1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

FOOD ADVISORY COMMITTEE MEETING

Advice on CFSAN\'S Draft Report:

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

Wednesday, July 13, 2005

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

Greenbelt Marriott

6400 Ivy Lane

Grand Ballroom

Greenbelt, Maryland 20770

2

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

FOOD ADVISORY COMMITTEE STANDING MEMBERS:

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

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

Patrick S. Callery, Ph.D.

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

Jean M. Halloran (Consumer Representative)

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

Margaret C. McBride, M.D.

Mark Nelson, Ph.D. (Industry Representative)

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

TEMPORARY VOTING MEMBERS:

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

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

Erica Brittain, Ph.D.

Ciaran P. Kelly, M.D.

Soheila June Maleki, Ph.D.

David O. Oryang

Marc D. Silverstein, M.D.

Suzanne Teuber, M.D.

FOOD AND DRUG ADMINISTRATION:

Catherine Copp, J.D. - Senior Policy Advisor

Food and Drug Administration, CFSAN

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

Food and Drug Administration

National Center for Food Safety and Technology

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

Food and Drug Administration, CFSAN

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

Food and Drug Administration, CFSAN

Stefano Luccioli, M.D. - Senior Medical Advisor

Food and Drug Administration, CFSAN

Marcia Moore, Food Advisory Committee, Executive Secretary

Jenny Slaughter - Director

Food and Drug Administration Integrity and Ethics Staff

3

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

GUEST SPEAKERS:

Rene Crevel, Ph.D. - Senior Scientist

Unilever, Safety and Environmental Assurance Centre, United Kingdom

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

> Food Allergy Research and Resource Program, University of Nebraska

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

> CFSAN, FDA Assistant Professor, Georgetown University

Anne Munoz-Furlong

> Director, Food Allergy & Anaphylaxis Network

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

> Food Allergy Research and Resource Program, University of Nebraska

Robert Wood, M.D. - Professor

> Johns Hopkins University School of Medicine

4

C O N T E N T S

PAGE

Call to Order, Welcome and Introductions

Charge to the Food Advisory Committee

Richard Durst, Ph.D., Acting Chairman 6

Conflict of Interest Statement & Other

Instructions

Jenny Slaughter, FDA 10

Welcome and Opening Statement

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

Use of Food allergen Thresholds

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

Introduction to Food Allergens

Robert Wood, M.D. 23

Patient Perspectives on Food Allergies

Anne Munoz-Furlong 72

Allergenicity: Analytical Methods

Susan Hefle, Ph.D. 99

Question and Answer Session 126

Oral Challenge Studies: Purpose, Design,

and Evaluation

Stefano Luccioli, M.D.

Senior Medical Advisor, CFSAN, FDA 133

Question and Answer Session 161

Threshold Modeling Approach

Rene Crevel, Ph.D. 170

Food Allergen Thresholds

Steve Taylor, Ph.D. 189

Overview of Approaches to Establishing

Thresholds: Allergens

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

5

C O N T E N T S (Continued)

PAGE

Public Comments:

Tracy Atagi 228

John Carroll 232

Diane Castiglione 242

Will Duensing 247

Martin J. Hahn, Esq. 250

Peggy Mockett 254

Kim Mudd 257

Kim Mulherin 260

Linda Webb 264

Jupiter Yeung 268

Committee Discussion:

Panel Discussion with Guest Speakers

Thresholds for Food Allergens - Questions 272

Adjournment

Richard Durst, Ph.D., Acting Chairman 414

6

P R O C E E D I N G S

CALL TO ORDER, WELCOME, AND INTRODUCTIONS

CHARGE TO THE FOOD ADVISORY COMMITTEE

CHAIRMAN DURST: I would like to call the

meeting to order.

Good morning. I am Dick Durst, professor

of chemistry in the Food Science and Technology

Department at Cornell University. I was asked to

chair this meeting over the next two and a half

days. I would like to make a few announcements

before we begin our meeting this morning.

I would appreciate it if everyone would

turn off their cell phones, unless they are

expecting a call of a super emergency nature. I

would also like to ask if the guest speakers could

make themselves available for the discussion this

afternoon, I would really appreciate it. We may

have some additional questions.

We have received a charge from the FDA to

give our evaluation of the draft report prepared by

the Threshold Working Group. I assume all of the

members have read that thoroughly. In my opinion,

7

I it was fascinating.

It was an excellent article and I commend

the Committee for coming up with it. It was very

educational. Not being an expert on food allergens

myself, it was extremely educational, and I was

able to follow it quite clearly.

Our charge is to evaluate this report to

determine whether the approaches that are presented

in there are the only ones or the better ones,

which of the ones that are in there might be the

most appropriate. This is the focus of our meeting

today, both on the food allergens and on gluten.

Let me also begin by asking the committee

members to introduce themselves. We will start

with Dr. Silverstein.

Marc, would you start it off?

DR. SILVERSTEIN: Good morning. My name

is Marc Silverstein, and I\'m a general internist

and geriatrician at Baylor Health Care System in

Dallas.

DR. TEUBER: Good morning. My name is

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

8

MR. ORYANG: Good morning. I am

David Oryang. I am a risk analyst and agricultural

engineer at the United States Department of

Agriculture, Animal and Plant Health Inspection

Service.

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

gastroenterologist at the Harvard Medical School in

Boston.

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

scientist with the USDA.

DR. BRITTAIN: Erica Brittain, I am a

statistician at the National Institute of Allergy

and Infectious Disease.

DR. BRILEY: Margaret Briley, University

of Texas at Austin, nutritionist.

DR. BOCEK: Good morning. I am

Petr Bocek, medical officer in NIH\'s National

Institute of Allergy and Infectious Diseases.

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

the FDA as the executive secretary of the Food

Advisory Committee.

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

9

nutritional epidemiologist at the University of

Hawaii.

DR. McBRIDE: I am Margaret McBride. I am

a child neurologist at Akron Children\'s Hospital.

DR. CALLERY: I am Patrick Callery, a

pharmaceutical scientist from West Virginia

University.

DR. GONSALVES: I am Dennis Gonsalves, a

scientist with USDA in Hawaii.

DR. HEIMBURGER: I am Doug Heimburger, a

physician and nutrition specialist at the

University of Alabama at Birmingham.

DR. BARACH: Jeff Barach with Food

Products Association, vice president for special

projects and regulatory affairs.

DR. NELSON: Mark Nelson with the Grocery

Manufacturers Association responsible for

regulatory and scientific policy.

MS. HALLORAN: Jean Halloran from the

Consumers Union where I am director of food policy

initiatives.

CHAIRMAN DURST: Thank you very much.

10

One other item is that we may have some of

our members leave early on Friday, depending on the

amount of time we can spend. What I propose is

that today and tomorrow that we anticipate having

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

that we have enough time for all of our

discussions.

Okay. Let me introduce our first speaker.

This will be Jenny Slaughter, director of Ethics

and Integrity Staff at the FDA, to describe the

\"Conflict of Interest Statement\" and other

instructions.

CONFLICT OF INTEREST STATEMENT

AND OTHER INSTRUCTIONS

MS. SLAUGHTER: Well, good morning and

welcome. The Food and Drug Administration is

convening today\'s meeting of the Food Advisory

Committee under the authority of the Federal

Advisory Committee Act of 1972.

With the exception of the industry

representatives, all members of the Committee are

special government employees or regular Federal

11

employees from other agencies subject to Federal

conflict of interest laws and regulations.

FDA has determined that members of this

Advisory Committee are in compliance with Federal

ethics and conflict of interest laws including, but

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

354\.

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

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

applicable to only FDA, Congress has authorized FDA

to grant waivers to special government employees

who have financial conflicts when it is determined

that the Agency\'s need for particular

interventional services outweighs the potential

conflict of interest.

Members who are special government

employees at today\'s meeting including special

government employees appointed as temporary voting

members, have been screened for potential financial

conflicts of interest of their own as well as those

of their spouse, minor child, and employer, which

are related to the discussions of today\'s and

12

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

Draft Report: Approaches to Establish Thresholds

for Major Food Allergens and for Gluten in Foods.\"

These interests may include investments,

consulting, expert witness testimony, contracts,

grants, research and development agreements, public

speaking, writing, patents, royalties, and primary

employment.

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

full waivers have been granted to the following

participants, Dr. Suzanne Teuber and Dr. Soheila

Maleki, please note that all of the interests in

the firms that could potentially be affected by the

Committee\'s decisions.

A copy of the written waiver statements

may be obtained by submitting a written request to

the Agency\'s Freedom of Information Office, Room

12A-30 of the Parklawn Building.

In addition, the following individuals are

participating as FDA\'s invited guest speakers,

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

Anne Munoz-Furlong, Dr. Steve Taylor, and

13

Dr. Robert Wood.

The following individuals will be

participating as FDA invited guest speakers

tomorrow, July 14th: Dr. Pekka Collin,

Dr. Alessio Fasano, Dr. Donald Kasarda,

Dr. Cynthia Kupper, and Dr. Joseph Murray.

Lastly, I would like to report that

Dr. Jeffrey Barach and Dr. Mark Nelson are serving

as the industry representatives on the Committee at

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

regulated industry.

Dr. Jeffrey Barach is employed by the

National Food Processors Association and

Dr. Mark Nelson is employed by the Grocery

Manufacturers of America.

A copy of this document will be placed on

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

it. I thank you.

CHAIRMAN DURST: Thank you very much.

We will now go on to the welcome and opening

statement by Dr. Michael Landa, the deputy director

for Regulatory Affairs at CFSAN, the FDA.

14

Mike.

WELCOME AND OPENING STATEMENT

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

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

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

(General laughter.)

MR. LANDA: Thanks again. Good morning to

everyone. Welcome to the members of the committee,

to the guest speakers, to members of the public who

have joined us today, and to my fellow FDA

employees.

I would like to give a special thanks to

the Committee members for your willingness to take

time from busy schedules to help us with your

expertise for a meeting that will be several days

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

chunk of Friday.

Let me just add that Dr. Brackett had

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

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

some portion of the meeting. He was called

downtown for a meeting this morning.

15

I am going to refer to a couple of points

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

apply to celiac disease as well. It is just less

cumbersome to start with the food allergens. The

agenda has been making, I think, an opening

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

that.

There are just a few points I want to make

as you go into your inquiry today. The first is

virtually every FDA speaker makes at this kind of

proceeding which is what we do really is based on

science.

We talk about being a science-based

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

In that context, I am going to paraphrase what may

be a rather obscure 19th century Senator, Karl

Shrews from Pennsylvania.

The paraphrase essentially is, Our science

correct or incorrect, when it is correct, help us

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

correct it. That is as much as anything else what

we want from you here in terms of your expertise in

16

the science.

If with respect to the threshold in the

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

know from you that we have gotten it right. We

want your help in keeping it right. If we have

gotten it wrong, we want your help in getting it

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

not considered an approach that we should have

considered, we want to know that from you.

The third point I will make is that

Americans suffer from food allergies, particularly

children. There is some evidence that the number

is increasing. If you add to that family members,

you really have tens of millions of folks who are

involved. At the moment their principle means of

protection really is exquisite attention to the

food label. That is their pathway to safety I

suppose.

We are hoping that eventually thresholds

will provide another path to safety. This is the

beginning of the inquiry into thresholds, that is,

the approaches that are outlined in the report. It

17

is the first step in a very important process.

The last point I will make is just that

this is as much as anything else for members of the

public, the docket is going to remain open until

about the middle of August.

If people have comments, based on what

they have heard today, for example, they should

feel free to submit those comments to the docket.

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

precise date, but it is the middle of August.

In that connection, I should say we are

especially interested, as I think is always the

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

outlined in the report.

Thank you.

CHAIRMAN DURST: Thank you, Mike. Since

Mr. Landa didn\'t want me conferring a doctorate

degree on him, I will not do it with Catherine

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

FDA, who will discuss the use of food allergens

thresholds.

USE OF FOOD ALLERGENS THRESHOLDS

18

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

(General laughter.)

MS. COPP: Thank you, Dr. Durst.

Good morning. As you know, the focus of

this meeting today and tomorrow and the discussion

on Friday is the Draft Report of CFSAN\'s Threshold

Working Group: Approaches to Establish Thresholds

for Major Food Allergens and For Gluten in Food.

I have been asked to provide a context for

the Draft Report in terms of CFSAN\'s programmatic

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

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

(Slide.)

MS. COPP: Last August, Congress enacted

the Food Allergen Labeling and Consumer Protection

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

awkward acronym \"FALCPA.\"

This new law amends the Federal Food, Drug

and Cosmetic Act, the principle statute

administered by FDA by requiring that the label of

a food product that is or contains an ingredient

that bears or contains a major food allergen

19

declare the presence of the allergen as specified

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

in \"consumer friendly\" terms.

FALCPA defines a \"major food allergen\" as

one of the eight foods or food groups or a food

ingredient that contains protein derived from one

of these foods. Those are listed on the bottom of

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

nuts and crustacean shellfish, which were

identified by Congress in the law.

(Slide.)

MS. COPP: The possible existence of

threshold levels for food allergens is an important

scientific issue, as Mr. Landa has pointed out,

associated with our implementation of FALCPA.

Although the law does not require FDA to

establish thresholds for any food allergen, there

are three possible ways, which are listed on this

slide, that such thresholds could be used to

implement the new law, these are: administering the

petition process provided for in FALCPA,

administering its notification process, and

20

addressing the issue or the occurrence of

cross-contact.

(Slide.)

MS. COPP: FALCPA provides two processes

by which an ingredient may be exempt from the

FALCPA labeling requirements, a petition process

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

own slides (laughter). No, okay.

Under the petition process, an ingredient

may be exempt, if the petitioner demonstrates that

the ingredient does not cause an allergenic

response that poses a risk to human health.

Given this language for the petition

exemption standard, we believe it will be very

important for us to both understand food allergen

thresholds and to have a sound scientific framework

for evaluating the existence of such thresholds.

Under the notification process, an

ingredient may be exempt, if the notification

contains scientific evidence that demonstrates that

the ingredient does not contain allergenic protein,

or, if FDA has previously determined under the food

21

additive approval process that the food ingredient

does not cause an allergenic response that poses a

risk to human health.

(Slide.)

MS. COPP: Given this language for the

notification exemption standard, we also believe

that it will be very important for us to understand

food allergen thresholds and to have a sound

scientific framework for evaluating the existence

of such thresholds.

(Slide.)

Finally, the FALCPA directs FDA to prepare

and submit a report to Congress. This report will

focus principally on the issue of cross-contact of

foods with food allergens and is to describe the

types, current use of, and consumer preferences

with respect to so-called \"advisory labeling.\"

Processed in a facility that also processes tree

nuts is an example of such labeling.

Cross-contact may occur during food

production when residues of an allergenic food are

22

present in the manufacturing environment and are

unintentionally incorporated into a food. Because

the food is not intended to contain the allergen,

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

label. In some cases, however, the potential

presence of the food allergen is declared by a

voluntary advisory statement.

We also believe that understanding food

allergen thresholds and developing a sound

scientific framework for evaluating the existence

of such thresholds may also be useful to us in

evaluating and addressing food allergen

cross-contact and the use of advisory labeling.

Thank you.

CHAIRMAN DURST: Thank you very much.

Does the Committee have any questions or

discussion of this presentation?

(No verbal response.)

CHAIRMAN DURST: If not, I think we will

proceed.

The next speaker is Dr. Robert Wood,

professor at Johns Hopkins University School of

23

Medicine, who will give us an introduction to food

allergens.

INTRODUCTION TO FOOD ALLERGENS

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

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

provide an overview of food allergens and food

allergy leading into the discussion that is going

to go on over these next couple of days.

(Slide.)

DR. WOOD: The beginning of this, any talk

about food allergy really requires that we have

some common definition that we can all agree on.

This is something that is not as easy as it might

sound and often generates a lot of confusion. The

reality is that a lot of what is called food

allergy is really not food allergy and may fall

under more of a food intolerance category.

When we are talking about food allergy,

there are a couple of key ingredients. One of them

is that there is an immunologic component to the

reaction. The reaction is typically to the protein

component of the food as opposed to a food

24

intolerance that is more often related to the

carbohydrate component of the food. Importantly to

this meeting, exquisitely small amounts may cause a

reaction and that these reactions can be severe and

even life threatening.

(Slide.)

DR. WOOD: The pathophysiology of the

allergic response is sort of very schematically

diagramed here. What we are thinking about is a

process that begins with exposure and with most

allergy, probably all allergy, you have to have

some prior exposure to develop your sensitivity.

(Slide.)

DR. WOOD: There is a genetic

predisposition that makes some people particularly

more prone to develop allergy in general, whether

it be food allergy or respiratory allergy, than

others. There are some people who no

matter what, how, when and where they are exposed

they will never develop an allergy, and others who

with very trivial exposure may develop a severe

allergy.

25

If you are in this group who is

genetically predisposed, your immune system then

goes through a process we will refer to as

sensitization. Sensitization is most often

involving the production of IgE antibodies. We

will talk about this in a little bit more detail

about some different food allergy syndromes.

However, it is also important to note that

not every food allergy involves IgE and that there

may be differences in the types of reactions and

the doses of food required to induce a reaction in

those patients that have IgE versus

non-IgE-mediated food allergy.

Once you have become sensitized, then

reexposure to this food will lead to symptoms.

These symptoms may be abrupt, they may occur within

seconds of eating the food, or they may be very

low-grade and chronic. This is another concept

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

With some patients it will be very easy to

determine a threshold, and in some patients it will

be virtually impossible to determine a threshold

26

because their symptoms will not appear in a

challenge test. They may take days or weeks of

chronic exposure and then develop very significant

disease based on that chronic exposure.

(Slide.)

DR. WOODS: The prevalence of food allergy

is substantial. The numbers that we would be most

comfortable with would be 5 to 7 percent of young

children; 2 to 3 percent of adolescents and adults;

at least 10 or 11 million Americans affected.

We do believe that the prevalence is

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

food allergy. There has been a substantial rise in

asthma and other allergic diseases as well as food

allergy.

Now, the reason that these numbers change

between childhood and adolescence and adulthood is

because a large proportion of food allergy is

outgrown over the first five to seven years of

life.

(Slide.)

DR. WOOD: There is a long list of

27

potential food allergens out there. At least 200

foods have been identified and characterized as

truly food allergens, but there is a relatively

shorter list that are focused upon because they are

responsible for the vast majority of food allergy

that occurs.

The list on the left-hand side

representing what is most common in young children:

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

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

older children, adolescents and adults and is

dominated by peanuts, tree nuts, fish, and

shellfish.

The reason that this list changes from

childhood to adulthood is because four of these

most common food allergens in your children \--

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

outgrown.

Eighty to 90 percent of children will

outgrow those food allergens and not carry them

into adolescence or adulthood, whereas the peanuts,

tree nuts, fish and shellfish are significantly

28

more difficult to outgrow, less commonly outgrown,

and tend to persist into adulthood and actually

through the patient\'s entire lifespan.

(Slide.)

DR. WOOD: Now, the signs and symptoms of

food allergy are highly varied. They may be

chronic and low grade as I mentioned, they may be

acute and life threatening. What I want to run

through in the next couple of minutes are just some

examples of allergic reactions that will point out

a number of things about not only the kinds of

reactions, but the exquisitely small amounts of

food that induce these reactions we are going to

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

patients with food allergy are facing.

(Slide.)

DR. WOOD: The first couple of patients I

am going to show you have urticaria or hives. This

is a total body hive reaction that this boy is

experiencing, a patient I have known since he was

an infant.

He is school age at this point. This

29

reaction occurred when he was in the grade school

cafeteria, was being teased about this food

allergy, another child blew a straw full of milk

across the table into his face, and he had this

really significant reaction.

(Slide.)

DR. WOOD: This baby here was identified

with milk allergy in the first few weeks of life.

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

allergy until they are two or three or four years

old, while there are others who are really

demonstrating food allergy in the first days of

life.

This was a baby who was so allergic that

he would react very acutely if his mother, who was

breast feeding him, ingested any milk protein. She

was on a very strict avoidance diet after we

identified his milk allergy, but on the occasion of

her birthday ate a piece of cheesecake, breastfed

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

hive reaction.

(Slide.)

30

DR. WOOD: Now, when we are thinking about

urticaria or hives, there are patients that may

have chronic urticaria. Food allergy is rarely a

cause of chronic urticaria.

However, when someone shows up with an

acute episode of hives, the chance that it is food

allergy becomes higher. Again, we are looking a

relatively short list of foods that are most

commonly implicated: peanut, nuts, eggs, milk,

fish, and shellfish.

Importantly, these reactions are usually

very quick in their onset. Ninety percent of them

or thereabouts will have an onset within 30

minutes; at least half of them, within 5 minutes;

and virtually all of them, within 2 hours.

When a patient has this type of reaction,

it is often very easy to identify the culprit food

because of the abrupt association of the ingestion

of that food with the onset of these hives.

Then, in more severe episodes, there may

be swelling or angioedema or associated

gastrointestinal or respiratory symptoms. That is

31

moving into more of a systemic reaction that we

would refer to as \"anaphylaxis.\"

(Slide.)

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

is having an anaphylactic reaction. When you look

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

you see her front, though, she is having swelling

and breathing difficulty.

(Slide.)

DR. WOOD: This is a patient who was

having a reaction in the midst of a food challenge

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

dose of egg protein, she went into this very

severe, anaphylactic reaction.

(Slide.)

DR. WOOD: This boy here is someone who is

having a dramatic episode of swelling. His

reaction occurred. Most patients, we should say,

who are having severe reactions know about their

food allergy and are making efforts to avoid it.

He was shellfish allergic \-- he is

32

shellfish allergic. He was making efforts to avoid

shellfish, and he had been reaction-free for

several years.

Then, on another birthday occasion, he ate

chicken in a restaurant and the chicken had been

fried in the same oil as shrimp had been fried.

With that cross-contact, this severe reaction.

(Slide.)

DR. WOOD: Anaphylactic reactions are

defined as a systemic allergic reaction,

involvement of multiple organ systems. These have

an abrupt onset typically. They are related to IgE

antibodies.

You can identify these by doing a skin

test or a blood test looking for IgE. The

manifestations are not always severe. There is an

impression that all anaphylaxis is

life-threatening. Some episodes are relatively

mild, but others progress rapidly to

life-threatening or fatal reactions.

We think that there are at least 150

deaths in the United States each year due to fatal

33

food-induced anaphylaxis. That number is probably

a substantial underestimation, but we would be very

comfortable saying that it is well identified of

100 to 150 deaths per year.

There are different types of reactions:

some are single phase and some have two phases,

where a patient may look better and then two or

three or four hours later have an even more severe

reaction than they had initially, some of those

lead to the worst outcomes.

(Slide.)

DR. WOOD: This is a patient with one of

the more chronic forms of food allergies, the

patient with severe itching due to his eczema. In

Eczema, a food allergy is often underappreciated

because there is not an obvious cause and effect.

This is one where it is more of a

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

harder for a patient or a family member to identify

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

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

reaction where you don\'t see these direct

34

relationships between ingestion of the food and the

outcome being their eczema or atopic dermatitis.

It is also a condition where food allergy

is underappreciated by physicians and where

patients may be treated with a variety of different

creams and lotions and only later on find out that

it was really a food allergy that was driving the

eczema.

