be trusted.

CHAIRMAN DURST: Yes.

DR. KELLY: Ciaran Kelly. A question for

you from your perspective and the perspective of

the people you represent, the patients with food

allergies.

I understand that you are frustrated and

find it very difficult to work with the current

system of many different types of wording. Would

it be better for you to have a two-level system,

"does not contain" and "may contain traces of" --

or even three levels, "contains" and "may contain

traces of" and "does not contain"? Would that be

acceptable?

MS. MUNOZ-FURLONG: Well, I will start

from the back end of your question. If you poll

our members or just the general consumers, they all

want "does not contain" labeling.

I would caution to you because of the

reports I've seen. This is very widely used in the

U.K., our colleagues in the U.K. have reported,

recalls to products that say "does not contain

peanuts" when they do contain peanuts undeclared.

From the way the consumer is going to

behave if they see "does not contain," they may not

read that ingredient declaration because that is

the guarantee they have been waiting for.

I am not in favor of "does not contain."

I am in favor of let's have them read the

ingredient declaration and know that they can trust

if it doesn't have peanuts in that ingredient

statement, the product should be safe for them.

When we start to see different allergen

statements, we want to make sure that those can be

trusted. When we are talking about "does not

contain," that is an implied endorsement or

guarantee, which makes me very worried. If the

company makes a mistake and that is on the label in

error, we could have someone pay for it by having a

reaction.

Now, if we have two levels, "contains" and

"may contain," as along as we know what that means

and that all companies are following this

guideline, that makes it much easier. Right now,

you can go poll 12 companies and they each do

different things.

CHAIRMAN DURST: I think we need to move

on.

Thank you.

Our next speaker will be Susan Hefle,

associate professor and co-director of the Food

Allergy Research and Resource Program at the

University of Nebraska, who will be speaking on

"Allergenicity: Analytical Methods."

Dr. Hefle?

ALLERGENICITY: ANALYTICAL METHODS

DR. HEFLE: Thank you, Chairman Durst.

Good morning. I am going to discuss the

basic analytical methods for allergens. The model

used is the ELISA-based model which has lateral

flow. This model has been used for several years

now. We will discuss this more later.

Our second bullet, the most successful

kids do use polyclonal antibodies but occasionally

a kit uses monoclonal antibodies directed against a

single protein. Usually, the antibodies are

directed against a crude extract of an allergenic

food not the specific proteins themselves. It is

not necessary to really measure the allergen.

The industry just cares if any peanut is

there, not if one particular protein from a peanut

is there. "Ara h 1" is a particular peanut

allergen. The industry just wants to know if any

100

peanut or whichever peanut is there.

A lot of times a lot of the successful

kids use a much more kind of crude approach to

detecting peanut rather than specifically horning

on the allergens themselves.

There is a challenge, though, in that

different standards are used in the different kids,

depending on the manufacturer, and also different

antibodies are used in the different kids depending

on the manufacturer. It is not like a standardized

approach across the board, necessarily.

(Slide.)

DR. HEFLE: The detection limits range

from around 0.1 to 2.5 parts per million for the

quantitative methods. There are also quality

methods; however, if we are talking about threshold

levels, we need to talk about quantitation here.

Using a method that has a very low

detection limit has certain challenges. Every kit

has the ability to have a low detection limit. Ten

years ago, when I started developing kits,

Steve Taylor and I sat around and thought about

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what the detection limit should be based on our

years of experience in dealing with consumer

reactions and things like that.

We set a certain level with the kits we

developed; we picked 2.5. It seems to have gone

very well over the last seven or eight years since

these kits have been on the market. Some of the

other companies have a little bit lower range of

detection limit, and that seems to work okay, too.

However, if you go way too late, I mean,

they can all push these kits really, really, really

low. The problem is, Is there clinical relevance

at that point?

If there is no clinical relevance,

companies may be chasing molecules around their

processing plant. They will have all of this

positive data at a low level, and they won't know

what it means. We like to call this "paralysis by

analysis."

We want the data to be relevant. We want

the data to be useful. If the industry goes back

in and says, "I want to fix this, but what if I get

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all of these positive results at a low level?"

Detection limits have to be kept in mind. They

should be tied to threshold levels, whatever we

decide the threshold levels should be.

It adversely affects the quality of life

for food-allergic consumers, if you use detection

limits that are really low or push those detection

limits without a good clinical basis. Because of

the industry reaction in the form of increased use

of "may contain" label.

When they did paralysis by analysis and

they get positive results, maybe they throw a lot

of "may contain" labeling on that product that they

are worried about and so they are going to put that

on there. That decreases the number of foods that

allergic individuals can eat.

The current detection limits that are set

that the industry uses right now have worked very

well for seven years in protecting the

food-allergic consumer.

I don't think at this point there is any

need to change them right now. But, again, as

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science comes in and we know more about threshold

levels, there might be an adjustment here or there.

We just finished an egg threshold study.

Contrary to what Robert Wood said, you can do

threshold studies in kids, because we did this in

30 egg-allergic children. That is the only kind of

people we could find to have egg allergy are kids.

When we crunch those numbers and look at

that data, if the threshold is low enough that we

need to adjust the kids for egg out there, the

manufacturers have all said they would be willing

to do that based on the science.

(Slide.)

DR. HEFLE: Many companies are testing for

allergen residues. What they are primarily testing

is not-finished product, but they are using it to

verify sanitation procedures. They have been using

them for as long as they have been on the market.

Certainly with the new law coming up,

there are a lot more using them than used to use

them. In general in the U.S., companies are

incorporating testing using these test kits. As

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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.