Overall, 40 to 50 percent of patients with

severe atopic dermatitis and 20 or 25 percent with

less severe cases have an underlying food allergy.

The same list of foods: egg allergy being

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

and fish. These six foods account for the vast

majority of food sensitivities seen in atopic

dermatitis.

From our standpoint, it makes it

relatively easy to screen patients and find which

of them are allergic by testing for a relatively

short list of foods.

(Slide.)

DR. WOOD: Now, the last category that I

35

want to mention is something that we will lump

together as gastrointestinal food hypersensitivity.

There are a variety of conditions that fall under

this umbrella.

There are some that are in the immediate

hypersensitivity category. This would be part,

say, of an anaphylactic reaction where someone ate

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

abdominal pain, or other gastrointestinal symptoms.

There is another condition called \"oral

allergy syndrome\" where patients have reactions

that are confined to their mouth or throat or lips,

particularly related to fresh fruits and

vegetables.

There is another group of conditions that

are lumped under a category of eosinophilic

disorders of the GI tract. There is a specific

condition, eosinophilic esophagitis, where only the

esophagus is involved. As most people in the

audience know, the eosinophil is a type of white

blood cell that is most affiliated with allergic

reactions.

36

If you take someone who is having a bad

hay fever day outside today and look at their nasal

secretions, their nasal secretions will be loaded

with eosinophils. If you take someone that is

having difficult asthma, their bronchial mucosa

will be loaded with eosinophils.

By the same token, if you have allergic

eosinophilic esophagitis, the lining of your

esophagus is loaded with eosinophils. It may be

isolated to the stomach, it may be more diffuse

where we would call it \"allergic eosinophilic

gastroenteritis.\" This is somebody who may have

disease anywhere in their GI tract, and oftentimes

very diffusely.

There are some other conditions,

enterocolitis syndrome and dietary protein

proctitis, that are much more common in very young

babies.

The importance of presenting these

different syndromes here is that some of these

syndromes are IgE mediated and some of them are not

IgE mediated, some of them are very acute and some

37

of them are very chronic.

It turns out that those syndromes that are

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

any acute symptoms, don\'t present with any clear

cause and effect of eating the food and having

increased gastrointestinal symptoms are going to

be, potentially, the most difficult for this

Committee to grasp. That is because these patients

are often reacting to remarkably small exposures.

I will come back at the end to sort of

give a couple of examples of the dilemma that kind

of patient is going to present to us as we really

try to figure out what is safe and what is not

safe.

It also turns out in the same vein that

the non-IgE conditions in general are probably

going to be most difficult to deal with, both

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

symptoms, and because they are predominantly

mediated by a different part of your immune system

that can recognize even smaller degrees of these

food proteins that identifying thresholds are going

38

to be much more difficult.

(Slide.)

DR. WOOD: Now, when we are trying to

approach a patient with a food allergy, one of the

real difficulties is making an accurate diagnosis.

The diagnosis, as in most everything we do, begins

with a history, talking about the foods they

suspect are causing problems, whether we think the

symptoms are consistent with food allergy, whether

this is something that may not be food allergy at

all, or whether it may be a food intolerance rather

than an allergy. We are going to be interested in

the timing of the symptoms and the reproducibility

of reactions.

It turns out that when you do a very

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

will be correct in the acute reactions, where you

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

scrambled eggs for the first time last week, and he

had hives all over.\"

\"She took her first bite of peanut butter,

and developed hives within 2 minutes.\"

39

It is very likely that the history will be

born out when you do further testing. However,

when you look at the bulk of patients with food

allergies, many of them will have these more

chronic conditions like eczema or the

gastrointestinal disorders. When you are looking

at those patients, you will only verify the history

when you do further testing about a third of the

time.

(Slide.)

DR. WOOD: The next set of tests we do

after taking a history would typically either be

skin testing or serologic testing. A RAST test,

\"radioallergosorbent test,\" is the most common

serologic test that is used.

These tests have some value and they also

have some problems. The problems they have is that

there is a relatively high rate of false-positive

tests. They do not have a terribly good positive

predictive accuracy.

They are generally accurate when they are

negative. Although, they will only be active when

40

they are negative when you are convinced this

patient has an IgE-mediated condition, because both

of these tests rely on the presence of IgE

antibodies to identify the specific food allergy.

An example would be if a patient develops

hives or anaphylaxis, which typically are

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

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

likely that they have that allergy. If you get a

negative test back, then you need to keep looking.

It was not likely that food that caused that

reaction.

However, if you have a patient with

something like the allergic eosinophilic

gastroenteritis where there may not always be IgE

antibodies, you cannot stop with a negative test

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

allergy.\" That is something that happens all the

time, but it is often going to lead to a

misdiagnosis and mismanagement of that patient.

The bottom line is that we need to

carefully interpret our tests in the context of the

41

overall clinical picture, and that we need to rely

on oral challenge tests as the more accurate tests,

so that we will say that they are not completely

definitive. They are more definitive but not

completely definitive.

Again, they are going to be less

definitive in the patients that have more delayed

type reactions or more chronic conditions where

they won\'t react in that four-hour observation

period of your food challenge.

(Slide.)

DR. WOOD: You are going to hear more

about food challenges this afternoon, but I will

just mention a couple of issues here in terms of

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

down as open challenges where both the patient and

the person administering the challenge knows what

is being given.

A single-blind challenge is where the

patient is blinded but the person administering the

challenge knows the food that is being

administered, whereas a double-blind,

42

placebo-controlled challenge is regarded as the

most accurate test because it eliminates the bias

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

may be feeling a great deal of anxiety about this

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

may have their own biases about this patient\'s

allergy and might overinterpret or underinterpret

symptoms.

We would say that these are going to be

the most accurate tests for the diagnosis of food

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

results don\'t provide a clear diagnosis. That is

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

that may not be accurate and laboratory tests that

may not be completely accurate.

Then, we also do them very commonly to

determine when an allergy has been outgrown. This

would be a patient who has been known to be

allergic to a food, and we would be monitoring them

with some regularity in determining at some point

that it is worth trying to retry that food.

We would typically do it in a controlled

43

setting, just because even in some patients you

don\'t expect to react at all there may be

significant reaction. Consequently, we have to do

these with considerable caution.

(Slide.)

DR. WOOD: I think I pretty much mentioned

this.

(Slide.)

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

briefly, a study that we published last year

looking at the risk of oral food challenges. What

we have presented in this paper were results on

almost 600 challenges, 253 of which were failed

challenges. The patients reacted in the challenge,

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

other 57 percent, the patients had no symptoms, so

it was a risk-free challenge once they might have

gotten over the anxiety of being there.

We collected a lot of information on

demographics, other atopic disease, symptoms during

challenges, treatment needed, doses at which

reactions occurred. Even though there is a lot

44

said about safety of food challenges, there has

been very little published before this paper on

what really occurs.

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

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

front here, that these results are not

representative of the general population of food

allergy.

These patients that are being challenged

in this either had an unclear diagnosis, so it

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

thought to have potentially outgrown their allergy

and were being challenged to potentially prove that

their allergy was gone.

We are really looking at very low-risk

population, and it is not representative of the

whole population of food allergy patients that are

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

times looking at the specific data.

(Slide.)

DR. WOOD: Now, whenever we are doing this

sort of analysis, we try to break things into

45

categories. One of the tough categories to decide

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

literature some different definitions that have

been used.

We chose to create our own for a series of

studies that we were doing, and talked about mild

reactions that were skin and/or oral symptoms only.

Oral symptoms is just at itching or they will often

have an obvious hive-like reaction in their mouth

or pharynx when they are having one of these

localized reactions.

A \"moderate reaction\" was described as

upper respiratory and or GI symptoms only or any

three systems. When we are talking about systems,

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

lower respiratory and cardiovascular.

Then, severe reactions were those that

were that were potentially life threatening, where

they have lower respiratory and/or cardiovascular

symptoms or any four systems were involved.

(Slide.)

DR. WOOD: When we broke things down into

46

these different systems which were involved in

which challenges, you will see here that when we

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

total in this paper we reported on milk, egg,

peanut, soy and wheat.

The greatest number of failed challenges

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

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

that skin manifestations were most common, 78

percent.

This is actually similar to what we have

seen and what is in the literature in terms of

reactions that happen out in the real world.

Eighty percent of food reactions, 80 percent of

anaphylactic reactions involve the skin, but about

20 percent do not.

Oral symptoms occurred in about a quarter,

upper respiratory in a quarter, lower respiratory

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

thankfully, had no cardiovascular reactions in this

population.

Now, why would that be the case? It would

47

be for two reasons. The biggest reason is that

cardiovascular reactions are not that common in

children.

The cardiovascular system of a child is

really sturdy enough to put up with the insult of

an allergic reaction without necessarily becoming

involved. Cardiovascular reactions are much more

common in adults, and this population was entirely

childhood.

The other reason that we might have seen

the absence of cardiovascular reactions would be

that we were dealing with a relatively low-risk

population.

When we break it down into those three

severity classifications \-- mild, moderate and

severe \-- you will see that the numbers are

relatively similar for each food. When we look at

the total category, they broke pretty close to a

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

severe.

When you look across the specific foods,

the most important point that came out of this is

48

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

this kind of setting is more dangerous than

another.

It turned out that the greatest number of

severe reactions occurred with egg challenges.

This was important information we thought to get

out to get out to people doing challenges.

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

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

I\'m not touching a peanut challenge because they

are really dangerous. However, I will do egg and

milk challenges out in my office any time.\"

The message there is that really all of

these foods have a potential to have severe

reactions and need to be done in a setting where

you are really equipped to deal with that potential

for a severe reaction.

(Slide.)

DR. WOOD: When we looked at the RAST test

score or the median IgE level for these different

challenge results, we found that there was really

no strong association between their IgE level and

49

the reaction severity.

Now, this is an example of where this

population is not a good one to look at for this

data. The reason is that we were essentially only

challenging people that had relatively or very low

levels.

We were not challenging people with very

high levels where they were extremely likely to

fail the challenge. There is no reason in most

instances to prove that they are allergic. When

you know with, say, 99 percent certainty that they

are allergic, we would not put that patient through

a challenge.

Consequently, if you went out in the real

world where the RAST test levels range anywhere

from zero to 100, you would typically see

escalating reaction severity with levels that are

higher. We have that data for peanut allergy where

the group of patients that had levels at 100 did

have more severe reactions when they had accidental

exposures.

(Slide.)

50

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

present from this study is whether reaction

severity was correlated or related to the percent

of food ingested in these challenges. It turns

out, if anything, it is inversely correlated. The

more severe reactions, and none of these were

statistically significantly, but if you look at the

general trends, you will see here that the more

severe reactions occurred with milk and eggs.

As you can see, the severe reaction for

milk is 15 percent and 30 percent for eggs. When

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

percent and 30 percent.

(Slide.)

DR. WOOD: What is the reason this

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

have your more severe reactions with smaller

exposures? The reason we think it happens is

because it is just identifying the more reactive

patients.

It is picking out those that even though

our test scores said that they are not so allergic

51

that they should do this, it is picking out those

that react more abruptly and have more severe

symptoms early in the challenge just because they

were higher risk patients.

Now, we have come up in our studies about

some decision making about when we would do food

challenges. This is purely for clinical purposes.

These are for those reasons of when we are trying

to decide if they are truly allergic or when we

think that the food allergy might have been

outgrown.

What we would say is that we would do food

challenges based on their history of reactions. If

they have reacted recently, we wouldn\'t feel the

need to do a food challenge.

We would base it on their laboratory

testing, the skin testing and the RAST testing.

Then he would base it on the importance of the food

to the diet. There are some foods that are

obviously much more important to the diet.

A family may never care whether that child

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

52

may elect to never have a pea challenge done, but

they may be jumping to do a milk or what challenge

at the first opportunity, because milk or wheat

back in the diet would make such a dramatic

difference in their day-to-day life.

Then, we have come up with some

recommendations based on RAST testing of when we

would recommend doing challenges. These cutoffs

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

greater than 50 percent chance of passing the

challenge, if you have levels below that range.

For other foods, it has been harder to determine

cutoffs, and we would challenge at higher levels

for things like wheat and soy.

(Slide.)

DR. WOOD: Just to go through an algorithm

of how we approach diagnosis, then, because it does

impact on the discussions that are going to happen

here, we would first take our history.

Based on the history, we would make some

distinction whether we think this is consistent

with an IgE type reaction or whether we think that

53

it is consistent with a non-IgE type reaction.

If it is IgE-mediated in all likelihood,

then a skin test or a RAST test will help identify

whether that food that was suspected to cause a

reaction probably did or probably didn\'t.

If the test is negative, because the

negative predictive accuracy is so high, we would

feel that you could stop worrying about that food

at that time. If the skin test is positive,

because there are false-positive tests that occur,

we need to do something more.

We might do a trial on an elimination

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

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

would arrive on the specific elimination diet

recommended for that patient.

If it falls into a non-IgE category, the

situation is much more difficult because we can\'t

rely on a simple screening test to weed out those

patients.

They are going to need some combination of

challenges \-- endoscopy, if it is a

54

gastrointestinal symptom; elimination diets,

rechallenges, maybe a reendoscopy \-- so there is a

much more difficult plan on this side of the screen

to sort out those patients.

(Slide.)

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

with a couple of conclusions and present a couple

of dilemmas. The conclusions are that food allergy

is very common. This is a remarkably worthwhile

initiative that is going on here, and that right

now avoidance is the only treatment plan.

We really hope in the next 5 or 10 years

that there are going to be other treatments for

food allergy. It may be enough so that even if

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

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

have these meetings, that small exposures won\'t

even be relevant. We are not even close to their

yet, so avoidance is the only option.

Strict avoidance is essential to prevent

reactions obviously, but we also think that in many

patients it also helps to promote the outgrowing

55

process.

Here is where we may have very different

thresholds. We may have a threshold that this

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

fact that they can eat this bread that has whey as

the tenth ingredient and never have a symptom.

They are perfectly fine with it.

What we have found that getting that bread

on a regular basis may keep their immune system

more revved up to maintain the allergy so this

thing that is way below their threshold for

reacting acutely may still drive the immune system

to maintain the allergy and prevent them from

outgrowing the allergy.

The next conclusion is that food

challenges are a useful means to diagnose food

allergy and a useful means to determine threshold

doses. There are going to be some limitations of

challenges, and one of them is that as opposed to

the study that I presented that Dr. Perry did with

me, you have to include in a threshold type study

the most allergic patients.

56

Doing the kind of patients that we are

studying on the lower end of the spectrum has

nothing to do with thresholds. It is irrelevant

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

looks like a threshold because we are not including

in those kinds of studies those highly allergic

patients.\"

The greater dilemma, and this one is

solvable, there are plenty of real allergic

patients out there. They won\'t necessarily want to

undergo these studies, because it is not a pleasant

thing to have allergic reactions, but that part is

potentially solvable.

The more difficult thing is a

determination of the threshold doses that I

mentioned for the chronic allergic conditions,

especially those that are not IgE mediated probably

isn\'t possible.

To give a couple of examples, if we take,

say, milk allergy, the most common food allergy of

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

formula, there are a bunch of different options we

57

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

them are also allergic to soy.

Some would go on to a formula like

Alimentum or Nutramigen, which is a formula where

the milk protein has hydrolyzed to a small enough

fragment that in 98 or 99 percent of kids with milk

allergy. It completely solves the problem. They

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

protein that remains in that formula.

That other 2 percent, though, may react

severely to that. They are typically the patients

with the gastrointestinal disease. They are

typically very sick; they are typically not

growing; they are typically malnourished.

They are a group of patients who aren\'t at

risk for the acute dangerous reactions, but they

may be at very high risk for chronic disease from

their food allergy.

Those patients will typically respond

dramatically to a formula that is based in a single

amino acids as a protein source, and that is a

formula like Neocate and Elecare.

58

Now, when you take that population, and

this is what I deal with every day, there is going

to be a group of them \-- and that is probably even

less than 1 or 2 percent, it is probably only 1 out

of 500 \-- who still react to the Neocate. They can

react severely to it.

We know that because of their

gastrointestinal biopsies, their biopsies that are

taken from their esophagus or stomach or intestinal

tract still show evidence of severe allergy.

What we think those patients are reacting

to would be either the absolutely trivial amounts

of, say, soy protein that is in the soy lecithin,

that is the eighteenth ingredient in Neocate, or

the trivial, trivial amounts of protein that may be

left in the safflower oil that is used as a fat

component of Neocate.

When we switched those patients off of

Neocate we can prove, and we have 15 patients now

who we have proven, that taking them off Neocate

resolved their food allergy. In this supposedly

non-allergenic formula, they were still reacting.

59

Now, whether the direction this Committee

needs to focus on is this very unusual patient or

not is sort of a separate debate all together, but

it is safe to say that there are going to be

patients out there who break all rules. No matter

what rules are established, there will be patients

who completely break them and make all of our lives

difficult from that standpoint.

I would be delighted to take any questions

from the Committee or otherwise. Thank you for

your attention.

CHAIRMAN DURST: Thank you, Dr. Wood.

Are there questions for discussion?

Suzanne.

QUESTION-AND-ANSWER SESSION

DR. TEUBER: This is Suzanne Teuber. I

had a question about your patients with the Neocate

sensitivity in terms of what the company reported

for the soy lecithin, did they have any values that

you could report back as to a chronic ingestion

threshold?

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

60

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

have that data on the protein content of their soy

lecithin. They say it is zero. These kids when

they were switched to Neocate One Plus, which has

no soy lecithin, their disease went away. We have

to assume that there was enough there to drive that

process.

CHAIRMAN DURST: Yes.

MS. HALLORAN: Jean Halloran. Could you

say something about the process about growing

allergies? How does that work? What actually

happens?

DR. WOOD: Well, that is a very good

question. There are a number of things that we

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

is that in the majority of patients we think that

outgrowing is most related to the immune system

gradually forgetting about that concern that it

earlier had.

That is where we think that strict

avoidance is likely to promote the outgrowing

process, and with a prolonged period of strict

61

avoidance for many of these foods, the immune

system has a memory that isn\'t long enough to

maintain the allergy and that it will gradually

wane and then full tolerance will be accomplished.

There are probably lots of other mechanisms going

on immunologically that are not well understood.

The other question with this that we have

no great explanations for, lots of theories but no

great explanations, is why you can take a food

allergy like milk, which in early infancy can be

every bit as severe as a peanut allergy, and have

most kids outgrow that allergy, while very few kids

outgrow the peanut allergies. There is something

very different about the immunologic memory of one

food allergen versus another.

CHAIRMAN DURST: Yes.

DR. KELLY: Ciaran Kelly. I wanted to

come back to the issue of challenging individuals

with severe allergies as a method for determining a

threshold. I would like to hear your comments as

regards the feasibility and safety and whether that

would be ethical to perform? I guess my concern is

62

that once the threshold is crossed, whatever that

threshold might be, isn\'t there a potential for

severe allergic reaction?

DR. KELLY: Yes. Absolutely. There have

been threshold studies done for the biggie, peanut,

with very allergic people so it is doable. Now,

what we can say about this is that these studies

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

happen.

That automatically limits your population

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

your group of milk-allergic adults to do these

studies on, you are limited.

Now, they do tend to be more severe

reactors. From that standpoint, you have some

patients out there, but there is no IRB that is

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

be demonstrated benefit to do a study with risk.

The safety element is one that we are

comfortable with, recognizing that you need to have

emergency management available to you because there

will be people that have bad reactions.

63

The safety that is built into that is

starting with exquisitely small doses and working

up very gradually and aborting the challenge

whenever you see your first symptom.

That may lead you to end some challenges

prematurely. You may end up with a false

threshold, but you are obligated to stop when you

have objective signs that patient is reacting.

The ethics beyond that to me is that if it

is an adult patient who is willing to consent to

that process, I have no problem with the ethics of

doing it and have no fear that I will ever lose a

patient to a food challenge.

CHAIRMAN DURST: Yes.

DR. BRITTAIN: This is Erica Brittain.

Since you can\'t study children in that way, do you

know how this threshold might be different in

children, if you\'ve got the threshold for adults?

CHAIRMAN DURST: No, we don\'t know that.

That data is, to my knowledge, not available in a

large enough sample to have any validity

whatsoever. It is a superb question. The argument

64

is going to be and will always be these children

are much more reactive than the adults for most of

these foods.

For peanut allergy it is going to be the

simplest, because allergy tends to persist. We

think that people usually hit their peak level of

severity as an adolescent or young adult, so that

would be fairly easy to solve.

However, when you look at the others like

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

large going to have the highest level of reactivity

in your first couple of years of life.

When we think about those allergies, we

usually think of growing into the allergy for one

or two or three years where they are becoming more

and more allergic, and then they are becoming less

and less allergic over the next one or two or three

or four or five years as they outgrow the allergy.

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

severe reactivity is likely to be early on.

CHAIRMAN DURST: Dr. Wood, I have a

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

65

clarification. On your slides where you indicated

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

as opposed to our discussion tomorrow on celiac

disease?

DR. WOOD: Yes, these results are entirely

IgE.

CHAIRMAN DURST: Okay. Do other grains

cause the IgE type reaction as the wheat?

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

challenges, came out of about 3,000 food challenges

that we have done. There were five most common

foods that I had enough data to make some

conclusions that we were comfortable with. All of

the grains cause allergic reactions.

It turns out that wheat and rye are very

cross reactive from an IgE-mediated allergy

standpoint, and that most patients allergic to

wheat are also allergic to rye; it turns out that

about half are allergic to barley; and 10 to 20

percent are allergic to oat. Beyond those grains,

all of the other grains and grain substitutes are

clearly capable of causing allergy in select

66

patients.

CHAIRMAN DURST: Thank you. One other

question as far as clarification at least for my

mind. One of your slides with the food challenge

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

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

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

of IgE in a specific assay that Pharmacia has

developed called an immunoCAP RAST. It all goes

back to this one technology that is thought to be

the most accurate quantitative measure of specific

IgE, and the results are represented in that kilo

unit of IgE, the specific IgE antibody per liter of

serum.

CHAIRMAN DURST: Thank you.

There is another question?

DR. KELLY: I have one other question.

Dr. Wood, you made a very important comment about

the potential for continued subclinical exposure to

allergens perpetuating an allergic response. How

well accepted and how well documented is that, or

is that largely a clinical impression?

67

DR. WOOD: Very well accepted, very poorly

documented. It is widely accepted. There is very

poor information to support it. There are only a

couple of studies. The problem we have is we tried

to do the study, and we were turned down because it

is so widely accepted that to go to the IRB and

propose to them that we are going to take this

group of kids with milk allergy and keep them on

low-dose milk and take this group and have them

strictly avoid it was turned down.

Now, there is some work being done that

has identified instead of looking at the IgE

against milk globally, it has turned out that if

you have IgE against certain portions of the milk

molecule it may be more predictive of a longer-term

allergy, and if you have it toward others, other

epitopes, it may be more predictive of an allergy

that is easier to lose.

We think that it may be feasible to focus

on that population that has a very good chance of

losing their allergy, even if we make a mistake, to

be able to do this study. It is doable, but the

68

outcome is about 10 years down.

CHAIRMAN DURST: Marc.

DR. SILVERSTEIN: I have had some

experience \--

CHAIRMAN DURST: Identify yourself.

DR. SILVERSTEIN: Marc Silverstein, Baylor

Health Care System in Dallas. I have had some

experience in studying the epidemiology of asthma

and anaphylaxis. In both of those conditions, your

findings are very much dependent upon your

diagnostic criteria.

In clinical medicine, we have diagnostic

criteria. You have described the criteria for food

allergy, which would involve components of:

history, physical exam, laboratory tests, food

challenge, and response to clinical management with

elimination diets.

Are there standardized criteria that you

would see moving the diagnostic criteria that you

would use from clinical practice to investigation

and publication in peer review literature and/or

perhaps the policy in making regulatory decisions?

69

I am interested in, Is there a set of

standardized criteria that professional

organizations or clinicians would use for

investigation or for recommending policy? I

understand there is some recent work on definitions

and standards for anaphylaxis?

DR. WOOD: The definitions for

IgE-mediated food allergy are pretty clear and it

is pretty well accepted that it is if you have a

history that is consistent, you have a positive

allergy test, and you either fail a challenge test

or pass a challenge with a dose that is generally

accepted to indicate full tolerance. It is fairly

straightforward and well accepted in the peer

review literature.

It is much more difficult on the group of

patients with, say, eosinophilic gastroenteritis

where they don\'t necessarily have IgE. You require

a histologic diagnosis to identify the condition,

and then figuring out whether they have food

allergy driving the process exclusively, partially

or not at all is a much more difficult process.

70

It is doable, but you have to eliminate

foods, rebiopsy, reintroduce foods, and rebiopsy.

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

much more difficult to do that there is much less

of an acceptance of an absolute diagnostic

criteria, much, much less.

It is being looked at. This is a form of

allergy that is clearly either happening much more

often or being identified much more often or both,

so that the potential is there, but it is much

further away from a definition that is well agreed

upon.

CHAIRMAN DURST: Yes.

DR. BRITTAIN: This is Erica Brittain. I

have a clarification question on the food

challenge. How is the placebo control implemented?

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

lot more about food challenges this afternoon, but

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

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

idea that it needs to be well disguised and

obviously safe from the perspective of that

71

patient\'s allergen \--

(Simultaneous discussion.)

DR. BRITTAIN: But \--

DR. WOOD: Go ahead.

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

dose? Is a particular dose placebo, or does a

patient get all placebo?

DR. WOOD: Yes. I\'m sorry I

misunderstood. The normal way the challenge is

done is to have a separate challenge for the

placebo and for the actual food being studied. The

usual way it is done is that the patient would come

in and have a day doing a placebo challenge and

come in and have a day doing the food challenge.

Challenges can be done in a matter of a

couple of hours in some situations, but to do

highly allergic people in a placebo-controlled

manner would usually take 8 or 10 hours for each

day.

CHAIRMAN DURST: All right. Seeing no

further hands in the air, I think we will thank

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

72

Our next speaker will be

Anne Munoz-Furlong, who is director of the

Food Allergy and Anaphylaxis Network, who will

discuss patient perspectives on food allergies.

PATIENT PERSPECTIVES ON FOOD ALLERGIES

MS. MUNOZ-FURLONG: Thank you. I would

like to thank the organizers of the meeting for the

opportunity to be here.

(Slide.)

MS. MUNOZ-FURLONG: What I would like to

do is in that time that I have been allotted is

give you a sense of who this food allergic consumer

is; the food allergen labeling from their

perspective; and then, most importantly, their way

of looking at threshold levels for food allergens.

(Slide.)

MS. MUNOZ-FURLONG: By way of background,

the Food Allergy & Anaphylaxis Network or \"FAAN\" is

a non-profit organization. We were established in

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

members. Eighty percent of these people come to us

from physician referrals, so we know we are talking

73

about IgE-mediated responses when we are looking at

our membership.

Our mission has four points: to increase

public awareness, provide advocacy and education,

and advance research on behalf of those with food

allergy.

(Slide.)

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

food allergy is believed to affect about 11 million

Americans or 4 percent of the population; fish and

shellfish allergy, 2.3 percent or 6.5 million;

individuals in peanut and tree nut, 3 million.

Consequently, between these four foods we

are talking about almost 10 million Americans.

These are the four foods, as was presented earlier,

that are lifetime allergies and also are believed

to cause the majority of the severe or fatal

reactions in this country.

The other point I want to make here is

that although we are talking about 11 million

patients, our data shows us over and over again

that most of these patients have families who

74

follow their restricted diet. The impact is

actually many times greater than the number of

patients.

(Slide.)

MS. MUNOZ-FURLONG: When we look at

shellfish allergy, this is looking at data that we

published about a year ago now. Te prevalence of

shellfish, we found about 2 percent of the

population or 6 million Americans.

The key foods responsible for the majority

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

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

the population: salmon, tuna, catfish, and cod

being the primary fish that cause reactions.

However, if you look at these a different

way, these foods, especially shrimp or salmon, are

available on almost every menu that you are going

to look at in a restaurant or food service

establishment. Therefore, the risk for these

individuals is constant.

(Slide.)

MS. MUNOZ-FURLONG: Talking about tree

75

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

peanuts; they are different. Most people with a

peanut allergy avoid tree nuts as a precaution but

not because they are allergic to them. About

20 percent of the 20 peanut allergic population is

allergic to tree nuts as well.

When we are talking about tree nuts, it

affects about 1.5 million Americans. Again,

looking at data from our patient registry of 5,000

patients, we find that walnut, cashew, almond and

pecan are the leading cause of tree-nut-allergic

reactions in this country.

(Slide.)

MS. MUNOZ-FURLONG: What does it mean to

have food allergies? It is vigilant label reading.

You have got to read labels not just for food

ingredients but anything coming into the home.

Bath products can have tree nuts, milk or eggs in

them, for example.

Pet food, if you have ever looked at the

ingredient statement on a pet food, it can have

almost every single one of the major eight

76

allergens.

That is something you have to worry about,

especially if you have a toddler who will pick up

food from the floor or anyplace else they can get

it. Also, medications have been known to have

allergens in them, particularly milk.

It is not just a question of label reading

for food; it is for anything. Trace amounts can

cause an allergic reaction, and that has been

proven over and over again.

Just one bite can cause a reaction.

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

allergic they are going to be or what their

tolerance will be to that food.

Currently, as Dr. Woods said, the only

cure now is a dose of epinephrine, if the patient

has a history of severe reaction. The onus is on

the patient or the family to read the label and

avoid the allergen and then be quickly prepared to

handle an allergic reaction, if they have made a

mistake or accidentally ingested the food to which

they are allergic.

77

(Slide.)

MS. MUNOZ-FURLONG: Because there is no

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

are centered around food allergy. This is what

makes food allergy so stressful on the family and

on the patients.

Whereas with other allergies you have

seasonal components and you might have an easy

spring but fall is the bad season or if you are

allergic to cats or dogs you can avoid those, with

a food allergy every decision every single day is

affected by your food allergy.

Food shopping can take two to three to

hours just from reading labels. Cooking, if the

family is bringing the allergen into the home, they

then have to prepare two meals, the

non-allergen-containing meal and then the

allergen-containing meal, and take precautions to

avoid cross-contact.

Decisions about dining out and socializing

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

food safe.

78

\"Can the manager be trusted to give us

accurate information?\"

\"Can the person we are visiting be trusted

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

Then, the decision is made to move forward

based on the answers to those questions.

Even what school or childcare the

individual will be sending their food allergic

child to are going to first be centered on food

safety from a food allergy perspective.

Vacation and travel where you and I might

decide whether we want to go someplace warm or go

skiing in the winter, these families have to think

first about food.

\"Can we ship food there?\"

\"Is there a safe place?\"

\"Can we rent a room with a kitchenette and

make some of the meals so that we can maintain some

level of safety?\"

Even family relationships, there is always

somebody in the family that does not believe the

food allergy is real, and so decisions are made

79

about whether they can visit that individual or

not.

(Slide.)

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

this, it has a tremendous impact on quality of

life. We published a study several years ago

looking at the impact of food allergy on quality of

life.

What we found is that families who have a

food-allergic child score lower on their perception

of whether their child has good health or not, the

emotional health and family activities than the

general population.

Certainly, they scored lower or worse than

families who are looking at or dealing with other

chronic diseases such as diabetes, juvenile,

rheumatoid arthritis and attention deficit

disorder, for example.

We also looked at some of the other

influences. If the individual has a food allergy

and asthma or atopic dermatitis, that further

lowers their score for the quality of life.

80

If a family has a child with two or more

food allergies, that group scored much lower in 9

out of 12 scales compared to those who only have

one or two food allergies that they are dealing

with.

When we look at our patient population at

FAAN, we see that it is not uncommon for our

members to report a child with a milk, egg and

peanut allergy simultaneously. You can imagine

eliminating those three foods and how it compares

to the impact on the quality of life for the entire

family.

(Slide.)

MS. MUNOZ-FURLONG: This is how, again

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

is \"General health\" perception. Food allergy lower

than the normal for asthma, attention deficit

disorder and some of these other symptom scores.

Now, in talking about label reading, which

is really the cornerstone of managing a food

allergy. Here is what goes on.

(Slide.)

81

MS. MUNOZ-FURLONG: The person with a food

allergy is told by the physician, as you heard

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

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

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

don\'t eat that product.

If the allergen is listed on the label or

the label says \"Contains allergen,\" they are not

going to eat that product because they are trying

to avoid a reaction. As a result, they expect

ingredient labels to be consistent and, most of

all, reliable because this is what they are basing

the decision about food on. It will affect their

health and safety.

When they see the same product with

different ingredient statements, it makes them very

confused and frustrated and sometimes very nervous

because they, again, are looking for consistency in

labeling.

What we are already seeing with some of

the companies complying with FALCPA regulations is

that there are products on the market that are

82

pre-FALCPA and FALCPA compliant with different

ingredient information regarding allergens.

Already we are getting calls from our members.

\"Which one of these labels is correct?\"

\"What if I hadn\'t picked up that second

label? How would I have known?\"

This is what we are heading into as we

start to change these labels.

(Slide.)

MS. MUNOZ-FURLONG: The challenge for

food-allergic individuals is that the patients are

told to strictly avoid the allergen, there is zero

tolerance or be prepared to handle an allergic

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

how severe that is going to be.

They are not aware that there are

scientific names to foods when they are newly

diagnosed. This is something FAAN spends a lot of

time doing. It will get better as FALCPA is

implemented because labels will have simple

ingredient terms on them.

We have to remember it is not just the

83

patient or the patient\'s family reading the label,

but it is the teacher, the scout leader, the

friends and family members. The impact for any

labeling decisions are going to be quite broad.

(Slide.)

MS. MUNOZ-FURLONG: Allergens can appear

in unexpected places. This is just one slide of a

number of examples that we have for \"Common Foods

in Unexpected Places.\" Every one of these examples

have caused an allergic reaction to one of our

members, because they were not expecting to find

the allergen.

Just to give you an example, if you have a

milk allergy, you would not have expected that

barbecue-flavored potato crisps might have milk in

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

that canned tuna might have soy in it. Therefore,

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

be looking for unexpected sources.

(Slide.)

MS. MUNOZ-FURLONG: We can see this

reflected in a study that was published in 2002 by

84

Joshi, et al. They took some food-allergic

individuals, gave them products that were on the

market, and asked them to read the label for the

food they were trying to avoid.

You can see here that families avoiding

milk, only 7 percent were able to accurately

identify milk on the labels that were presented to

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

percent; but peanut, only 54 percent got the label

reading correct, and most of this was because of

confusion about allergen labeling information.

(Slide.)

MS. MUNOZ-FURLONG: The problem with

allergen labeling information, there are no

guidelines or standards for use. This is

completely voluntary. As a result, every company

has their own decision tree and algorithm and

wording for what terms they will use and under what

conditions.

This makes it very difficult for us to

educate consumers and the others who are reading

labels on their behalf and telling them what to do

85

and what these mean.

The proliferation of \"may contain\"

labeling has really caused us some problems. Just

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

volunteer go out in the Northern Virginia area to

one grocery store and look at products from

cookies, crackers, candy and bakery. We were

trying to follow the model of a previous FDA study.

She came back with 28 different versions

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

perspective, what does that mean? Can they be

trusted, or should we ignore them?

(Slide.)

MS. MUNOZ-FURLONG: The current

environment because of this, there are some

physicians that advise their patients to ignore

precautionary labeling, because it is everywhere

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

There are others who tell them, \"Heed the

warning and avoid those foods.\"

Then, there are some companies who tell

the consumers, \"It is on the package only because

86

our legal counsel has advised us to put this on

there.\"

Then, there are others that say, \"You have

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

How does a consumer determine which is

which?

We are also seeing advisory statements for

peanut allergy only. The way the consumer

interprets these statements is that they are

shortcuts to label reading.

If they see \"contains peanuts\" or \"may

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

ingredient declaration if they are looking for milk

or soy, because they think that the company

understands food allergy and would have listed all

of the allergens on there.

As a result of all of this, consumers are

confused and frustrated. Particularly what is

going on as their food choices are further

minimized is that there is risk taking behavior by

parents of kids with food allergies who decide,

seemingly randomly to us, that some companies can

87

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

contain\" on the companies they trust.

Then, the teenagers, our highest-risk

population for a severe reaction, want to be like

everyone else are reporting that they are ignoring

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

foods they have eaten the food and not had a

reaction, so they don\'t really believe that these

are true.

(Slide.)

MS. MUNOZ-FURLONG: This is one of the

labeling studies that we conducted with our FAAN

members during a spring meeting a year or two ago.

We asked a question. They were supposed to answer,

\"I would never purchase a product that says it

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

that almost 100 percent of them would avoid a

contain statement.

However, as you go from very specific to

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

that also produces,\" say, peanuts or nuts or

whatever the allergen might be, only 74 percent

88

would avoid purchasing that product.

Consequently, 25 percent of the allergic

consumers are going to purchase products where they

don\'t really understand the precautionary labeling.

If the company is putting this on here because of

some risk, we\'ve got a miscommunication or a

communication gap going on.

(Slide.)

MS. MUNOZ-FURLONG: Let\'s talk about

thresholds, then. Again, from the consumer\'s

perspective, their physicians advise, as you heard

from Dr. Wood, is strict avoidance or a reaction

may occur and you will not outgrow this allergen.

They are very motivated to try to strictly avoid

that food.

When we talk about thresholds to our

members, and these tend to be the most motivated

and well-educated of the food allergy population,

this is what we consistently get back. They

believe that threshold levels may put their

children at risk because their child is so

allergic.

89

They also wonder whether the threshold

levels, the whole discussion is based on the

industry or the government trying to figure out a

way not to have to clean or label for allergens.

Again, they are wary that this might be a loophole

that is trying to be directed at them.

(Slide.)

MS. MUNOZ-FURLONG: The catch 22 here,

from where we are at FAAN, is that we understand

that if we label for all allergens at all levels it

will further restrict diets. If we further

restrict the diet, we are going to increase

frustration which will yield risk taking.

It is going to undermine the integrity of

the ingredient label. As I showed already with

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

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

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

reaction, we are going to diminish the validity of

that statement.

If we undermine the integrity of the

ingredient label this will potentially lead to more

90

allergic reactions as they take more risk, which is

going to increase the number of doctor visits;

hospital visits; and, potentially, fatalities.

(Slide.)

MS. MUNOZ-FURLONG: Here is an example of

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

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

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

had safely eaten soy lecithin in the past. Most of

our members, although we tell them to read the

ingredient declaration on products every time they

purchase them, become brand dependent and stop

reading the ingredient label. That is exactly what

happened here.

This was a product that the child had

safely eaten in the past. The mother did not read

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

it. She then started reading the label and saw

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

nervous and screamed that it contained soy and

asked the child to spit the food out.

Immediately, he started having itching,

91

leading to hives, and a feeling of impending doom.

The mother gave him medication and thought she was

having a full-blown reaction.

The question we have to ask ourselves, Was

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

called the manufacturer and was told that the

\"contains soy\" is because it contains soy lecithin.

Therefore, the ingredients hadn\'t really changed

from the product that they had safely eaten before.

From our perspective, we do not want to

see consumers or their families subjected to this

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

that once this reaction is taken care of, it takes

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

have reports of children developing eating

disorders and just being very cautious about being

around other people once they have had a reaction.

(Slide.)

MS. MUNOZ-FURLONG: From the consumer\'s

perspective, if we are looking at developing a

threshold level, and as I said there are pros and

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

92

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

got to educate physicians and registered dieticians

so that they can counsel patients accurately.

As you saw, we have done no training for

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

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

threshold levels.

We also have to educate patients and their

families and assure them that the food is still

safe and that they can trust the information on the

label. We also have to do outreach to the food

industry so that they can answer the queries from

food-allergic consumers in a way that will give

them confidence instead of make them nervous or

suspicious about whether they can trust the

information on the label.

(Slide.)

MS. MUNOZ-FURLONG: In summary,

food-allergic consumers want as many food choices

as safely possible. This is really why we are here

and why we are seeing some of this behavior with

advisory statements.

93

They want to open the diet. The children

want to be like everyone else, and they want the

least amount of restrictions, but they need to be

safe.

The consumer needs to understand the

information on the ingredient statement. They need

most of all to trust that that information is

reliable and it is going to be consistent from one

product to the other. They also need a minimal

number of precautionary allergen statements and a

guideline so that they understand what these

statements mean and what they should do as a result

when they see these on products.

(Slide.)

MS. MUNOZ-FURLONG: In conclusion, the

current labeling and manufacturing practices

present enormous challenges to food-allergic

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

patients is increasing.

To give you an example, we conducted a

prevalence study of peanut and tree nut allergy in

1997, repeated that same study in 2002, and found

94

that in that five-year period the number of

children with peanut allergy had doubled. We don\'t

know how it is continuing to trend, but reports are

that it is still increasing.

(Slide.)

MS. MUNOZ-FURLONG: The bottom line is

above all we must protect the integrity of the

ingredient information. Because from the

food-allergic consumer\'s perspective, they depend

on this information to avoid an allergic reaction

and, most of all, to maintain their health and

safety. We already have data showing that food

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

to further diminish their quality of life.

With that, I will end here and open for

questions.

CHAIRMAN DURST: Thank you.

Does the Committee have any questions?

Yes.

MS. HALLORAN: I mean, obviously a person

can survive without ever having to buy any packaged

food. I am wondering in terms of the kinds of

95

things you were talking about \-- teenager\'s

preferences, the needs of a busy mother, et cetera

\-- are there particular categories of food that are

prepared and packaged that are most sort of

important and essential in our modern life? I

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

MS. MUNOZ-FURLONG: If they ate

vegetables, they would be fine. How many kids want

to eat vegetables?

(General laughter.)

MS. MUNOZ-FURLONG: I think it really goes

back to quality of life. Children want to be like

everyone else, and they will do everything they can

to fit that mold.

I have a daughter that was diagnosed with

milk allergy and egg allergy when she was an

infant. I will tell you that I did everything I

could to make sure that she felt like her friends.

It is not just the patient or the child,

it is also the family wanting to not have their

child isolated or feel stigmatized because of the

allergy.

96

If everyone else is having breakfast in a

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

to make sure that those labels are accurate, if the

family makes that decision.

Granted, there are some families that are

very cautious and will only make food from home,

make it from scratch. However, as the child gets

older and is out with friends, that is just not

doable.

MS. HALLORAN: Are there any particular

categories of foods?

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

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

are seeing allergens everywhere. We have just got

to make sure that all of the labels are correct and

can be trusted.

CHAIRMAN DURST: Yes.

DR. KELLY: Ciaran Kelly. A question for

you from your perspective and the perspective of

the people you represent, the patients with food

allergies.

I understand that you are frustrated and

97

find it very difficult to work with the current

system of many different types of wording. Would

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

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

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

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

acceptable?

MS. MUNOZ-FURLONG: Well, I will start

from the back end of your question. If you poll

our members or just the general consumers, they all

want \"does not contain\" labeling.

I would caution to you because of the

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

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

recalls to products that say \"does not contain

peanuts\" when they do contain peanuts undeclared.

From the way the consumer is going to

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

read that ingredient declaration because that is

the guarantee they have been waiting for.

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

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

98

ingredient declaration and know that they can trust

if it doesn\'t have peanuts in that ingredient

statement, the product should be safe for them.

When we start to see different allergen

statements, we want to make sure that those can be

trusted. When we are talking about \"does not

contain,\" that is an implied endorsement or

guarantee, which makes me very worried. If the

company makes a mistake and that is on the label in

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

reaction.

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

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

and that all companies are following this

guideline, that makes it much easier. Right now,

you can go poll 12 companies and they each do

different things.

CHAIRMAN DURST: I think we need to move

on.

Thank you.

Our next speaker will be Susan Hefle,

associate professor and co-director of the Food

99

Allergy Research and Resource Program at the

University of Nebraska, who will be speaking on

\"Allergenicity: Analytical Methods.\"

Dr. Hefle?

ALLERGENICITY: ANALYTICAL METHODS

DR. HEFLE: Thank you, Chairman Durst.

Good morning. I am going to discuss the

basic analytical methods for allergens. The model

used is the ELISA-based model which has lateral

flow. This model has been used for several years

now. We will discuss this more later.

Our second bullet, the most successful

kids do use polyclonal antibodies but occasionally

a kit uses monoclonal antibodies directed against a

single protein. Usually, the antibodies are

directed against a crude extract of an allergenic

food not the specific proteins themselves. It is

not necessary to really measure the allergen.

The industry just cares if any peanut is

there, not if one particular protein from a peanut

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

allergen. The industry just wants to know if any

100

peanut or whichever peanut is there.

A lot of times a lot of the successful

kids use a much more kind of crude approach to

detecting peanut rather than specifically horning

on the allergens themselves.

There is a challenge, though, in that

different standards are used in the different kids,

depending on the manufacturer, and also different

antibodies are used in the different kids depending

on the manufacturer. It is not like a standardized

approach across the board, necessarily.

(Slide.)

DR. HEFLE: The detection limits range

from around 0.1 to 2.5 parts per million for the

quantitative methods. There are also quality

methods; however, if we are talking about threshold

levels, we need to talk about quantitation here.

Using a method that has a very low

detection limit has certain challenges. Every kit

has the ability to have a low detection limit. Ten

years ago, when I started developing kits,

Steve Taylor and I sat around and thought about

101

what the detection limit should be based on our

years of experience in dealing with consumer

reactions and things like that.

We set a certain level with the kits we

developed; we picked 2.5. It seems to have gone

very well over the last seven or eight years since

these kits have been on the market. Some of the

other companies have a little bit lower range of

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

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

they can all push these kits really, really, really

low. The problem is, Is there clinical relevance

at that point?

If there is no clinical relevance,

companies may be chasing molecules around their

processing plant. They will have all of this

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

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

analysis.\"

We want the data to be relevant. We want

the data to be useful. If the industry goes back

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

102

all of these positive results at a low level?\"

Detection limits have to be kept in mind. They

should be tied to threshold levels, whatever we

decide the threshold levels should be.

It adversely affects the quality of life

for food-allergic consumers, if you use detection

limits that are really low or push those detection

limits without a good clinical basis. Because of

the industry reaction in the form of increased use

of \"may contain\" label.

When they did paralysis by analysis and

they get positive results, maybe they throw a lot

of \"may contain\" labeling on that product that they

are worried about and so they are going to put that

on there. That decreases the number of foods that

allergic individuals can eat.

The current detection limits that are set

that the industry uses right now have worked very

well for seven years in protecting the

food-allergic consumer.

I don\'t think at this point there is any

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

103

science comes in and we know more about threshold

levels, there might be an adjustment here or there.

We just finished an egg threshold study.

Contrary to what Robert Wood said, you can do

threshold studies in kids, because we did this in

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

people we could find to have egg allergy are kids.

When we crunch those numbers and look at

that data, if the threshold is low enough that we

need to adjust the kids for egg out there, the

manufacturers have all said they would be willing

to do that based on the science.

(Slide.)

DR. HEFLE: Many companies are testing for

allergen residues. What they are primarily testing

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

verify sanitation procedures. They have been using

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

Certainly with the new law coming up,

there are a lot more using them than used to use

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

incorporating testing using these test kits. As

104

the test kits get faster and easier to use, it is

easier for them to use them.

Again, the ELISA or lateral flow, which is

kind of like a dipstick method are the preferred

methods. Some do the test in house. They really

like it if they can do that because they can fix

things right away.

However, if you don\'t have in-house

capabilities, they will send it out to a contractor

lab or if they want third-party verification, they

will do that.

Most companies, as I said, are not testing

finished product. They are testing to validate

sanitation methods or doing environmental swabbing

to try to find where the problem is before they get

to the final product. They want to fix the problem

before they get there and figure out if their

sanitation is accurate before they get to the final

product.

Some testing of finished product on

certain occasions though is done, especially when

you can have the product under full control. They

105

don\'t usually want to release something that they

have tested and they find out there is a problem

and they have to call it back from the marketplace

later and perhaps put consumers at risk.

There are tests that are based on DNA

detection, and they are called \"PCR.\" We don\'t

advocate these for allergenic residue detection

because it doesn\'t prove the presence of the

protein. You need the protein to have the allergic

reaction. It just says that there is DNA from that

particular allergenic food there.

It is not practical at all for in-plant

use. You can\'t put one of these machines next to a

processing line. It is very expensive and requires

a lot of segregation and things. It is meant more

for a regulatory agency or a big corporate lab who

has this ability. It does not prove the absence or

presence of the protein or the allergen. It is

just an indirect kind of a marker.

There are ATP tests out there. This is a

test that is commonly used in the industry for

sanitation assessment. Some companies would like

106

to use this to detect allergens, specifically the

ATP does not detect protein also. Right now, it is

not knowing that these correlate well with the more

specific protein-based tests.

(Slide.)

DR. HEFLE: Three peanut, like ELISA test

kits, have been performance tested by FDA through

AOAC-RI. Those companies with those tests are

Neogen, R-Biopharm, Tepnel.

Five peanut ELISA kits have been studied

in one JRC interlab trial. This is the European

Union\'s group in Belgium that does these sorts of

things, and they put these three tests plus two

more through a validation trial. They are

currently doing another validation trial on the two

peanut lateral flow devices. They are not finished

with that yet, but they are only doing one matrix

not several matrices. They are just testing it in

cookies right now.

(Slide.)

DR. HEFLE: FDA works with AOAC and has

said they plan more validation studies with other

107

test kits, and that has been the case for more than

a couple of years now with no apparent progress on

this front, though.

The U.S. food industry and other

regulatory agencies \-- for example, the Canadian

regulatory agency, the JRC \-- has moved way ahead

of FDA/AOAC at this point. The industry is not

running validation trials themselves, but they run

in-house validation things like that.

However, there are regulatory agencies who

have said, \"Well, we\'re going to move ahead. We

can\'t wait for AOAC anymore. We have to get these

things done in validated interlab trials.\" There

are several trials that are planned right now

internationally to, hopefully, get some of these

things \"validated\" in the next few years.

The U.S. industry has been testing for

about seven years now, since the first peanut tests

came out. They have increased the amount of

testing each year and, I\'ve got to say, have spent

millions of dollars once they\'ve gotten test

results to change equipment, to make modifications,

108

for allergens specifically.

Before about 10 years ago, we didn\'t have

any tests at all to do this. Since the tests have

become implemented, they have used them to make

changes in how they manufacture food.

Health Canada/CFIA has a Compendium of

Food Allergen Methodologies. They crunch through a

lot more of these kind of in-house validations that

they do so that they can use them for their

purposes. There is a Web site for that. They use

both commercial and their own in-house methods.

(Slide.)

DR. HEFLE: Validation of kits, there are

more JRC trials coming out of the EU more likely.

We know of several that are planned, and other

groups have them planned, too. Other groups are

planning more interlab trials, some with kind of

\"modeled\" foods.

A lot of these tests are done where you

spike peanut into something else. It is not really

like a manufactured product, so it doesn\'t really

mimic the manufacturing process.

109

A \"model food\" is actually where the

allergen is manufactured into the matrix, so that

it more appropriately represents what would happen

in the food industry.

Therefore, those are king of challenging

to make. You can\'t just make them in your back

yard or in your home kitchen. You need to make it

on an industrial level, so it can be quite an

undertaking.

(Slide.)

DR. HEFLE: Kit companies do much more

extensive validation than ever will be done by any

regulatory agency or academic center. It is

usually that the are in the process of selling

kits, and they don\'t necessarily share the data

like they should. I have been encouraging all of

them to go ahead and publish all of this great data

they have, and it would be a lot easier for all of

us to evaluate how good their kits really are. So

far, they still want to sell kits and not spend

time writing papers.

However, they do have liability issues.

110

Their kits have to work. They have liability

issues. They have reputation issues if the kits

don\'t work, so it behooves them to do their own

validations before they put a product on the

market.

(Slide.)

DR. HEFLE: Reference materials are solely

lacking for allergens. It would be really nice if

we had a bunch of reference materials we could do

all of these interlab validations with.

However, we are having a problem finding

the appropriate reference materials. There are not

many available, and they are really needed. NIST

is one source of reference materials.

Unfortunately, the NIST standards that are

available were not made for allergen testing, were

not designed for that and often do not represent

the type of allergenic materials used in the food

industry.

A case in point was the standard that was

used in the AOAC-RI-FDA study. It was peanut

butter made by a major manufacturer. It is fine

111

for things like aphlatoxin determination and other

things. Unfortunately, the varieties are not known

with certainty, because the manufacturer wouldn\'t

tell FDA about every little peanut that might be in

there. They wouldn\'t divulge it. I\'m referencing

NIST not FDA, I\'m sorry.

Different peanut varieties have different

responses in the kits. It is imperative to know

exactly what is one of these standards.

Unfortunately, there aren\'t a whole lot of other

standards around the world around to do that.

There are other sources of materials that

could be used as reference materials, but we have

to come to a worldwide decision on what is the

appropriate criteria for considering something in

the reference material. Is something the JRC makes

in Europe representative of something we use in the

United States?

There are several of these materials

available, and we could begin to talk about going

through some interlab trials with some of these, if

they met certain criteria.

112

(Slide.)

DR. HEFLE: Processing can have a huge

effect on extraction and kit performance. Most

kits are not validated using these model foods, so

we have to do some more of this stuff;

international call for more use of modeled foods.

The old method of spiking, which is where

you put a peanut extract into some of the matrix

and mix it together and see how it performs. This,

again, does not truly represent what happens in the

food industry.

However, the spiking does provide some

useful information, but the manufacturing of these

model foods gives the best information about how a

kit will work.

Model foods have to be made on a pilot,

plant or industrial size scale. If you make this

in your backyard or your kitchen, then it doesn\'t

really appropriate what a model food is in the

industry, either.

If you make many cookies in a home-size

oven or a Suzy Homemaker or Easy-Bake Oven, it is

113

not going to be the same thing as what Keebler or

what Pepperidge do on a huge scale.

The results of these are not practical or

useful for the food industry. Let\'s make some real

model foods. They are involving for assessing how

a kit is going to work with a specific commodity,

how efficient the extraction method is under

industrial conditions.

It is becoming more and more important to

use these types of standards in assessing the kit\'s

performance for certain commodities and processing.

I think spiking is pass.

I get yelled at in my professional

society, AOAC, because spiking is the way of the

food chemists. However, we have to do some spiking

and look at things, but we have to make these model

foods and do that sort of assessment also.

(Slide.)

DR. HEFLE: The extraction method, is it

sufficient? We\'ve got to think about it. Is it

sufficient? Is the recovery good? Can we trust

the results?

114

Some foods are challenging. There are

tannins and polyphenols in dark chocolate that bind

protein. It is a famous matrix, one of the most

difficult matrices to do with allergen

determination.

High fat levels can hide the allergen in

other types of ingredients. If the product is

hydrolyzed, you cannot analyze hydrolyzed or

fermented ingredients in these test kits. They

were never designed for this. When you start

chopping up the proteins, the ELISA signals go

away. The methods are meant to detect intact

proteins and not peptides.

Processing, if you burn stuff, it is going

to be less detectible; it is less soluble. That is

a factor. Now, most companies don\'t burn their

food, but sometimes they want to detect burned

foods on band ovens or something they can\'t readily

clean. These are challenges to kit performance,

too.

(Slide.)

DR. HEFLE: Most kits for most allergens

115

have good reactivity with processed forms of the

allergenic food in my experiences over the last 15

years, and that is just my experience.

The use of polyclonal antibodies and crude

extracts and making antibodies against processed

forms are recipes for successful kits. There are

several on the market today that do very well.

Monoclonals are okay if they use a

heat-resistant epitope in making the monoclonals.

They can accommodate the processing changes that

occur.

Some of the egg residue kits have some

issues in this regard. The industry has been able

to adjust and adapt. Many survey the raw material

instead. Instead of worrying about the processed

egg, they will just do the raw egg and handle it

that way, or use a kit that has antibodies against

raw and processed egg, to get around that

particular issue.

Matrix effects, my lab has used all of the

ELISA-based test kits available on the market in

our own validations and tests. It is kind of my

116

hobby so I like to do this. The matrix effects are

usually not a problem for most of the test kits out

there, for the vast majority.

Kit companies have added extraction

additives to their extraction buffers to assist.

When it was recognized dark chocolate was a

problem, they added some secret extraction

additives to help you pull the protein out of dark

chocolate easier.

Model foods, though, again are going to be

of great use in assessing the true extraction

performance of a kit. Again, I can\'t stress enough

we need to make more of these.

In cross-reactivity issues, even though

most methods do use polyclonal antibodies, which

those of you who know something about polyclonal

antibodies could say, \"Boy, there could be a lot of

cross-reactivity problems with them.\"

We really don\'t see this happening. The

kit companies really couldn\'t sell any kits if

their peanut kit cross reacted with everything

else, too. Therefore, we don\'t usually see these

117

problems in that they have looked at that before

they have launched it, so we don\'t see the

cross-reactivity. I am not saying that there isn\'t

one that is going to crop up sometime.

(Slide.)

DR. HEFLE: Again, we\'ve got a problem

with hydrolyzed proteins, hydrolyzed vegetable

proteins, hydrolyzed soy proteins. You can\'t

really detect them.

The industry would love to do this, to

chase them through the facility and see if they

have cleaned up afterwards because we know there

can be some residual allergenicity in hydrolyzed

protein preparations.

However, the ELISAs are pretty much

rendered useless when trying to analyze for

hydrolyzed protein. It is not what they are

designed to do. The company has had to make a

decision, \"What is most of our market?\" It is not

chasing hydrolyzed proteins, but it is chasing the

intact proteins. We have to balance the kits to go

towards that, so you can\'t use it for this.

118

Unfortunately, a negative result in an

ELISA in this case does not mean that there is no

allergenic residue left. You have to ascertain

residual allergenicity via a different method using

human allergic IgE in something like a Western blot

or a RAST analysis.

Another related area is the analysis of

fermented ingredients: gums, Lactobacillus

cultures, starter cultures. Once they start eating

at the substrate, the proteins are partially

hydrolyzed and the ELISAs won\'t detect them

anymore. You need to use an IgE-based method to

just ascertain the true allergenicity.

Companies don\'t tell contract labs the

nature of their samples. They just say, \"Here is

Sample X.\" They are not going to tell them it is

hydrolyzed, so we have some challenges.

I try to communicate with the contract

labs and say, \"Be sure you ask the question. Just

don\'t give them a negative result, because it

couldn\'t be truly negative maybe from an allergenic

standpoint.\" I think this is the minority of the

119

samples out there.

(Slide.)

DR. HEFLE: My lab performs testing for

food-allergic consumers, their physicians, their

lawyers when they call for free when they report a

reaction to a food. We work with some members of

the Food Allergy & Anaphylaxis Network when they

have a problem.

If there is an analysis I can do, I will

try to help a food-allergic consumer identify what

happened with that particular food, if they have

managed to keep it in the height of the moment.

In 10 years of doing this, we have only

seen \"large\" \-- now notice I say \"large\" with a

quotation around it, I don\'t want to make a lot of

judgments on that right now \-- amounts of

undeclared allergenic food causing reactions.

(Slide.)

DR. HEFLE: We cannot currently do

immediate monitoring in the food industry, though.

The technology doesn\'t exist. It is getting

120

better. These lateral flow devices can sometimes

get down to 5 minutes now. I think in the future

they will be able to make a more immediate

response.

Right now, a lot of them are 30 minutes

long. If you are swabbing things and waiting

around for 30 minutes to see if the result is

positive and then having to go back and clean

again, it is pretty impractical for the food

industry to do.

Sanitation and verification is the most

practical, not the test and release kind of thing.

My dad is a fisherman, so I like to the catch and

release and test and release kind of analogy.

We do not have tests for some of the

allergens, and fish is a notable example. You

cannot test for the hydrolyzed or the fermented

allergen sources using these types of methods.

Some types of cross-contact are not

homogenous or 100 percent cleaning is not possible

due to the nature of the product. Food equipment

was never historically designed for allergen clean.

121

Sometimes these facilities are quite old,

and there is no room. There is no room to bring in

different equipment. They have to try to redesign

as they can, but they can\'t get completely rid of

hangup areas.

You cannot take enough samples to

practically test, to be a hundred percent sure all

of the time. That is impossible. If I get a

statistician in to tell me how many samples I would

need, the industry would just spend the whole day

testing rather than trying to make food product.

In some of these cases, precautionary

labeling is justified due to the nature of the

product and the process in FARRP\'s opinion. For

example, dark chocolate and milk chocolate on the

same line is one example where we think

precautionary labeling is justified. That doesn\'t

mean we think precautionary labeling is justified

in every case.

(Slide.)

DR. HEFLE: This is a study that we

recently completed and published in 2004 of some

122

incidents from milk allergic consumer complaints.

These were the casein levels we found in those

particular products. They range from 5,000 on up

to 44,000 parts per million in things that were

supposed to be free of milk or labeled even

\"dairy-free\" or \"kosher,\" quite high numbers of

parts per million.

They also asked me to talk a little bit

about highly refined oils. What does HRO mean? In

FARRP\'s opinion, \"highly refined oil\" means

neutralized, bleached and deodorized or refined

bleached and deodorized.

The definition of what \"refined oil\" is,

is kind of debated a lot right now in terms of

FALCPA, opinions based on scientific review of oil

challenges with oils in the literature and what we

feel refined oil should be.

The available quantitative methods, there

are methods used in the literature including ELISA

and other methods that reports the levels of

protein in highly refined oils. None of these,

though, have been validated in interlab trials or

123

other types of validation for protein and oil

determination to date.

Somebody will run something and they will

report it, and they will do a certain number of

samples, but no one has looked at whether that is

an appropriate method across the board for

detecting this.

There is a question as to whether a small

amount of protein in the HRO is completely

extracted in aqueous buffer. \"Aqueous buffer\" is

something that people often use to do these sorts

of biochemical tests. It means trying to partition

the proteins from the oil into an aqueous buffer.

If they really like oil, they might not

all come over. They might want to stay in the oil.

The question is, Does this capture the true protein

content of the oil or whether some of the more

hydrophobic proteins stay in the oil fraction, and,

therefore, do not get extracted and therefore

determined?

My lab uses an amino acid determination

based on Edman degradation, but we also use aqueous

124

extraction. We try to maximize that aqueous

extraction.

We use heat; we use a large amount of

buffer; and we concentrate the sample. However, I

cannot guarantee that I\'m pulling all of the

protein out of that highly refined oil when I

measure that.

We report the results as relative and not

a complete picture of the possible protein count

out of HR oil. I still think you are capturing

most of the protein that is there, but I just can\'t

sit up here and say we are covering a hundred

percent of it.

(Slide.)

DR. HEFLE: The protein levels of HRO are

reported in the literature, and there are lots of

different reports and levels. The caveats again:

The use of aqueous buffers in the determination,

how good if they use an immuno-chemical-based

method is the epitope recognition of the antibody?

Does it really recognize those soy proteins at that

level of processing?

125

Relating \"total\" nitrogen, sometimes they

use the total nitrogen amount to what the protein

is. Well, total nitrogen can be free and running

around in the protein and not associated with \--

free and running around in the oil and not

associated with the protein. Consequently, it may

be an overestimate actually of the protein amount.

Limitations of certain types of methods

like dye binding. \"Dye binding\" is a method that

will bind to certain proteins preferentially and

not bind to others as well. When you use a

dye-binding method, is it really representative of

everything that is in there? You can\'t absolutely

tell.

The protein levels reported in the

literature are usually a few milligrams per

kilogram, which are a few parts per million. You

will see some widely ranging estimates, though,

from different investigators. A lot of times I

question their methods sometimes or their ability

to reproduce that particular result.

I think that is the end of my

126

presentation, and I thank you very much for your

attention.

CHAIRMAN DURST: Thank you.

Committee, do you have any questions or

comments?

QUESTION-AND-ANSWER SESSION

DR. MALEKI: Soheila.

DR. HEFLE: Soheila.

DR. MALEKI: Yes, Soheila Maleki. I was

wondering, just based on your experience and you

have been around a lot of industry, if there is any

kind of correlation or if there are any standards

between what the companies use to label \"may

contain\" versus \"contains\"? Do they use the same

2.5 parts per million that the kits provide as a

may contain or a not contain and so forth?

DR. HEFLE: They don\'t really use the

analytical results to make a definite decision

about that. Usually, the companies make a decision

to put precautionary labeling on through a certain

stringent set of criteria. It is something they

have tried to clean up, and they are still having

127

issues.

They have intermittent contamination.

They would never allow something that consistently

had a significant amount of allergen in it to be

called a \"may contain.\" They would try to clean up

more, if it is not supposed to be there.

They don\'t set a level like that. They

use the analytical results to help them determine

whether that is justified or not. It has to be

potentially hazardous, intermittent, hard to clean.

Those sorts of things are taken into consideration

much more than just the simple analytical result.

DR. MALEKI: Thank you.

CHAIRMAN DURST: Yes.

DR. NELSON: Mark Nelson. I just wanted

to follow up to that in response to Soheila. In

2001, the food industry, a group of associations

representing their members did put together

guidelines on labeling.

The preference is obviously and clearly

the requirement is to label the ingredient in the

presence of an allergen when it is directly added

128

to the food. In the situation where there is a

potential for cross contact, we did establish some

guidelines before companies should use \"may

contain\" labeling because of the concerns we have

heard about before.

One of those key guidelines was to make

sure that we could not avoid it even after applying

good manufacturing practices: appropriate cleaning,

appropriate separation, and so on and so forth.

DR. MALEKI: I see. Depending on how much

you detected, it didn\'t matter, if you detected, it

went to \"may contain,\" if it was on the line or \--

well, if it contains it was directly added to the

product? I\'m trying to make sure I understand that

correctly.

DR. NELSON: Yes, I think it is more to

Sue\'s point that we aren\'t necessarily measuring

the finished food so much. It is not a catch and

release situation.

DR. MALEKI: I see.

DR. NELSON: It is understanding your

system; what ingredients are going into the food;

129

what other products might be made on that line;

validating your cleaning processes between

products; scheduling products, depending on the

ingredients that they contain; the sequence in

which you might make the product and so on. There

are a lot of things that go into it.

CHAIRMAN DURST: Anything else?

Yes.

DR. CALLERY: Pat Callery. It appears

that the allergens themselves are not that well

defined, especially when you can find in actuality

generated new allergens by treating food in a

certain way. I am wondering how you address the

analytical problem of false negatives and false

positives?

DR. HEFLE: For a lot of foods the

allergens are indeed known, and there are very rare

cases where you make new allergens through

processing. That is an extreme case in the

literature, I think.

However, false positives and false

negatives are evaluated at the company level first

130

by testing tens of thousands of food commodities

and looking for potential issues. Also, I kind of

poke around myself and see if there is anything

that I can challenge the kits with.

In my experience, the false positive/false

negative rate for most of these methods is very

low. I can\'t give you a number. I can\'t tell you

how good that is, because I haven\'t done a

systematic study.

However, I think that the use of these

interlab trials with model foods will help us look

at some of those issues a little bit more, but I

don\'t have a good sense of how much false positive

and negative is out there.

I just know in our experience, and we use

these every day, we don\'t have a lot of issues.

When the occasional issue crops up, and we call the

manufacturer. We usually work through it pretty

easily.

They do tell the manufacturers to validate

or run their own in-house validations before they

truly test the results. The manufacturers do tell

131

the manufacturers to do that, so, theoretically,

they should hopefully find some of these things.

However, every method has a chance of a false

positive or a false negative.

DR. CALLERY: I\'m not sure how you do that

without standard materials.

DR. HEFLE: I\'m sorry?

DR. CALLERY: I don\'t know how you do any

of that without standard materials to validate

them.

DR. HEFLE: Some of the manufacturers will

give you a standard to work with, either the

standards from the kit or a recognized standard or

perhaps one of the NIST standards, which is what we

are all defaulting to because we have nothing else.

DR. CALLERY: I think you mentioned that

one kit, they have some secret materials that they

put into the kit to help extract protein. This

seems inconsistent with being able to validate a

method if you don\'t even know what the test

material, how it was made and what the scope of the

antibodies are that are made.

132

DR. HEFLE: Well, the extraction additive

is not a reference material. The extraction

additive is just an aid in extraction. Usually,

the companies will tell you what it is. It is

usually non-fat dry milk or soy protein. It is

secret, but it is not that secret.

It is just an additional protein in the

mix that helps pull the proteins out of oily

matrices or hard to extract matrices. The

companies know this, and they share that with

customers. However, these sorts of extraction

additives aren\'t really the reference materials or

the standards used in the kit.

CHAIRMAN DURST: Sue, will you be around

for discussion this afternoon?

DR. HEFLE: Yes, I will.

CHAIRMAN DURST: I think we will hold

further questions until that time because we are

running a little bit late.

DR. HEFLE: Okay.

CHAIRMAN DURST: I would like to take the

recess now. We will take a 10-minute break and

133

reconvene at 10:45.

Thank you.

(Thereupon, from 10:30 a.m. to 10:40 a.m.,

there was a pause in the proceedings.)

CHAIRMAN DURST: We will start with our

next speaker, who is Dr. Stefano Luccioli, who is a

senior medical advisor to CFSAN, FDA. He is also

assistant professor at Georgetown University. He

will be speaking on \"Oral Challenge Studies:

Purpose, Design and Evaluation.\"

ORAL CHALLENGE STUDIES:

PURPOSE, DESIGN AND EVALUATION

DR. LUCCIOLI: Thank you, Dr. Durst.

Good morning. Today, I really want to not

talk to you as an FDA medical officer, but as an

allergist who has experience in performing and

evaluating oral challenge studies.

(Slide.)

DR. LUCCIOLI: The goals of my talk today

are basically just to give you a basic overview of

oral challenge studies, the purpose, why they are

done, the design and conduct, and also spend a

134

little time on evaluation and interpretation of

data, especially with regard to sensitivity of

subjects as well as clinical response and severity

and maybe present some data gaps that may be of

interest while you deliberate on thresholds

(Slide.)

DR. LUCCIOLI: The purpose of challenge

studies are manifold, but the primary reason is to

diagnose allergy, food allergy. The gold standard,

as we have already heard, is the double-blind,

placebo-controlled, food challenge.

As we have heard, also people outgrow

their allergies. They are done also to evaluate

tolerance where those individuals have outgrown

their allergies. They have also been done to

evaluate specific ingredients that are allergens in

specific populations. For instance, there have

been some studies on highly refined oils in

peanut-allergic populations.

However, in recent years, there has been a

lot of emphasis on using oral challenge studies to

determine minimal eliciting doses. This has

135

important implications potentially to determine

sensitivities of individuals within a population,

but also potentially some therapeutic opportunities

in that, as Dr. Wood had mentioned, there is a

feeling that maybe if we can\'t cure food allergy,

maybe we can raise people\'s sensitivity levels so

that they may not react to very low trace amounts

of food.

For reasons that you are all here today,

also for establishing threshold challenges, they

may be able to provide you data on low-effect

levels and no-effect levels.

A problem in this field is that there are

insufficient animal models which are commonly used

to evaluate toxicologic ingredients and also

scattered data about case reports where there is

not a lot of information about exact doses that

cause reactions.

Very few studies are done or have been

done. One study was reported by Dr. Wood on

evaluating reaction severity, and we don\'t have any

current biomarkers to predict severity. This is an

136

important, I think, factor when we are looking at

evaluating minimal eliciting doses.

(Slide.)

DR. LUCCIOLI: I\'m just presenting this

slide, but I\'m not really going to go into it, to

just give you an overview that oral challenge

studies are somewhat different to traditional tox

models that are used to determine potential

thresholds or acceptable doses. I will, hopefully,

be able to highlight some of these issues in my

talk and present, as I said, some data gaps.

(Slide.)

DR. LUCCIOLI: When you are designing oral

challenge studies, obviously the selection of

subjects is an important factor. Usually, you have

populations of adults, children or infants just to

keep the statistics in order. Most studies involve

both men and women as well as are from foreign

countries and most high ethnicities.

The selection of subjects is basically

geared to what the purpose of the study is for,

whether you want to diagnose individuals with an

137

equivocal IgE or clinical history; evaluate

evidence of outgrowth of tolerance, as we have

mentioned; and also potentially to evaluate

co-existent allergies, for instance, milk-allergic

individuals who may have soy, especially in the

infant population and also for evaluating specific

ingredients, in this case how to evaluate infant

formula.

Obviously, for specific ingredients, you

may want to pick particular populations for that.

In fact, most infant studies are done to evaluate

infant formulas, and the majority of studies are in

adults.

Another important factor is that there is

a notable exclusion of individuals from these

studies. As Dr. Wood had alluded to, there are

individuals who have a cutoff level of their IgE

where above this level they have a 95 percent or

more risk of already failing the challenge. The

challenge is basically useless. You already have

the information, and you tell those individuals to

avoid the food.

138

However, these individuals may represent a

fairly sensitive population. Now with IRBs as they

currently stand, it is very difficult to get these

individuals tested in studies.

Also, classically individuals who have had

anaphylaxis or very severe reactions which were

fairly convincing for the actual food are excluded

from the studies, because another rule of thumb is

do no harm.

Consequently, you don\'t really want to

test people who could have potentially severe

reactions when you have already had a high clinical

index that they are allergic.

Of course, there are a lot of people who

self-exclude themselves from studies who may be

part of a sensitive population. I also mentioned

here unstable asthma because in any study you don\'t

want to test individuals who are unstable to begin

with.

Individuals with asthma tend to have more

severe reactions and are probably the group most

representative of fatal reactions. By not

139

including these individuals, you may be missing not

only sensitive individuals but individuals who are

potentially very severe responders.

(Slide.)

DR. LUCCIOLI: With regards to test

materials, there is a variety of test materials

that can be used. Various preparations, if you

just look at peanut, you can have peanut flour,

ground peanut, peanut butter.

There is evidence that the processing

method of these various preparations may affect the

allergenicity profile of proteins within these

foods.

You may have some individuals who are more

sensitive to peanut flour versus peanut butter.

The importance, too, with choosing the material is

that for logistic purposes you want to have it for

an increased time, if you are going to be doing

challenges over multiple months or time points.

A preferred method for these types of

ingredients are dried ingredients. You get into a

problem where dried milk or spray-dried egg are not

140

very commonly ingested ingredients in the

population. It is more common, I mean, the raw or

cooked egg or milk, liquid milk. Therefore, these

are factors that need to be assessed.

Also, fresh versus processed foods, some

individuals are more likely to react to the fresh

food versus the processed as well as raw versus

cooked. These are issues that need to be

considered when you choose a food for a particular

challenge.

Then, the dose units are different within

these challenges. Some studies report milligram

for food; others milligram for protein of food;

and, very rarely, milligram per kilogram which

would be fairly ideal if we wanted to evaluate

potential differences between adults and smaller

adults, infants.

(Slide.)

DR. LUCCIOLI: Obviously, people who

partake in these studies are people who think they

have an allergy; may have had a fairly significant

reaction; and are, understandably, under a lot of

141

stress and are afraid.

Blinding is an important fact, since there

is unfortunately a high incidence of the \"nocebo

effect,\" which is actually the opposite of placebo,

people reacting to a substance that they think is

going to harm them.

In blinding it is important to mask the

food, because you don\'t want the subject to know

what they are eating. Factors that are used are

called \"vehicles\" in one sense, and they are

basically other types of foods that are thick that

can hide the taste and smell and texture and that

are also pleasant tasting, you hope.

However, when you are thinking about doing

a challenge study over a few time limits, obviously

you don\'t want to give some of these vehicles too

much of this, too many milkshakes \-- you have to

make sure that the individual is not milk allergic

\-- but also they may cause some GI effects or other

things independent of what the actual food that you

are studying would have.

In some cases, they don\'t always mask the

142

taste. Therefore, some researchers have preferred

to use capsules, since this basically bypasses the

taste issue.

However, using a capsule is difficult,

especially if you are going in higher doses of

food, it is hard to put a serving of some food into

a capsule. I think people would know when they see

a big capsule that there is more food in that.

Also, an important factor is that you may

delay the absorption of that food putting it in a

capsule, and also you bypass the oral cavity which

may be a primary target organ for the initial

allergic response. You may have not only a delayed

response but potentially a less severe response.

I won\'t talk about the protocol, I think

that was basically well-mentioned by Dr. Wood, but

also a question about placebos. There are some

studies that use placebos within the challenge.

They use a dose and then the next is a placebo.

You know, it is a very complicated process

where you usually need some other people that blind

those to both the researcher and the subject, but

143

they are used as well. However, I think the

preferred method and the easier method is to do a

separate placebo day.

(Slide.)

DR. LUCCIOLI: Now this is just a

schematic of an example of a dose protocol. I

think the important factor is this is an escalation

study of divided doses. One of the important

things, too, is you don\'t want to be there all day,

and you don\'t want the patient, too, to be there

all day.

To be able to determine a dose of food and

get up to the final dose, which is usually a

serving of the food, which is like 10 grams of

solid or 60 grams of wet food is what you want to

achieve.

If there is no response at that dose,

there is a good likelihood that the challenge is

negative. However, in many cases you still want to

have the patient come back and do an open

challenge.

Now, with choosing the starting dose, this

144

varies among studies. In many diagnostic studies,

because of this issue about not wanting to be

there, you choose a dose that is roughly half of

the dose that caused the reaction.

Now, I don\'t know how a lot of people

figure that out, but that is what has classically

been used as the starting dose. Even within a

study, these doses shifts. This dose usually comes

out to be in the milligram range.

Now, more recent studies that have

actually been targeted to study minimal eliciting

doses, have started in doses in the even microgram

range. However, there are a variety of studies

when you are looking at evaluating studies for

eliciting doses.

Also, in this protocol, it is important to

know the time interval differences. Usually, also

that is tailored to the patient when their symptoms

first occurred. Most allergic reactions occur

within 15 to 30 minutes, so that is usually the

time gap, but some other reactions may be a little

bit more delayed.

145

As Dr. Wood discussed, there are

individuals who have delayed reactions as well.

Unfortunately, it is just not logistical to do a

study and wait for these people\'s reactions to

occur, because they might not occur that day; they

may occur on a separate day.

In this model that I use, I just use a

twofold dose incrementation, but also this could

vary. Some studies go up to even tenfold, so this

could affect also the starting dose and

interpretation of doses in the dose response.

Now, you go and you do the challenge. If

it is negative, it is negative, or you stop it

after the first objective symptom occurs. Some

studies will also record the subjective symptoms,

but that is not always the case, because the

objective symptom is the symptom that denotes a

positive allergic response.

When you record the dose, you can either

record it as the 4X, which is the discrete dose

recorded or the 7X, which would be the cumulative

dose adding the X, 2X or 4X.

146

Just to put this also into some

perspective in terms of safety assessment, when we

are talking about LOAELs and NOAELs, the 4X would

be the low-effect level for this study. If there

are doses before that, at least for this individual

you can say that this dose did not cause a response

and could be considered a no-effect level.

(Slide.)

DR. LUCCIOLI: Some other issues are don\'t

do this at home. People can have a very severe

reaction. These studies are done in a clinic or an

office where there is emergency equipment and

personnel. It is not a challenge that is done out

in the open. It is in an experimental setting, so

that can also affect the interpretation or results.

Medications, too, most studies now have

people stop the medicines, but with some earlier

studies this was not a factor. Antihistamines and

other things, if people are on these drugs, may

block the early responses so that can factor in.

Fasting, too, most people fast before the

study, but in some studies this was not necessarily

147

explained. If you have a full meal right before

the challenge, this could affect, potentially

affect, absorption of the allergen and therefore

affect the interpretation of the study.

The clinical history or reactivity, too,

is important. Dr. Wood talked about oral allergy

syndrome, but he did not mention about exercise.

There are some individuals who eat a food and have

no problem. However, if they eat the food and

exercise, they have a problem.

Some studies actually test the individual

and then put them on a treadmill and have them

exercise to see if you can elicit the reaction. I

mean, this is very rare, but that is something that

also can be done in terms of the oral challenge

setting.

(Slide.)

DR. LUCCIOLI: Statistical endpoints, I

think these are fairly straightforward for most

challenge studies. You want to just know what

percentage of individuals will react or not react

to the challenge, or in cases where you are

148

studying reaction severity which ones will have a

mild versus a severe reaction.

If you assume that all of these

individuals in the study are part of the sensitive

population or general population, you can maybe

make some assumptions about that and decide a

percentage that will or will not react to a

specific food concentration.

Also, there an importance in this is also

when you are designing a study, you may want to try

to achieve a certain number of individuals to give

you confidence levels for the incidence of allergic

reactions.

In this example, this is a table that

shows over here (pointing) the number of

individuals that need to be tested to give you a

confidence level that the incidence will be less

than this.

For instance, if we were to design a study

with 66 people, that would give us 99 percent

confidence that 1 in 10 would potentially react, so

90 percent would not react. Also, you could use if

149

66 is more than 59, you could also say, well, 95

percent confidence that 95 percent, 1 in 20, will

not react.

Twenty-nine has been usually seen as a

magic number for infant formulas. If 29 patients

do not react, if the infant with milk allergy does

not react to a cow\'s milk infant formula, that is a

basis for hypoallergenicity.

(Slide.)

DR. LUCCIOLI: I will spend the rest of my

talk on evaluation and interpretation of challenge

study data. Basically, a general interpretation as

we just talked about the statistics, many of these

studies are done in a very small population of

patients, therefore you cannot make a very general

assumption for the general population.

(Slide.)

DR. LUCCIOLI: Because some of these

studies do test the same food, there is a tendency

to group these studies together to try to get the

power higher and then potentially make some

assumptions.

150

The problem with this is that I think it

is important to note that all of the studies that

are currently available are not standardized. I

think that was a question asked just a little

earlier.

This is not standardized data. They are

not standardized to dose. Starting dose or

blinding or testing could also be a factor and also

interpretation of clinical symptoms, which I will

address a little later.

Another issue here is that all sensitive

populations, are they included. If you have

information only on adults, is that going to

predict what harm it will be to infants.

Again, in terms of statistical power, if

you get individuals who are not reactive, if you

are looking at total numbers to say \"This is how

many people did not react to this dose,\" well, what

about people who didn\'t react to the challenge at

all? Should they be included in the final analysis

of individuals, or should only the ones who react

to the challenge be part of that analysis?

151

What about foreign study data. For

instance, China has a very low prevalence of peanut

allergy, presumably because peanuts there are

boiled or fried versus in this country they are dry

roasted. If you have all of this data in the

United States about peanut allergy, could that be

transferred to data in China?

(Slide.)

DR. LUCCIOLI: I just should mention, too,

that with standardization it is important to note

that there have been some very nice reviews on

actually proposed protocols, standardized

protocols, for food challenges which have been

published in the last year or so. However, to my

knowledge, there have been no studies that have

used this protocol at least for a major food

allergen for evaluation.

Another general interpretation is that

this is an experimental exposure. It is not real

life. There could be false negatives. Individuals

who have had a negative food challenge go out and

have an open challenge and react. It is not always

152

a definitive assessment of allergy. Also, I think

it is difficult to predict reactions to future

exposures. I will try to talk about that as we

come up.

(Slide.)

DR. LUCCIOLI: Subject sensitivity, this

is I think an important issue to consider when

looking at evaluating food ingredients. The

genetic heterogeneity of individuals, there are

multiple allergens in food.

People can be sensitized specifically to

certain allergens within that food. If you cook

the food in a certain way or process it, you may

affect their allergenicity positively or

negatively. This may be what is apparent when they

do studies and you see this enormous gap in

responders.

You have almost a millionfold gap between

the high responders or I should say the least

sensitive who respond to low doses and the most

sensitive to who respond to high doses.

There is also this potential link with

153

severity, as Dr. Wood study has suggested and some

others, that some studies suggest that the

individuals most sensitive to low doses appear to

have the most severe reactions. Are we talking

about a specific subpopulation of individuals here

who are not only sensitive but severe? Also, there

is a sensitivity issue between foods and between

food products.

Another important aspect is that the

individual sensitivities may vary over time.

Allergies can progress and individuals with food

allergies develop asthma later in life. This

asthma, therefore, makes their reactions a little

bit more severe.

Telling somebody right now that they

reacted at a certain dose and that it is okay to

ingest doses before that may not be relevant a year

or five years from now.

(Slide.)

DR. LUCCIOLI: This just is a hypothetical

dose curve adapted from Jonathan Hourihane, who has

done some nice research in this area, basically

154

just to show you how severity and sensitivity may

factor in. I don\'t really want to spend time on

that.

(Slide.)

DR. LUCCIOLI: Evaluation of clinical

responses, this is where interpretation of

eliciting doses is important with regards to

subjective versus objective symptoms as well as

reaction severity in the dose response.

This table summarizes some of the

reactions that you can see from an allergic

response. Basically, they are divided into

subjective versus objective. \"Subjective\" means

that they are reported by the individual or the

subject, and \"objective\" are responses that are

actually visible or observed by the observer.

These reactions are reported in this

manner. As I said, it is when objective symptoms

occur, that is when the study is felt to represent

a positive reaction and stopped.

(Slide.)

DR. LUCCIOLI: To just show you some of

155

these reactions, not only is there a wide range in

reactions, but there are some fairly milder

reactions, hives. You down here to shock and this

is anaphylaxis. Wheezing and syncope are very

close to systemic reaction and potential

anaphylaxis. Consequently, even within an

objective response, you may have a severe

anaphylactic response.

There are also some subjective reactions

that may be somewhat severe: throat tightness,

dizziness, sense of impending doom. I haven\'t had

the pleasure, fortunately, to experience a patient

with this, but I hear it is fairly dramatic. They

have this sense of impending doom and go rapidly

into anaphylaxis. It is very, very serious. It

doesn\'t take much for a subjective reaction to go

to something severe.

Also, there are some reactions that kind

of are in between the line of what is subjective,

what is objective: fussiness behavior, abdominal

pain. In adults, that could be suggestive of a

nocebo effect. However, in infants, infants don\'t

156

mess around. This is their symptom, so these could

be positive responses for infants.

At the same time, you could have skin

flushing or shortness of breath leading to

increased respiratory rate, which could be an

objective sign. However, many times this could be

due to also a nocebo effect. Whether these are

actual positive reactions is hard to determine.

There is some clinical interpretation differences

that can occur here.

(Slide.)

DR. LUCCIOLI: Subjective versus objective

symptoms \-- as I told you, the measurable indicator

of allergic response is the objective symptom. It

has got many different endpoints, and the

interpretation may vary. This could also be true

for the subjective reactions.

Many times, subjective reactions do occur

as part of a nocebo effect. However, there are

some that are potentially indicative of an allergic

reaction.

How should these be factored into the

157

assessment? Many times they are not recorded in

the study, so we don\'t know if there are earlier

reactions to the objective dose, which may

represent an earlier adverse event level.

(Slide.)

DR. LUCCIOLI: Some other eliciting dose

considerations, the starting dose is important. If

the response occurs at this dose, you cannot

determine the no-effect level. Obviously, there is

no dose below that that doesn\'t cause an effect,

but is this starting dose the low-effect level?

Could you have given a dose a little lower and they

could have still reacted?

With dose increments, some are twofold and

some are tenfold. Using tenfold, you may miss some

increment in between that there could have been a

reaction, even maybe a fivefold difference.

Also, time intervals between doses, as

Dr. Wood has explained, some doses are delayed.

However, time intervals, if you don\'t give enough

time, you might not know when a subjective response

has become a subjective response or so forth. This

158

could also affect interpretation of these eliciting

doses.

Of course, discrete versus cumulative

dose, some studies report just a discrete dose;

some the cumulative; some both, which is better.

However, how do these factor into a true exposure

assessment or prediction?

(Slide.)

DR. LUCCIOLI: I just want to just show

this, a few more slides, just to kind of put this

into perspective here, give you a mechanistic view

that allergy is a unique toxicologic response.

When you get food that gets challenged, it

causes a massive release of mediators and

cytokines. This is an amplification system that

the immune system uses to protect itself.

Now, in many cases, this response occurs

locally and may not amount to very much, but in

some cases this amplification can involve other

organs and spread systemically very rapidly.

(Slide.)

DR. LUCCIOLI: What has been observed is

159

that the severity of an allergic response is on a

continuum. You can have subjective responses at

some point, objective anaphylaxis, and potentially

death in worse cases.

A few points to note is that this is not a

fixed response. The early objective system may

rapidly progress to something worse. Also, the

degree of amplification, this is not always

predictable or reproducible, so symptoms may not

always be reproducible on subsequent rechallenge.

(Slide.)

DR. LUCCIOLI: To end, with the reaction

severity, most studies only report the actual

symptom. You don\'t know where this symptom is in

the continuum of severity many times. Those few

that do report the symptoms, they report them as

mild, moderate, and severe.

You have to interpret the researchers, I

guess, response to this, how they interpret it; so,

there is some interpretation. Also, when you have

severe response, like in Dr. Wood\'s study, in some

cases a third of individuals reacted and had mild

160

reactions, a third had moderate, and a third had

severe. How do you factor in those severe

responses when you determine uncertainty or other

issues?

Also, potentiating mitigating factors are

important: anxiety/stress, medications, and so

forth. These can either potentiate the reaction or

stop it.

Then, the challenge stops after the first

response. A lot of times we don\'t have the luxury

of knowing how far or how many more doses would

have caused a more severe response. Having that

information is important when you are wanting to

make some risk assessment decisions. Again, it is

a dose distribution, not a dose response.

(Slide.)

DR. LUCCIOLI: In conclusion, the oral

food challenge does provide data on clinical

sensitivity to minimal eliciting doses and also

reaction severity to the initial dose. However,

challenge data currently available for

interpretation is not standardized among studies.

161

The current data pool may not include

extremely sensitive populations with regards to

severity. Challenges have a proven value as a

diagnostic tool but less value in predicting

reaction severity to future exposures.

Thank you, and I will be glad to answer

some questions.

CHAIRMAN DURST: Thank you very much.

Are there any questions from the

Committee?

We will start here.

QUESTION-AND-ANSWER SESSION

DR. BRITTAIN: Yes. I have a comment on

the sample size table that you showed us. I am not

sure that is incorporating the statistical power

education we need to have more than these

individuals. Are you familiar with what I\'m

talking about like the 29 there?

DR. LUCCIOLI: Yes.

DR. BRITTAIN: I\'m wondering if you get

zero out of 29, then your confidence interval

excludes \--

162

DR. LUCCIOLI: Well, what that 29 is, that

is usually a number that is targeted to challenge a

number of study subjects. If you show that 29

individuals with the specific allergy do not

respond to that ingredient, that gives you 95

percent confidence that 90 percent will not react.

DR. BRITTAIN: I guess what I\'m saying is

that means if you observed 29, you get the desired

confidence interval. However, if you were planning

a study and you wanted statistical power to be a

certain amount, you would need to have a bigger

study.

DR. LUCCIOLI: Sure.

DR. BRITTAIN: You couldn\'t assume that

nobody would react.

DR. LUCCIOLI: Yes. Yes, I mean, you saw

that to be totally assured you would have to test

quite a few people.

DR. BRITTAIN: I do have another question.

You mentioned the placebos again, if someone does

have a reaction with a placebo, how is that

interpreted in terms of if they also have a

163

reaction?

DR. LUCCIOLI: Well, yes, many times you

don\'t know, so then you unmask the study and then

you find out that they reacted to the placebo.

Now, technically, some studies will rechallenge

that patient again. They will have them come back

just to say, \"Well, maybe\" \-- sometimes people do

react.

The difficulty is when they react to the

active dose, to a real challenge, and to the

placebo. If the placebo is too close to the

active, it may be that by the time you gave the

placebo, they are still having the active reaction.

Basically, if they are rechallenged and

show again, they are excluded from the analysis.

Now, that is what should happen. Unfortunately,

you never get that information a lot of times from

these challenges.

CHAIRMAN DURST: Suzanne.

DR. TEUBER: One of the aspects that we

are all very concerned about is which threshold to

use and when it may cause a subjective reaction.

164

Actually, oral itching is a very important

subjective reaction that you didn\'t have on your

table up there in this presentation.

DR. LUCCIOLI: Okay.

DR. TEUBER: However, if that is

reproducible with two active challenges and not

seen with two placebos, which I think Dr. Taylor

may address a little bit later, but some of the

studies that Dr. Wensing and Bindslev-Jensen and

Dr. Hefle have been doing, they have been looking

at that. All of these have been followed by

objective reactions at higher doses.

DR. LUCCIOLI: Yes.

DR. TEUBER: I would really like people to

comment on that because this may be a much safer

way to approach obtaining thresholds to get these

extremely sensitive populations, if we can use

reproducible subjective data knowing, too, that

there are those other factors that may affect it.

DR. LUCCIOLI: Sure.

DR. TEUBER: For instance, in these

threshold studies that are being designed

165

specifically for thresholds, people with unstable

asthma would still be excluded. I am curious if

anybody knows anything about how unstable asthma

would affect the threshold for a LOAEL that is

seen? Is it a lawful difference? I mean, is there

any anecdotal experience with how that might

change? We want safety here.

DR. LUCCIOLI: Obviously, a speaker that

is coming after me would have some information on

that, but some information from Jonathan Hourihane

would suggest \-- and I think some European studies

actually do test some severe patients. Now, I

don\'t think that any of these patients are

unstable.

I think that they are all excluding

patients who have unstable asthma, but with asthma

in general they haven\'t found that these

individuals have a lower minimal eliciting dose

than other individuals. However, when they do get

a reaction, they can have a much more severe

reaction.

The assumption, though, is that because of

166

the fatalities and other things that when their

asthma becomes unstable their sensitivity could

change and become more severe very quickly.

CHAIRMAN DURST: Marc.

DR. SILVERSTEIN: Marc Silverstein. I

have two comments that deal with sort of

clarification of terminology and one comment that I

think deals with a more difficult issue. I thought

this was a wonderfully helpful and concise summary

of a variety of complex factors.

In terms of the two clarifications, in

clinical medicine from the first days of medical

school we are taught the difference between

\"symptoms,\" which are subjective, and \"signs,\"

which are objective.

Some of us from the clinical side who will

be reading the report will think that subjective

symptom is redundant and objective symptom is an

oxymoron.

To help the wide dissemination of the

report and presentation, I would like to suggest

that we in our thinking we may say \"subjective

167

finding such as symptoms of the disease\" and

\"objective signs\" is the sense that I use that.

DR. LUCCIOLI: Sure.

DR. SILVERSTEIN: I think it is helpful

because there will be a variety of readers of the

report who may not appreciate that on the clinical

side there is a clarification about that.

The second clarification had to do with

the incidence versus prevalence in the sample size

table. What we are talking about is the proportion

of subjects being tested to the proportion of

individuals in a population, so that sample size

table or the table we have is the expected number

of sample you would need. You label it \"incidence\"

but it is really a \"prevalence\" of a condition in a

population.

DR. LUCCIOLI: Okay.

DR. SILVERSTEIN: I believe that what you

are getting at is the sample size so that the lower

confidence interval is that 10 percent or 1 percent

rather than the sample size necessary to show that

two populations differ in proportion or the sample

168

size to show how tight you are around a rate of

zero, which would be a different population.

DR. BRITTAIN: Can I respond to that?

DR. SILVERSTEIN: Sure.

DR. BRITTAIN: I don\'t think when you are

designing a study you want to think of it in terms

of statistical power, which would be greater than

the sample sizes.

DR. SILVERSTEIN: The third comment I

have, which is substantive and I think we may need

to address this later in greater detail, has to do

with sources of error. There are two sort of

classes of errors that we made in our inferences.

One types of error an epidemiologist or a

clinical epidemiologist may say is biased, one of

the most common sorts of types of errors we could

make would be making inferences in the presence of

certain biases. The most common of which would be

selection bias.

Of course, the selection of individuals

who are referred to a physician, who are referred

to an allergist, who are selected for an oral

169

challenge, food challenge, study would potentially

lead to erroneous inferences if there were

non-representative selection.

That is something that in reading the

literature and making decisions about inferences

for studies or for policy I think we need to be

aware of up front, so that is an important class of

errors that we need to be alerted to.

The second would be an epidemiologist

would talk about confounding. In your example of a

study subject who has asthma, whether it is stable

or unstable and how that is defined, asthma might

be considered an extraneous factor that affects the

relationship between the allergen and the response

to the test. We could use the framework of

thinking of it as a confounding benefit.

Factors such as bias and factors such as

confounding, I think, are useful as we make

decisions about the report and the evidence for

that. I would like for us to be alert to that as

we think about the presentations.

DR. LUCCIOLI: Thank you for the

170

clarification.

CHAIRMAN DURST: Are there any other

Committee comments?

(No verbal response.)

CHAIRMAN DURST: If not, thank you very

much.

Our next speaker is Dr. Rene Crevel,

senior scientist at Unilever, Safety and

Environmental Assurance Centre in the United

Kingdom. He will be speaking on the \"Threshold

Modeling Approach.\"

THRESHOLD MODELING APPROACH

DR. CREVEL: Well, first of all, thank you

for inviting me to share some thoughts on the work

we have been doing on modeling thresholds.

(Slide.)

DR. CREVEL: You have asked me to talk

about the following, to look at different modeling

approaches including what is named the

\"hyperallergen.\" This is the model, and the

Bindslev-Jensen, et al., allergen model; talk about

the data requirements and underlying assumptions

171

behind them; and then say something about

interpreting the results of applying these models.

(Slide.)

DR. CREVEL: Now, just to take a step back

and think about why we are doing this, we\'ve got a

challenge in allergen risk management as far as

industry certainly is concerned.

We want to protect allergic consumers of

course, but we also are aware that protecting them

by certain measures of risk management such as we

have heard about this morning like precautionary

advisory labeling does actually affect their

quality of life.

We want to minimize the effects on their

quality of life, the adverse effects on their

quality of life. We ultimately also want to

maintain economic operation of food manufacturing,

because if that doesn\'t happen, then that will

affect the quality of life of a considerable number

of individuals and people throughout society as

well. It is an important point to bear in mind.

(Slide.)

172

DR. CREVEL: How can we meet the

challenge? Well, first of all, of course we could

label where the allergen is present, and that is

fine. You have legislation over here now in the

U.S. for that; we have legislation in Europe; and

many other regions and nations also have

legislation.

(Slide.)

DR. CREVEL: Or, we can ensure that the

residual allergen content of product is low enough

to be harmless. I put in brackets here (to the

vast majority of allergic consumers), because we

have heard here this morning some instances of

people reacting to extremely low amounts.

I think it is questionable, and I think

the Committee must address that particular

question, whether those people can be protected by

whatever we can do in the food industry. We need

to think about what alternative measures may need

to be done, whether they can ever eat the sort of

foods we can produce.

(Slide.)

173

DR. CREVEL: How can we determine what is

harmless to an allergic consumer? Well, we have

several sources of data, which I have listed on

this particular table.

We can look at case reports from the

literature, and those we have heard. We have heard

about people reacting to very low amounts.

Unfortunately, the usefulness in risk assessment,

actually an allergen risk assessment in my view is

actually quite limited.

They do establish the hazard. Yes, they

tell you that a certain amount will affect some

individuals, will provoke a reaction in some

individuals. They don\'t tell you in how many

individuals that will happen.

We can use control challenge studies. In

fact, those of course provide the bedrock of what

is needed, the information needed in allergen risk

assessment because the population can actually be

quite accurately describe.

You can describe them in terms of the

symptoms they have experienced, the allergological

174

history, or the medical history as appropriate \--

all of the demographics that you can think about.

Finally, dose distribution modeling, which

I am going to spend obviously some time on, also is

very useful in allergen risk assessment. But of

course it relies on the experimental clinical data

which is generated in control challenge studies.

It cannot operate in a vacuum. We do not have

enough of those sorts of data at the moment.

(Slide.)

DR. CREVEL: I have been asked to say

something about the hypoallergenicity approach. As

I understand it, it is an unofficial standard for

designating infant formula as hypoallergenic.

The original reference I found goes back

to 1991, although I think the American Academy of

Pediatrics has actually updated or at least issued

the guidance more recently, I think, in 2000 or

something of that sort.

The statistics of this approach are based

on the binomial theorem, quite simply. This shows

that, for instance, if you have a study with 29

175

participants, as we have already heard, and you

observe no reactions, then you can be 95 percent

confident that only 90 percent of the population

from which these people have been taken will not

react.

You can also extend that a bit, so if you

observed one reaction and you added people to the

study, then you would 46 for the same degree of

confidence.

If you wanted 95 percent confidence then

fewer than 99 percent would not react, then you

have got those other numbers which already become

very challenging, pardon the pun, for a challenge

study both in terms of recruiting the people do it,

to participate, and the economic cost of actually

doing it.

(Slide.)

DR. CREVEL: However, those are very

useful data when they are generated, but protecting

90 or 95 percent or even 99 percent of the allergic

population is not sufficient as far as we are

concerned as an objective for the food industry.

176

What we asked ourselves is, How can we

improve this? There are several ways. We could

try to look at the conventional toxicological

approach and apply a safety factor to the lowest

observed adverse effect level or the no observed

adverse effect level as the case may be, if you\'ve

got the no observed adverse effect level.

However, that particular safety factor, I

would say, would be arbitrary because we don\'t

actually know enough about interindividual

differences within the allergic population to apply

a science-based factor, I think. The level of

protection still is undefined. You do not know how

many people you are protecting by applying that

particular safety factor.

What about modeling of those distribution

of minimum eliciting doses? Well, that can

actually define the level of protection for

individual allergen level. You can actually use a

safety factor there. You can use something which

is like a lower 95 percent confidence interval

instead of using the figure itself.

177

(Slide.)

DR. CREVEL: Does modeling actually work?

We asked ourselves could we fit a curve to the

distribution of minimum eliciting doses that are

generated by challenge studies, and could that

curve be useful to predict the number of reactions

likely to occur as a result of exposure to a

specified amount of inadvertently present allergen

in the food?

What I have to say, of course, is we are

not so much concerned about \"declared allergen,\"

people who are allergic can avoid that, but what

our concern is about is that which is present by

cross-contact, mainly inadvertently.

(Slide.)

DR. CREVEL: This just gives a very quick

model curve. It is just used to illustrate some of

the points, right, okay. From this particular

curve, okay, we have got the data points

schematically indicated like this. The dose on

this (indicating) particular axis an the proportion

of the study population reacting here. Obviously,

178

it goes up to 100 percent.

Then, you have these particular points,

which I have named \"ED

50\" here. This would be the

dose expected to provoke a reaction in 50 percent

of the study population or 10 percent. This

particular one is an extrapolation, one way of

extrapolating, which one could use.

(Slide.)

DR. CREVEL: What is the impact of the

choice of model on the predicted minimum eliciting

doses? I should go back a bit actually and say

something else.

We collaborated actually with

Dr. Bindslev-Jensen of Denmark in the initial

development of the model. At that particular point

we used the lognormal distribution. Having the

papers published and so on, after that we decided

to go back and look at a few more parameters and

try to refine this particular approach.

Good clinical data were available for egg,

milk and peanut. We fitted the data using the

following statistical distributions and calculated

179

ED10s, the dose which would be predicted to cause

responses in 10 percent of the population; and

ED1s, in 1 percent of the population for each of

those. We used the following linear extrapolation

from lowest observed adverse effect level to zero

dose, which I showed you that was the red line; the

lognormal model, which was the original one in the

2002 paper; the Weibull model; and the loglogistic

model.

(Slide.)

DR. CREVEL: What I want to do is to

illustrate how these variously fit using the

different distributions. This is using real data

actually from the study by Wensing, et al., in 2002

on roasted peanuts. You have got the data points

here. That is still a normal fit, which is the

original one we used.

You can fit loglogistic pretty well as

well and the Weibull as well. You can even fit a

linear \-- you can even correlate these points

linearly as well.

Although I haven\'t got the parameter fits

180

here, I can tell you that they are all pretty good

for all of those. Basically, the fit which you use

doesn\'t actually tell you which is the most

appropriate one for the particular distribution.

(Slide.)

DR. CREVEL: This is illustrated in the

differences between ED10s and ED1s between studies

and models. Now, this is just using data on peanut

actually from \-- in this particular case, we are

just comparing the number of studies on peanuts

including studies performed by Bock and May in the

1970s and the later study by Wensing.

What is quite clear actually is for ED10s,

which are still within the experimental zone, what

I call the \"experimental zone\" in one of the

previous slides.

The data actually drives what the

predictions are. I mean, there is not a lot of

difference between the ED10s, even though it is log

scale, I know, even in this particular case.

(Slide.)

DR. CREVEL: When you move away and go

181

outside of the experimental zone to the ED1 and

even further actually, the case is even stronger

beyond that, the actual choice of model starts to

drive the predictive responses. That is an

important point to bear in mind.

This is summarized on this slide for the

ED10s in the experimental zone, that the

differences between studies is greater than between

models. In order to address that, the best way of

doing that is to focus on standardizing protocols

and having consistent patient selection criteria

for the studies which you wish to undertake.

For the ED1 values, the differences

between models are much larger as I showed and

increase of course as we move further away from the

experimental zone.

What this actually illustrates is that you

need to validate the particular approach. You need

to validate whatever model you have chosen and

adjust parameters in accordance with that. What

I\'m going to talk about is actually how we might go

about doing that, what sort of data is needed.

182

(Slide.)

DR. CREVEL: Now, there are a certain

number of assumptions underlying the values

generated by the model. We are talking here about

undeclared allergen, and that is quite important in

relation to the one of these particular points.

First of all, we assume that the

participants in a controlled challenge study are a

representative sample of the whole allergic

population. That is a very important assumption,

and one which actually is sometimes shall we say

overlooked.

We have heard a lot about whether people

are included or not included in particular studies.

I would tend to argue actually that the population

used in challenge studies, because of the way they

are selected, is actually shall we say at the more

severe, more sensitive end of the allergic

population, basically because there are people who

actually normally are referred to tertiary care

centers.

There are people whose allergies are

183

actually troubling them. They are not people who

might just get a small rash and just ignore it or

ignore the particular food that caused it. There

are people who actually need to manage their

allergy and they need some serious advice in doing

so.

The second point is actually in terms of

validating the model the allergic people actually

eat the same foods as the non-allergics. In this

particular case, it is quite important because if

they are already avoiding them, the number of

reactions that you will be able to enumerate in

epidemiologic studies will not be the correct one.

The distribution of allergic reactivity

study at the population level, now we\'ve heard

thresholds for individuals. Minimal eliciting

doses for individuals do vary. However, what we

are saying here actually is that overall it will be

studied in these particular challenge studies.

Finally, the responses to a given dose of

allergen are similar in the clinic to those

experienced outside. We are doing some work

184

actually with Jonathan Hourihane, in fact, to try

to quantitate the differences that may exist

because, in fact, we are very aware that particular

assumption probably does not hold entirely.

(Slide.)

DR. CREVEL: Okay. What data do we

require for validation and application of a

modeling approach? We want to arrive at the risk

assessment. We have the hazard characterization.

I would put it to you that actually what we are

doing by the modeling approach is actually

characterizing the hazard. We are establishing how

many people are likely to respond to a particular

amount, and we use all of these. These particular

factors all influence it.

However, we also need to know the number

of allergic consumers. That is quite important in

terms of prioritizing allergen management and so

on. Effectively, what the legislation does is also

to acknowledge that particular fact.

The legislation either here, in Europe or

anywhere else does not protect everybody because of

185

course it only specifies a certain number of major

common allergies rather than all of the 200 or so

foods that may provoke allergic reactions.

We also need to know what the exposure is.

We need to know what residual allergen levels are

in the foods, residual allergen levels that are not

declared. Finally, we also need to know what the

number of reactions is overall in the community.

Taking all of that together, we can

actually validate the model. Using those sorts of

data, we can also apply it properly.

(Slide.)

DR. CREVEL: To summarize, I think the

modeling approach complements clinical studies and

it certainly compliments clinical studies to

establish minimal eliciting doses. Of course, it

relies on the data generated in those studies.

I think the advantage compared to just

using the data as such is it actually permits more

complete use of those data using the whole dose

distribution rather than just one particular point,

say, the lowest observed adverse effect level or

186

the no observed adverse effect level.

It also, I think, makes the whole process

of risk management more transparent, I guess you

would say, allowing a more informed discussion of

risk management objectives by all stakeholders.

That is very important I think.

In order to agree on objectives, I think

people need to know how or need to see the process

by which they are reached. However, and this is a

big proviso, it does require validation before it

can be fully operational.

We are doing work at the moment to see how

we can address that. Some of the data actually I

should say will contribute to this particular

assessment will be generated by some European

projects which are currently running, but of course

it will take a few years to get there.

That was my last slide. Thank you.

CHAIRMAN DURST: All right. It is open

for discussion.

Yes.

DR. BRITTAIN: That was a really

187

interesting talk. There was one aspect of it that

I\'m a little \--

DR. CREVEL: I\'m sorry? I can\'t hear you.

DR. BRITTAIN: There is one aspect of it

that I\'m a little confused by, and that was in one

of your last slides with all the graphics about the

needing to know the number of allergic consumers.

If you are trying to find the dose at

which the risk of a reaction, given you are

allergic, which is what I thought we were trying to

do, why do you need to know the number of allergic

consumers?

DR. CREVEL: Well, you need to know the

prevalence of the condition within the population.

In fact, perhaps the confusion is there isn\'t,

because I mentioned validation as well as

prediction in this particular context actually.

For validation, you certainly need to know

how many reactions are occurring in order to see

whether the model actually predicts the numbers of

reaction which you are actually observing.

I mean, this is a big data gap at the

188

moment. I mean, I don\'t think either in the U.S.

and certainly not in Europe do we have data on

actually the number of reactions that do occur.

Certainly, we do not have any information on the

total number of severe reactions or less severe

reactions.

DR. BRITTAIN: You mean the number of

reactions that occur across a population as opposed

to your study?

DR. CREVEL: Yes. No, across a

population, sorry. Sorry, that was in the

population, sorry, yes.

CHAIRMAN DURST: Any further discussion or

questions?

(No verbal response.)

CHAIRMAN DURST: If not, thank you very

much, Dr. Crevel.

Our final speaker for this morning\'s

session is Dr. Steve Taylor. He is the Maxcy

distinguished professor and director of the Food

Allergy Research and Resource Program at the

University of Nebraska, who will discuss Food

189

Allergen Thresholds.

FOOD ALLERGEN THRESHOLDS

DR. TAYLOR: Well, I would like to thank

the Food and Drug Administration for giving me the

opportunity to make a presentation to this panel.

There are advantages and disadvantages to being the

last speaker of the morning. Much of what you are

going to see on my slides may just be a reemphasis

of some things that have already been said.

I think I got a rather difficult topic,

also by being the last one on the agenda, because

I\'m supposed to talk about uncertainty factors,

what are uncertainty factors and how are they

derived and what is the underlying scientific

rationale for such a factor. I only wish I thought

I knew the definitive answers to all of those

questions.

(Slide.)

DR. TAYLOR: I think the National Academy

of Sciences outlined risk assessment approaches a

number of years ago, and I always like to start

with this slide, even though I\'m not going to

190

discuss all of these different points, because I

think that the same assessment can be used for food

allergens as is used for pesticide residues and

food additives and other things. This is a very

robust risk assessment approach.

(Slide.)

DR. TAYLOR: I am only going to focus on a

few things on this slide today, and one is

dose/response evaluation. I have been thinking

about this issue for probably 30 years.

This is one of the earliest slides that I

created. At that point in time we didn\'t know very

much, and I would argue we only know a little bit

more now than we knew when I wrote this slide a

long time ago.

Trace amounts can elicit reactions. I

would argue that the severity of the response is

directly related to the dose. The higher the dose,

the more severe the response.

I would agree that individuals can have

different responses on different days to the same

191

dose. However, I don\'t think those responses are

as dramatically different, or at least I would say

that is an unproven point regarding some of the

things that have been said this morning.

There are a lot of assumptions that are

made in this field, and I think as a panel you need

to identify all of the assumptions and question

them.

Stefano Luccioli made a good point, that

individuals vary widely in their degree of

sensitivity in these controlled challenge studies a

millionfold. I completely agree with that. That

is kind of amazing in itself.

The big question is, How much is too much?

The food industry has been focusing on trying to

get an answer to this question for a long time for

some of the reasons that Dr. Crevel just pointed

out.

(Slide.)

DR. TAYLOR: I think there is another part

that we haven\'t heard quite enough about, and Rene

kind of pointed it out in his presentation. It is

192

the exposure assessment piece of the equation.

How frequently are food products

contaminated with potentially hazardous levels of

unlabeled allergens, and how frequently do

food-allergic consumers suffer reactions? We

really don\'t know that part very well. Only

recently, as Dr. Hefle pointed out, do we have the

methodology necessary to determine with any degree

of confidence how frequently food products might be

contaminated and at what levels.

(Slide.)

DR. TAYLOR: Gil Houben from TNO \[The

Netherlands Organization\] prepared

this slide, and I always like to steal good slides

from speakers that I invite to be on programs. I

think this kind of pictorially describes the

situation that exists.

We have food products in the marketplace

that contained for one reason or another some level

of undeclared allergen. This may be from

cross-contact, this may be from use of ingredients

derived from commonly allergenic foods that are

processing aids and historically haven\'t been

193

labeled in most countries.

Then, we have individual thresholds for

clinical response that varied by a millionfold as

Dr. Luccioli pointed out. There is an intersection

here between products that have enough undeclared

allergens that at least the most sensitive

individuals have some probability of reacting to

those.

If I was going to draw this slide myself,

I would lengthen the tail of this curve because we

know from analytical studies that there are

products in the marketplace that are quite

hazardous for these individuals containing

comparatively higher levels of allergens that

provoke severe reactions. Dr. Hefle showed some of

those data today.

(Slide.)

DR. TAYLOR: I wanted to say just a little

bit about the different kinds of clues that we can

have for determining allergen thresholds. Stefano

already pointed this out, too.

Probably the best data we have comes from

194

double-blind, placebo-controlled food challenges or

clinical threshold experiments using double-blind,

placebo-controlled food challenges and

immunotherapy trials that also use challenge data.

(Slide.)

DR. TAYLOR: I actually don\'t think that

allergen cross-contact episodes turn out to be very

useful in determining thresholds, and I wanted to

emphasize that point, because there is a lot of

anecdotal material in the clinical literature about

these cross-contact episodes.

A lot of them are deficient, because the

analytical methods used to detect the residues in

those studies were probably not as accurate as the

methods that Dr. Hefle described in her

presentation, the methods that we have had for the

last few years. There is often a lot of lacking

information in the investigation of these studies.

(Slide.)

DR. TAYLOR: As I pointed out, this

question of how much is too much has intrigued out

group for a long time in the food allergy research

195

and resource program.

I want to point out that we are funded by

the food industry. We have more than 40-member

companies scattered around the world. We began to

focus on the threshold question in earnest in the

mid-1990s and beyond.

(Slide.)

DR. TAYLOR: We have held a series of

threshold conferences. The first one was held in

1999\. I was asked to say a little bit about these,

and it is really hard to summarize it in 15 minutes

or less.

I will point out the fact that the results

of the First Threshold Conference have largely been

published in the peer reviewed, scientific

literature.

The question we asked at the First

Threshold Conference is we invited a number of

clinicians from around the world to come to South

Carolina, because we thought that perhaps they had

information on low-dose challenge trials.

When you hear studies of the kind that

196

Dr. Wood reported this morning, recognize that most

diagnostic challenges start at 400 to 500

milligrams.

No wonder some people have severe

reactions at those dose levels, because those are

quite high in my opinion. We were interested in

clinicians who sometimes, because of the patient\'s

history, started the challenge at a much lower

level.

(Slide.)

DR. TAYLOR: What did we find out? We

found out that there was considerable data on

low-dose challenges for peanut, egg and milk in

particular and more scattered data for some of the

other foods.

The data were really hard to evaluate

because of the lack of standardized protocols. I

will come back to that in a little bit. The lowest

provoking dose \-- we had 306 patients for peanut,

281 patients for egg, and 299 for milk. These

physicians brought this data to this conference.

(Slide.)

197

DR. TAYLOR: The lowest provoking dose for

peanut was about 1 milligram of peanut, which is

.25 milligrams of peanut protein. However, I have

to tell you that Dr. Hefle and I spent an entire

weekend in the conference room trying to figure out

what the doses were in these challenge trials,

because the physicians don\'t calculate that,

particularly carefully in some cases.

Our personal favorite is the physician

that used a drop of peanut butter as his lowest

dose. We had him send us his dropper bottle and we

tried to figure out how much that actually was.

These data look really finite when you show them

this way, but there is a lot of glorified

guesswork. I just want you to understand that.

(Slide.)

DR. TAYLOR: We determined that minimal

eliciting doses or threshold doses do exist for

commonly allergenic foods, that the threshold doses

are finite, measurable and above zero.

However, it was really difficult to reach

consensus, and we didn\'t reach consensus. We had

198

about 20 clinicians at this conference, and we did

not reach consensus on what threshold doses should

be.

In fact, for most of them this was their

first introduction to this concept. We had to

teach them what NOAELs and LOAELs were. They make

risk assessments every day but not these kind.

(Slide.)

DR. TAYLOR: We also found that reactions

occur to hidden or undeclared allergens in foods.

No big surprise there. However, severe reactions

to undeclared allergens tended to occur at higher

dose levels.

We also determined that at least in these

populations with these low-challenge doses that

low- or very low-dose exposures, LOAELs, result in

mild reversible symptoms.

(Slide.)

DR. TAYLOR: The Second Threshold

Conference was held in 2002 and was geared to

address the biggest concern we had from the first

one, and that was a lack of a consensus protocol.

199

(Slide.)

DR. TAYLOR: I don\'t have time to describe

the consensus protocol other than to indicate that

it has been published; it does exist; and there are

ongoing low-dose challenge trials underway around

the world using this protocol or slight variations

of it.

As Dr. Luccioli pointed out, most of those

haven\'t been published yet because it takes a year

to two years to do these studies to find the number

of subjects to enroll in these studies.

(Slide.)

DR. TAYLOR: We did have the Third

Threshold Conference where we tried to determine

what you do with the data once you collect it.

(Slide.)

DR. TAYLOR: I won\'t go into that very

much, because much of it relates around the

modeling stuff that Rene Crevel already described.

Because the binomial approaches are just plain

difficult, because it is very difficult to identify

even 29 soybean-allergic individuals in the world

200

to do a challenge trial. Believe me, we\'ve been

there, and we know how hard it is.

It is easier to do peanut trials than

perhaps others. It is hard to do milk and egg

because young children outgrow their allergies, so

you\'ve got to be concerned that the child, the

patient, still has the allergy that you are looking

for.

(Slide.)

DR. TAYLOR: There were a number of

advantages to modeling. I think Rene pointed those

out. I will just make the point that the consensus

of the group was that you could do modeling. Of

course, you\'ve got to figure out which model you

are going to use.

Maybe we haven\'t validated them yet so we

don\'t exactly know; however, using this lower

confidence interval as the threshold might be a

reasonable approach to consider.

(Slide.)

DR. TAYLOR: Well, classical risk

assessment involves determining the NOAEL for a

201

food additive or a pesticide residue or something

like that and dividing it by 100.

Classically, tenfold is for extrapolation

from animals to humans, and tenfold is for

intraindividual variation. Consequently, what

uncertainty factor should we use?

(Slide.)

DR. TAYLOR: For allergens, since you have

human subjects that can be used, the ideal thing

would be to determine the no observed adverse

effect level for specific allergenic foods among a

human population that is allergic to that food, and

then apply an uncertainty factor to get your

threshold dose.

(Slide.)

DR. TAYLOR: To do that with any degree of

confidence, you have to challenge a fairly large

number of allergic individuals. You would have to

identify the NOAEL for each patient.

You would probably also have to identify

the LOAEL for each patient to prove the person is

still allergic to the food that is under

202

consideration.

It would be good to determine the

variation between individuals in NOAELs because it

is probably a millionfold. A standardized protocol

would be handy so that you didn\'t have uncertainty

about the differences in protocols.

(Slide.)

DR. TAYLOR: There is no animal to human

extrapolation needed for food allergy

considerations because we have human data. We have

already selected a sensitive subpopulation of the

human population.

The question arises, Did we include the

most sensitive individual? I think that is an

important consideration for this panel. We have

heard several speakers say, \"Well, maybe we have

not.\"

My argument is that perhaps in terms of

representing the whole allergic population to a

particular food we have actually excluded the other

end of the dose distribution curve, and we actually

have included a number of people from the most

203

sensitive subpopulation.

(Slide.)

DR. TAYLOR: I want to point to this study

again. People have interpreted this study as a

publication involving the dose distribution for the

whole food-allergic group allergic to peanuts,

eggs, and milk. It is not that; it is a study of

the most sensitive individuals in clinical

population.

(Slide.)

DR. TAYLOR: Well, how much data is out

there? Is there enough data to make your

decisions? I think there can be if you can wrestle

with the uncertainty factors and the differences in

protocols from one study to another.

I just went through what I think is the

most relevant literature. Some of these are in

your \"FDA Report,\" which contains a big table at

the back that somebody very laboriously put

together. I think they actually found most of the

relevant studies.

I congratulate them for that, because that

204

is not particularly easy to do. I went through

those studies and added up the number of patients

that are in each one of these studies that were

subjected to double-blind, placebo-controlled food

challenges and for which a published LOAEL exists.

Now, there are lots of differences in

protocols, so there are uncertainty factors with

how to plug this data into one of Rene\'s curves.

What you can see is there are lots of subjects.

This is for peanut. Note, I put an asterisk by our

2002 paper, and that is because that is not

original data. Some of those patients may also

appear in some of the other studies. We got

concerned about whether to count them twice.

(Slide.)

DR. TAYLOR: This is for egg.

(Slide.)

DR. TAYLOR: This is for milk.

(Slide.)

DR. TAYLOR: We have got a lot of data

points. What are the uncertainty factors? Well,

you\'ve got adults, adolescents, children, infants.

205

Many of the studies have been done on pediatric

populations; fewer studies have been done on

adults. You can do challenge trials on both of

those. A lot of the diagnostic challenge trials

are done on infants, but they are not done in

threshold study types of experiments.

(Slide.)

DR. TAYLOR: You\'ve got the problem with

the nature of the challenge material and the

allergen content of that challenge material. This

is again from our 2002 study from Threshold 1.

You can see the number of different

materials: ground peanut, peanut flour, peanut

butter, egg white, dried egg white, whole egg,

dried whole egg, and raw versus cooked for most all

of those. Then, you\'ve got whole milk, non-fat dry

milk and even infant formula as the milk challenge

materials.

In many of these cases, the physicians

didn\'t determine the protein content of the

challenge materials, so you\'ve got to make

glorified guesses. There are uncertainties about

206

the challenge materials.

(Slide.)

DR. TAYLOR: I would argue that studies

should be compared using protein content. This

failure to provide that data makes the evaluations

really difficult. If the protein content of the

challenge material was not determined or cannot be

determined using reliable data in the literature,

then the study probably has to be rejected from

consideration by groups like this.

There are well-characterized challenge

materials like non-fat dry milk, dried egg white

and soy flour that I think you can assume what the

protein level is based on standardized industry

data. Thresholds should be established in terms

that can be related to analytical methods like

milligrams of food or milligrams of food protein.

(Slide.)

DR. TAYLOR: There are also issues related

to blinding that Stefano already talked about.

Some clinicians use labial challenges. They put a

drop of the food on the patient\'s tongue or lip.

207

That is often used for young infants.

I think that is particularly difficult to

interpret what the dose was. However,

diagnostically it is good procedure, but otherwise

it is kind of difficult to figure out what was

going on. Then, there is the choice of dosages

used for the challenges.

Probably the biggest uncertainty is this

issue of the fact that most of the publications

were done for diagnostic purposes, and so when you

look at the published literature you get the LOAEL

and not the NOAEL. I actually think a lot of the

NOAELs are clinically available; they are just not

published.

There is more uncertainty in using a LOAEL

rather than a NOAEL to established threshold doses;

there is patient selection criteria; exclusion of

people on probably both ends of the curve; and

there is variability in individual threshold doses.

Diagnostic challenges tend to report only

the LOAELs; the NOAELs in some cases may not be

recorded. As Dr. Wood pointed out to us in his

208

study, in many cases the patient reacted to the

lowest dose administered.

However, if it was 400 or 500 milligrams,

that is a pretty sizeable dose. I think there is a

lot of uncertainty if you use that as your LOAEL to

try to try and figure out what the threshold dose

might be. You are much better off to focus on

lower dose challenges where there is less

uncertainty even if you have to use the LOAEL.

How far above the NOAEL is the LOAEL; and

if using a LOAEL, how big should the UF be? I

think that is the question that they wanted me to

try to answer.

(Slide.)

DR. TAYLOR: I got bold and I did try to

answer it. If the LOAEL is based on subjective

symptoms, \"My mouth itches,\" then I don\'t think we

have to be very concerned about uncertainty

factors, because in the limited experiences that

exist in the literature there is a ten- to a

hundredfold variations between the doses that begin

to provoke subjective symptoms and the doses that

209

tend to provoke objective signs. I learned

something today. I\'ll try to say \"signs.\"

Now then, if you have a LOAEL based on

objective reactions, what uncertainty factors

should you use? Well, then I think you would need

to have very careful expert analysis of the

clinical study you are looking at.

I could argue that if you looked at one of

these clinical threshold trials that have been done

using microgram and low-milligram dose level, that

you could use a very low uncertainty factor.

However, if you are going to rely on

publications like Perry, et al., from 2004 where

you only have data on the reactions that occur at

the lowest diagnostic challenge dose and it is 400

or 500 milligrams, then you\'ve got a much bigger

uncertainty factor because you could be a long ways

above the NOAEL.

I don\'t know what you would do in this

particular case, so I put a question mark by it. I

actually think those kinds of studies are not very

helpful.

210

In fact, if you read Perry, et al., they

don\'t tell you what the lowest challenge dose is.

I just think they follow the standard protocol, and

it is 400 or 500 milligrams. Obviously, if you had

NOAELs, that would be better yet.

(Slide.)

DR. TAYLOR: Well, what about this patient

selection issue? I think that is another key

uncertainty. I\'m not sure that the published

diagnostic evaluation are representative of the

whole population of allergic individuals.

Someone mentioned that this referral

clinic bias, if the go to a referral clinic, then

they are more seriously affected individuals in the

first place.

Those are the ones that we tend to publish

data on, and even we tend to publish data on

individuals that are selected from that population

because their history suggests they may react to

lower doses.

I would say that the clinical threshold

studies that are published in the literature are

211

distinctly skewed toward the more highly sensitive

patients.

Now, have some people actually been

excluded from diagnostic evaluation and clinical

threshold trials? Yes. People with history of

severe allergic reaction, people with histories of

unstable asthma.

There is no way you can involve an

unstable asthmatic in one of these trials; they

will react to everything you do including the

placebo. In all likelihood, the ethical thing to

do is to see if you can get their asthma under

control.

Some physicians exclude severely affected

individuals, but I think it is discoverable to

figure out how many. I think this panel needs to

know the answer to that question.

Is that 1 percent of the population,

5 percent of the population, .1 percent of the

population? I think that is discoverable, but we

don\'t have the information.

(Slide.)

212

DR. TAYLOR: I present this information to

you because I think it is very relevant. This is a

paper from Scott Sicherer and Hugh Sampson and

Hugh Sampson published a few years ago. I only

picked out the soy allergic data from this paper.

It is a double-blind placebo. They

purport data similar to that in Perry, et al. It

is a double-blind, placebo-controlled food

challenges of 53 soy-allergic people. I wanted to

point out that 28 percent reacted to the first

dose, which was 400 or 500 milligrams. Although,

good luck figuring out how many it was 400 and how

many it was 500; it is not in the publication.

Fifty-three percent reacted at some

intermediate dose and 19 percent reacted at the

final dose, which was either 2 or 2.5 grams or an

open challenge with like 8 grams.

That tells you that there are a lot of

individuals that are in these very high dose

ranges, at least for soybeans, that is their

individual threshold doses. We tend to focus on

these people, but just remember this is 25 percent

213

of the population.

(Slide.)

DR. TAYLOR: Another deficiency with this

paper is they don\'t tell you whether the milligrams

are soy protein or soy flour, so I\'m not sure. It

is probably soy flour, but that is just a guess.

Then, this is a study from the French group,

Moneret-Vautrin\'s group. I just wanted to show

this to point out that the levels, the individual

threshold doses for individuals, can vary

enormously in big, clinical trials. This was 103

individuals.

(Slide.)

DR. TAYLOR: Have they been severely

affected? People have been excluded from challenge

trials? Do they have lower or minimal eliciting

doses? Do they experience severe reactions at very

low doses? Or, are they simply individuals who

have made big, dumb mistakes in their avoidance

diets? I mean, I think that is a considerable

possibility.

(Slide.)

214

DR. TAYLOR: This study was mentioned,

Jonathan Hourihane\'s study. He took individuals

with asthma and without asthma and those with

food-induced asthma are more likely to have a

severe reaction. That is pretty well documented.

You can see that there is not a big

difference in threshold doses for asthmatics and

non-asthmatics \-- a little bit of difference down

here, but it is not all that dramatic compared to

the other uncertainty factors.

(Slide.)

DR. TAYLOR: Now, Wensing\'s study gets

mentioned a lot, too. The thing I want to point

out here is there are only five subjects in this

study that had objective symptoms. For all of the

others, Wensing, et al., stopped the study with

subjective reactions, \"My mouth itches.\" That is

going to have a big impact on the minimal eliciting

dose.

They did look at people who had histories

of severe reactions versus people who had histories

215

of mild reactions. Remember, most of these are

subjective reactions. You can see that maybe there

is a 10- to 100-fold variation amongst these

individuals.

(Slide.)

DR. TAYLOR: In conclusion, I would say

that there is a lot of uncertainty factors. I

think the biggest ones are the use of LOAELs versus

NOAELs in the published information and the patient

selection biases in these studies.

I do think we have a lot of information

out there in the clinical literature, but whether

that data is that of an appropriate form to allow a

regulatory agency to make a reasonable decision,

I\'m not sure.

I do know that there is lots of clinical

threshold trials underway around the world, that

within a few years we will have more data done with

a consensus protocol or some minor variation of

that, and that might make some of this easier to

interpret.

Thank you.

216

CHAIRMAN DURST: Thank you.

Are there any questions or discussion for

Dr. Taylor?

(No verbal response.)

CHAIRMAN DURST: All right, I guess not.

Thank you, Dr. Taylor.

Marcia Moore has an announcement to make.

MRS. MOORE: I guess that is the hardship

of going just before lunch as you said.

(General laughter.)

MRS. MOORE: For the public comment period

that we have at 2:15, can I see a show of hands of

the folks who are here right now for that and will

be speaking. If you could stay when we break for

lunch for about 5 to 10 minutes, it appears that

several of you didn\'t get the full instructions.

We want to go over the instructions with you for

that.

That\'s all I have.

CHAIRMAN DURST: Okay. Thank you very

much.

I guess if there is no further discussion

217

at this point, we will break slightly early for

lunch and reconvene at 2 o\'clock as the schedule

indicates.

Thank you very much.

(Luncheon recess.)

218

A F T E R N O O N P R O C E E D I N G S

CHAIRMAN DURST: Before we begin our

public comments, we have one final presentation,

and that is by the lead author of the document that

we are discussing today, and that is Steve Gendel.

Dr. Gendel is a senior scientist in the

National Center for Food Safety and Technology of

the FDA and he will describe the overview of

approaches to establishing thresholds for

allergens.

Steve.

OVERVIEW OF APPROACHES TO ESTABLISHING

THRESHOLDS: ALLERGENS

DR. GENDEL: Thank you. I guess I would

like to start by acknowledging that I am aware of

the awesome responsibility that goes with being the

first speaker after lunch.

(General laughter.)

DR. GENDEL: I am going to try and be

quick before everybody has a chance to drift off.

Also, the purpose of what I\'m doing here, since the

report has been out for several weeks and I\'m sure

219

that everybody on the Committee has had a chance to

review it in great deal, I\'m not so much going to

present an overview as a refresher or a reminder

for you as to what is in it specifically today on

the parts related to food allergens, with the idea

of sort of setting the stage leading into the

discussion for the Committee later this afternoon.

(Slide.)

DR. GENDEL: To start, what I would like

to do is look at the purpose of the report, why we

wrote it. This is important for the Committee to

think about because the purpose of the report was

to identify approaches that could be used to

establish thresholds for the major food allergens

and for gluten, with the emphasis on \"approaches.\"

The report was not intended to make a

decision about whether to establish thresholds or

to choose an approach, and it was not aimed at

discussing thresholds for individual allergens. We

were interested in identifying the approaches that

are available and looking at the advantages, the

disadvantages and the data needs for each approach.

220

It is something to keep in mind when we look at

what the contents of the report, the \"Draft

Report,\" actually are.

(Slide.)

DR. GENDEL: The overall organization is

fairly straightforward. The mandatory introductory

material which in this case put the report in

context as to why we were doing this and how this

relates to the FDA\'s mission, then there was a

scientific review of what was known about food

allergy and celiac disease, and then discussions of

the approaches that they Working Group identified

for establishing thresholds, so very

straightforward.

(Slide.)

DR. GENDEL: In terms of the scientific

review of food allergy, we considered a lot of

factors, some of which are listed here and there

were some others beyond this.

Two points I think to bring out are under

the area of exposure. We did talk about the

effects of processing on allergens, how that

221

affects both consumer responses to the substances

and also we discussed the methodology related to

the detection and quantitation of the major food

allergens, and, again, how processing affected

that.

Then, as Dr. Taylor mentioned, we spent

some effort at trying to identify and discuss the

clinical literature, the published challenge

studies, which are the fundamental basis for any

discussion of understanding how the allergic

consumer responds to these foods.

(Slide.)

DR. GENDEL: In terms of the approaches

that we identified, there were four of them that

the Working Group identified: analytical

methods-based, safety assessment-based, risk

assessment-based, and the statutorily derived

approach. I\'m going to say a couple of words about

each of these as we go along.

The analytical methods-based approach is,

as the name implies, one in which any thresholds

are established based on the sensitivity of the

222

methods available.

This approach is useful for those

allergens where validated methods are available,

but the Committee was cognizant of the fact that

this method, this approach, is not linked to public

health outcomes or public health concerns directly.

The safety assessment-based approach is

one which we have heard a lot of discussion of this

morning. In this case, it would involve using

published values for LOAELs or NOAELs as the basis

for establishing thresholds and applying

uncertainty factors.

As we heard, the appropriate uncertainty

factors would be dependent upon the gaps that were

identified in the data, how much data was

available, and what was contained in that data

would determine what the appropriate uncertainty

factors would be. This is an approach which has

moderate data needs.

The risk assessment-based approach, on the

other hand, is one which would use clinical

response distribution data, that is, information on

223

responses across the whole spectrum of

concentrations of allergen.

We were referring to this in the

quantitative sense of quantitative risk

assessments, where by the use of modeling and other

techniques such as we discussed before, the

approach could be used to derive quantitative

estimates of risk and of the associated uncertainty

at any particular level you might be interested in.

This is scientifically a very powerful

approach, but it is also an approach which has the

greatest data needs. Again, this morning we heard

some discussion about what those data needs are and

what the limitations of the available data are.

Finally, the statutorily derived approach,

the statutorily derived approach is one in which

thresholds are determined based on language that

appears in a relevant law as promulgated by

Congress which is then used to extrapolate

thresholds from that language.

In the case of the FALCPA, there is

language which exempts highly refined oils from the

224

labeling requirements, so the statutorily derived

approach could be used the same based on protein

levels in those highly refined oils. Those levels

could serve as the basis for establishing

thresholds in other foods besides the

highly-refined oils.

This approach is also one in which the

links between any potential thresholds and public

health issues and public health outcomes is not

clear, although it is an approach that could be

used.

Based on the review of food allergy that

was present in the \"Draft Report\" and based on the

discussion of the approaches that we were able to

identify, the Working Group came out with five

findings related to food allergens.

The first one, which I think is an

important point to make, is that whatever decisions

are made regarding the establishment of thresholds

and the approaches that might be used to establish

thresholds and any thresholds that might be derived

using these approaches need to be reevaluated

225

periodically and probably frequently as new data

and analysis methods become available.

We heard a lot today about ongoing

clinical trials, ongoing studies, developments and

new methods, so whatever decisions are made now

need to be reevaluated as these new data become

available.

Secondly, the Working Group found that the

analytical methods-based approach could be used to

establish thresholds for allergens, if the

validated methods were available.

However, we felt that if this method is

used, it should be replaced by thresholds

established using one of the methods with a link to

risk and public health as soon as that is possible.

The Working Group found that the safety

assessment-based approach is a viable approach for

the major food allergens using published LOAELs or

NOAELs, using a standard of the initial objective

symptoms in clinical trials as the basis for

determining LOAELs or NOAELs, and, as I mentioned,

appropriate safety factors which would be

226

determined by analyzing the literature.

The risk assessment-based approach is,

obviously, potentially the strongest scientifically

of the different approaches. We realize that this

approach is one which is just now being applied to

allergens for the first time, and we still feel

that there is a need for more data and more

analysis of the appropriate assessment tools,

modeling tools, and ways of analyzing the data at

this time.

Finally, the statutorily derived approach

could be used to set thresholds, but based on the

levels of proteins that are found in the highly

refined oils it is possible that this approach

would provide thresholds which are unnecessarily

protective of public health.

We felt that the Working Group felt that

if this approach was used, that the results should

be reevaluated again as soon as possible when the

data became available on the methods for using one

of the risk assessment-based approaches for

establishing thresholds.

227

That is, briefly, the reminder of what is

in the report.

QUESTION-AND-ANSWER SESSION

CHAIRMAN DURST: Are there any questions

or comments for Steve at this point? I\'m sure we

will involve him in our discussions later.

Yes.

DR. BRITTAIN: This is Erica Brittain. I

want to commend the group together that put

together the report. It is really easy to read and

very interesting. One part of it that I found a

little confusing that I didn\'t really understand

was the analytical method.

Am I correct or not in understanding that

to be basically the level of detection? If

something is below the level of detection, it would

be considered a threshold, or have I misunderstood?

DR. GENDEL: Yes. Basically, as I said,

the idea was we were trying to identify all the

available approaches. As we mentioned in the

report, there are some examples where effectively a

threshold has been set at the level of detection of

228

the methods available.

DR. BRITTAIN: Thanks.

CHAIRMAN DURST: Anything else for Steve

while we\'ve got him up there?

(No verbal response.)

CHAIRMAN DURST: Okay.

DR. GENDEL: Thank you.

CHAIRMAN DURST: Thank you, Steve.

I guess now we can get into the public

comment part of our program. We have a number of

speakers lined up. Just as a reminder, each

speaker will have three minutes, and then the hook

comes out.

(General laughter.)

PUBLIC COMMENTS

CHAIRMAN DURST: There will be additional

time for questions beyond the three minutes. Okay,

our first speaker will be Tracy Atagi from the Food

Allergy Anaphylaxis Network.

MS. ATAGI: Hello, my name is Tracy Atagi.

I am actually not from FAAN, I\'m a member, but I\'m

speaking here for myself. I am a mother of a

229

six-year-old boy with a severe peanut allergy.

I am speaking here today because I have

four specific concerns with the methodologies that

are discussed in the draft paper. Due to time

constraints, I will try and summarize these

briefly, but I hope the Committee will also

consider my longer written statement.

My four concerns are, first, the draft

paper fails to consider sensitization as a health

endpoint of concern. Second, the oral challenge

data are unacceptably biased, because they are

likely to only represent the least allergic

individuals excluding not only the most sensitive

individuals but also your average allergic

individual.

Third, contrary to the findings of the

\"Draft Report,\" the use of initial objective

symptom is not generally protective.

Fourth, the proposed methodology for the

statutory based threshold does not meet minimum

data quality requirements. The data on oils with

no detectible protein were arbitrarily excluded and

230

the data on protein levels that were included in

the paper appear unrelated to highly refined oils.

The issue of sensitization is important

because without sensitization there is no food

allergy. Parents of children with a family history

of food allergies are advised to delay introduction

of allergens to help the immune system develop

fully.

When I read labels, I read it both for my

allergic son and also my, hopefully, not allergic

daughter. For my son, it is a matter of life and

death. He has had an anaphylactic reaction. I

hope never to see that again.

However, it is also in a way a matter of

life and death for my daughter, because if delaying

introductions of an allergen can keep her from

developing that food allergy, then the risk to her

life is greatly reduced. Thus, I would urge the

Committee to consider sensitization as a possible

health endpoint for the health-based methodology.

Apart from the issue of sensitization, the

safety assessment-based threshold contains serious

231

biases. The \"Draft Paper\" explains that the oral

challenge study data are used for diagnostic

purposes, but fails to reach the obvious

conclusion.

Individuals who would volunteer for these

studies are those whose initial diagnoses are in

doubt. In other words, these individuals who are

volunteering are likely to be the least allergic in

the population, not only are the most sensitive

individuals like my son not included but also your

average allergic individual.

This bias is compounded by the

recommendation that the threshold be based only on

the initial observable symptom \-- I\'m sorry,

objective symptom.

As the draft paper notes, a particular

dose could result in mild symptoms on one day and

life-threatening reactions the next. Excluding

data on subjective symptoms is unprotective, given

the range of reactions even within the same

individual.

Finally, the methodology on the statutory

232

derived approach is fatally flawed. The draft

paper offers no evidence that the oils examined in

the study are highly refined, and the decision to

exclude all oils with no detectable protein appears

arbitrary.

Frankly, I would assume that oils that

have no detectible protein would be the only ones

that would meet Congress\' intent in exempting

highly refined oil. Instead of using protein

levels in different oils to define the threshold,

FDA should use the lack of protein in an oil to

define whether it has been highly refined.

Thank you very much.

CHAIRMAN DURST: Thank you.

Are there any questions or comments?

(No verbal response.)

CHAIRMAN DURST: Okay. Well, we will move

on.

Our next speaker is John Carroll of the

Enzyme Technical Association.

MR. CARROLL: Good afternoon. I am from

the Enzyme Technical Association. I am the current

233

chairperson from that group. As you can tell from

the title of the association, this is about

enzymes, which are Mother Nature\'s wonderful and

ubiquitous tools.

I wish to thank you for letting us,

allowing us, to give a brief presentation here

today. We also wish to thank and compliment the

Committee and the FDA for this effort here.

Anybody who is at all looked at any of this stuff,

and we have tried for a year or two, this is a

complicated, complex area, a full gamut including

emotion. This is a very difficult task that you

have, but we know that our FDA is up to it.

We are going to talk about where enzymes

fit and the view of the Enzyme Technical

Association. We put this in a question-and-answer

type modality.

Our first question is, Where do enzymes

fit within the scope of allergen labeling as

defined by FALCPA? Our answer, after quite a

lengthy period of trying to evaluate this is, no,

they don\'t fit.

234

After reviewing FALCPA, after looking at

the \"Draft Report,\" which is excellent, plus a

multitude of allergen literature, we have come to

the conclusion that enzymes do not fit, and here is

why.

Enzymes are not proteins within the Big 8

allergens. Some enzymes, but not all, are

manufactured using fermentations in which raw

materials obtained from one or more of the Big 8

are used to feed the microorganism from which the

enzymes are extracted.

Enzyme products obtained from

fermentations are not directly derived from the Big

8 list. They are derived from microorganisms fed

on media that may include protein from one or more

of the Big 8 list.

Furthermore, enzymes are normally purified

to remove the biomass and to achieve a certain

concentration. Why are we here today? is our

second question. Why is the Enzyme Technical

Association here today talking to the Committee?

Well, the Enzyme Technical Association has

235

been asked whether enzymes need to have allergen

labeling, because the enzyme industry uses some of

the Big 8 allergens for enzyme production, as I

explained, as food for the microorganisms.

While ETA is convinced that FALCPA never

intended to regulate the labeling of enzymes, as an

as association we are prepared to share the

information we have collected to support our

conclusions.

We would also like to point out in the

form of a question, What is the policy of other

regulatory bodies in the international arena? The

United States, like every country, tends to think

we are the center of the world; it is not true.

There are other people who, as we have

heard today, have addressed this question. They

have actually addressed it also specifically in the

case of enzyme products.

The U.S. needs to understand that both the

EU and Japan, the regulatory bodies in those

countries, have concluded that enzymes are not

required to have allergen labeling.

236

CHAIRMAN DURST: Your time is up. Can you

conclude?

MR. CARROLL: This is the last point.

Indeed, the European Commission Health and

Consumer Protection Directorate has clearly stated

that enzymes are outside the scope of their

Directive 2003, which was November 2003, a similar

directive, very similar to FALCPA.

Thank you.

CHAIRMAN DURST: Well, I have a question

as far as the enzymes. Are they used in a way that

they can be considered a food? Are they in a form

that is eaten, or are they just used then as a

method of processing?

MR. CARROLL: They are used as a method of

processing. As it sounds like you\'re aware, they

are used to catalyze reactions, biocatalysis. They

are used as processing aids. They are used at

levels, like any catalyst, that are very low.

Roughly, the enzyme protein in a normal

process would be at a maximum of 1 part per million

of the enzyme protein itself. Part of the nature

237

of that is the nature of biocatalysis that they use

at very low levels.

CHAIRMAN DURST: Okay.

MR. CARROLL: No, they are not an

ingredient. They are not part of the food, per se;

they are processing aids.

CHAIRMAN DURST: They are purified so that

initially they have small amounts of any

potentially allergenic proteins, and then in

addition they are used in even smaller quantities

in the processing, or they come through in\--?

MR. CARROLL: If you step through it, the

first thing is any allergenic protein that might be

part of the raw material used, of the fermentation

that is being used, is food. The first thing is it

is consumed.

We are trying to make enzyme protein.

Just like you and I at lunch are trying to make

hair or skin or human protein, we are trying to

make enzyme protein. That is our business; and if

we don\'t do it, we lose.

Then, the next step is we are talking

238

about purification of the biomass of any residue

non-enzyme protein material because that is our

interest is that enzyme activity.

Furthermore, if you look down, it is the

way a biocatalyst is used. They are used at very

low levels and that is why they are not typically

ingredients. They are processing aids to achieve a

reaction, to achieve an effect. They are not in

the final product for a purpose \--

(Simultaneous discussion.)

CHAIRMAN DURST: Do you perceive that

there would ever be a situation where their level

of allergenic protein would be at a point where

they would be considered an allergen in a food?

MR. CARROLL: We have looked, and that\'s

why we said we are willing to talk with FDA about

our overall analysis. However, the levels that we

are talking about are orders of magnitude below

anything we\'ve heard today.

CHAIRMAN DURST: Okay.

Did you have one?

DR. MALEKI: Yes.

239

Just a comment as far as I know, to the

best of my knowledge, they haven\'t been reported as

allergens, enzymes that are used in processing.

Most of the allergens are pretty well characterized

\-- well, not necessarily characterized but groups

of enzymes or proteins that fall under that

category of allergens have been recognized.

As far as bioprocessing, I don\'t think,

and one of the clinicians can probably comment on

that, but I have not heard of a reported reaction

to something like that.

MR. CARROLL: We have looked into the

literature, and there are no cases of enzymes as

food allergens. They are not basically food

allergens. They are ubiquitous.

DR. MALEKI: In foods, I realized that

they are used very ubiquitously. I think if there

was a reaction, that they probably would have been

reported.

MR. CARROLL: Also, in the apple \--

actually if you eat some nice, raw vegetables

today, you were taking in all sorts of DNA and

240

enzymes, that is where we are at. We are just

actually using Mother Nature\'s tools for specific

applications.

Anything else?

DR. KELLY: Yes, a question.

MR. CARROLL: This is great (laughter).

DR. KELLY: Do you want to make the point

that enzymes should be outside of the exemption

standards?

MR. CARROLL: I guess the easiest way to

capsule it is out of the scope of FALCPA. It is

not intended to be part of it, because we are not

ingredients.

DR. KELLY: You would prefer not to engage

in the notification process?

MR. CARROLL: Right, I mean, I don\'t think

it is actually appropriate in this case.

DR. KELLY: How does that differ from

sharing your data with the FDA?

MR. CARROLL: Well, we can share it in

terms of showing them how we got to this

conclusion.

241

DR. KELLY: Isn\'t that what the

notification process consists of?

MR. CARROLL: No. I think in this case it

would be more appropriate to be ready to meet with

them to show were we are. I think it is so

straightforward that it is not \-- that would be a

misuse, I think, of the system.

DR. KELLY: Yes.

MR. CARROLL: I mean, they are going to be

very busy getting this right. From what I see \--

and I\'ve actually tried to study this also

personally, taking it as a hobby, it is quite a

fascinating area \-- this is a hard job. I think it

would be disingenuous to use even the

administrative system for such a case.

CHAIRMAN DURST: Could you put some

information together for the Committee as far as

these points that are being raised? I think at

this point we are getting off track, and we want to

get back onto the main thrust of our work, and that

is, the consideration of the different approaches

for setting the thresholds.

242

MR. CARROLL: Right, I agree.

CHAIRMAN DURST: Thank you very much.

MR. CARROLL: You\'re welcome.

CHAIRMAN DURST: All right. Our next

speaker will be Diane Castiglione from the Food

Allergy Anaphylaxis Network.

MS. CASTIGLIONE: Good afternoon. My name

is Diane Castiglione. I promised myself I wasn\'t

going to do this (weeping). Oh, well.

My 13-year-old son is allergic to milk,

eggs and wheat. While I know that gluten is the

subject for tomorrow\'s hearings, I should also note

that I have celiac disease and maintain a

gluten-free diet.

My son\'s allergies were diagnosed shortly

before his first birthday. The message from his

allergist was clear. He must avoid all foods

containing milk, eggs and wheat. This task is even

more daunting and challenging than it sounds,

especially given the prevalence of milk and wheat

in food products.

Fortunately for me, Michael was so young

243

that he had barely started to eat table food. I

was able to do my research before I introduced new

foods to him.

Since his initial diagnosis, a lot has

been accomplished with regard to food allergy

awareness, and I have been pleased to see the

voluntary efforts made by food manufacturers with

respect to identifying allergens on their labels.

However, at the same time the hodgepodge

of labeling methodologies create a confusion for

those of us who depend on the accuracy, clarity and

transparency of these labels (weeping).

When a product that my son has been eating

for years without any problems suddenly begins to

carry a \"may contain\" statement, more questions are

raised in my mind rather than less.

Has there been a change in the ingredients

or in the processing? Has the allergen always

potentially been present in the product without my

knowing it? Or, the skeptic in me wonders has

nothing changed, and the statement merely reflects

a lawyer\'s concerns about potential lawsuits? I

244

must make the difficult decision of continuing to

purchase the product or removing it from my son\'s

already limited diet.

I cheered when the new labeling law was

passed. At last some rationality and clarity would

be established so that I could read food labels

with confidence. My life would be simplified at

least a little.

However, the subject of this hearing

raises doubts in my mind and makes me uneasy. How

will these thresholds be established? What will it

mean if an ingredient falls below the threshold

levels? Will manufacturers begin to implement

their own set of statements resulting in a

hodgepodge similar to that which exists today? How

am I then to interpret those statements?

When I told my son about today\'s hearing

and asked his opinion, after all he is the one who

lives with allergies, he told me that if an

ingredient list on a product that he consumes

suddenly included something to which he is

allergic, while he might regret having to give up

245

the product, he would not have a problem doing so

as long as he knew that the label was based on

established fact.

While we know that the medical and

scientific communities have not yet established

specific universally applicable thresholds, I think

my son\'s comments raise two key points about this

process.

The process of establishing thresholds

must be transparent. The thresholds must be

clearly defined so that all manufacturers are held

to the same standard. The question of how to

handle products in which the allergen falls below

the threshold must be addressed in order to avoid

the development of inconsistent disclaimers on

packaging such as currently occurs.

Food labels are our lifeline. We depend

on them for the health, safety and well-being of

our children and ourselves. When reading a label,

there should be no doubt in our minds as to its

veracity and accuracy.

There should be no doubt in our minds as

246

to the motivation and rationale behind any

statements regarding the ingredients and/or the

processing of the product.

There should be no doubt in our minds that

we are consuming a product that is safe for us. If

the new law does achieve its desired effect, we

need to ensure that its implementation does not

replace one state of confusion and distress with

another.

Managing food allergies on a daily basis

is challenging. Please help us to take a step

closer to reducing that challenge and to make the

lives of those with allergy simpler and therefore

richer (weeping).

Thank you for your time.

CHAIRMAN DURST: Thank you.

Any comments or questions?

(No verbal response.)

CHAIRMAN DURST: Thank you very much.

Our next speaker is Barbara Desa from the

Food Allergy Anaphylaxis Network.

(No verbal response.)

247

CHAIRMAN DURST: Okay. She is not here,

so we will move on.

Will Duensing?

(No verbal response.)

CHAIRMAN DURST: Let\'s see, I don\'t have

his affiliation.

Bunge Milling on behalf of the North

American Millers\' Association.

MR. DUENSING: Mr. Chairman and Committee

Members, thank you for this opportunity and good

afternoon. My name is Will Duensing, and I am

director of Quality Assurance and Technical

Services for Bunge (pronounced Bun-gee) Milling, a

large dry corn milling company with mills in the

United States, Canada and Mexico. I am also here

today, however, representing the North American

Millers\' Association as chairman of the Technical

Committee.

\"NAMA,\" as it is called, is a trade

association representing the wheat, corn, oat and

rye milling industries in the U.S. and Canada.

NAMA\'s 48 members operate 168 mills in 38 states

248

and Canada with aggregate production of more than

160 million pounds per day of milled products or

about 95 percent of the industry capacity.

As Anne Munoz-Furlong and several previous

speakers pointed out in their presentations this

morning, it seems to me it would be to us a

disservice to the allergenic population if products

that clearly have shown a long history of safe use

would be labeled as containing allergens due to

unrealistically low thresholds as a result of

FALCPA\'s requirements or regulations.

At issue in our industry is the presence

of trace quantities of soybean protein, which may

be present from the country in milled corn and

other cereal grain products.

While the establishment of thresholds is

obviously critical to the practical application of

FALCPA regulations, these thresholds should not be

unduly or unnecessarily restrictive to the allergic

person\'s food choices.

In that regard, we offer these following

comments. First, these thresholds should be based

249

on the best possible scientific data regarding the

effect of an allergen on the allergenic individual

and certainly these thresholds should not be set at

zero.

Secondly, the use of analytical-based

methods would appear not to be appropriate as this

approach is very likely to result in a threshold

which would be unnecessarily low.

Additionally, FDA should probably avoid

the establishment of artificially low thresholds

with the \"intent\" of adjusting them later.

Historically, this has not taken place despite good

intentions. Additionally, any future adjustments

would prove to be confusing to the consumer and

disruptive to the food industry.

Finally, FDA must provide a clear

timetable for the establishment of these

thresholds. In our opinion, they must be prepared

to provide financial support for studies where

critical gaps exist in the current database.

Thank you for the opportunity to offer

those comments.

250

CHAIRMAN DURST: Thank you.

Committee, any questions or comments?

(No verbal response.)

CHAIRMAN DURST: Thank you very much.

Our next speaker is Martin J. Hahn from

Hogan & Hartson.

MR. HAHN: Thank you. My name is

Martin Hahn, and I\'m speaking on behalf of the

Grocery Manufacturers Association, and I do have

financial ties to the food industry and that

association.

GMA and its member companies have been

actively involved in the allergen issue. Indeed,

GMA was one of the instrumental agencies or

instrumental associations that was responsible for

the development of the voluntary allergen labeling

guidelines that Mark Nelson mentioned earlier.

Those guidelines have resulted in the use of common

English names on food labels well before FALCPA was

passed.

The established of allergen thresholds is

integral to the effect of enforcement of FALCPA.

251

FALCPA suggests incidental additives such as

processing aids to the allergen labeling

requirements. This exemption becomes problematic

when the allergenic protein in a food is present at

such low levels that it does not pose a risk to

human health.

For example, typical uses of soy lecithin

can result in levels of soy protein from soy

lecithin in a part per billion and part per

trillion range. These foods have been consumed by

consumers without incident.

The legislation will fail the

food-allergic community if it results in allergen

labeling of foods with inconsequential levels of

protein from major allergens.

Given the time limits for today\'s

presentation, we offer the following brief

comments, which we do intend to supplement with

written comments at a later time.

With regard to the statutorily derived

approach, we agree with the Agency assessment that

it would be appropriate to develop interim

252

thresholds using a statutorily derived approach.

FALCPA specifically excludes highly

refined oils from the definition of major allergen.

Highly refined oils do contain small, yet

detectible, levels of protein, which evidences a

congressional recognition that it is appropriate to

exempt from the major allergen definition products

that contain very small levels of protein.

GMA believes the statutorily derived

approach would support the establishment of 10 ppm

as an interim threshold level. We note that many

in the food industry have used this 10 ppm level

for years as an informal threshold for food

allergen labeling, particularly when it comes to

processing aids.

We previously provided FDA with marketing

data demonstrating that the presence of undeclared

soy lecithin, fish gelatin, wheat starch

contributing 10 parts per million of less than

major allergenic proteins did not result in a

measurable increase in allergenic responses over

baseline.

253

We have reviewed the published literature

and identified studies reporting various levels of

proteins in highly refined oils. This review has

identified that some oils have levels of 48 parts

per million while some of them have less than

20 parts per billion.

Because highly refined oils do have

varying levels of protein, we believe it would be

appropriate to set the threshold at 48 parts per

million, a level that is present in oils.

While we believe that may be appropriate,

we would advocate the establishment of 10 parts per

million as the interim level, because that is the

level that is in the midway point of allergenic

proteins found in products.

With regard to the method of analysis

approach, we believe it would be inappropriate to

se the threshold on the basis of validated methods.

We only have one validated method, and that is for

protein.

We also are concerned that as new

methodologies become available there will be

254

ever-increasing sophistication of the analytical

method which sets a number which is constantly

changing.

CHAIRMAN DURST: Your time is up. Thank

you.

Any questions or comments?

(No verbal response.)

CHAIRMAN DURST: Okay. Thank you very

much.

Our next speaker is Ann McKay from the

Food Allergy Anaphylaxis Network.

MRS. MOORE: Next.

CHAIRMAN DURST: The next speaker is

Peggy Mockett from the Food Allergy Anaphylaxis

Network.

MS. MOCKETT: Hello, my name is

Peggy Mockett. I am the mother of Alexander, a

10-year-old boy who has life-threatening food

allergies to tree nuts, peanuts, and corn. He is

also allergic to soy, penicillin, latex, and has

asthma.

I have administered epinephrine to him

255

during one of his anaphylactic reactions. My son

has gone into anaphylactic shock before,

experienced anaphylaxis three times, and managed

through reactions involving skin rash, vomiting and

hives

Two of my son\'s anaphylactic reactions and

four of his milder reactions were due to labeling

issues. We have been seen by five doctors, and all

five instructed us to completely avoid his

allergens. We were advised to decline food

challenges to his major food allergens.

It was stressed and has been experienced

that the smallest amount can cause a serious

reaction in our son. There is no room for error

for us. We have a rule that says you read it once,

twice, and then again before you eat it. If you

cannot read it yourself and I didn\'t make it, don\'t

eat it.

Unfortunately, reading the label is not

always enough. There have been times when

ingredients were omitted because it wasn\'t

considered a significant amount of the total recipe

256

or it was simply done in error.

Shopping for skin, hair and food items is

a lengthy process. You must read each item every

time and more than once, because mistakes are not

an option for us. Even with perfect disclosure,

ingredients change and must be checked.

Toothpaste is risky, because flavoring is

not a detailed ingredient. Medicine flavoring is

especially difficult, because pharmacists don\'t

always know the added ingredients and the type of

flavoring is not specific.

We are sometimes told, \"It is not crucial

to the product, so don\'t worry about it.\" We have

to worry about it. Our son reacts quickly to

minute amounts of his allergens. For him buying

prepared foods is no longer an option.

Our past labeling issues have made it

impossible. Even with flour and cream cheese, I

have to call the manufacturer to be certain that

the details are accurate.

I cannot imagine allowing someone who

doesn\'t fully understand my son\'s individual

257

situation to determine at what level he will or

will not have a reaction, a decision that could

take his life. Setting threshold levels at

anything higher than zero would be tantamount to

playing Russian roulette with his life.

Thank you.

CHAIRMAN DURST: Thank you.

Any questions or comments?

(No verbal response.)

CHAIRMAN DURST: Thank you very much.

Our next speaker is Kim Mudd, Food Allergy

Anaphylaxis Network.

MS. MUDD: Good afternoon. My name is

Kim Mudd. I am a nurse at University of Maryland,

and I am also a research study coordinator. I am

on the Program Committee for the Food Allergy and

Anaphylaxis Network.

I have been working with food-allergic

patients and their families for over 14 years. I

think I have performed thousands of food

challenges. The integrity of food labels is

important to the FDA, and it is important to the

258

U.S. consumer.

For the food-allergic consumer, the food

labels are part of a life-and-death decision. When

a patient is diagnosed with food allergy, they are

counseled to read every label of every food when

they buy it, when they serve it, and when they eat

it.

If a food label contains an offending food

protein, they are told to avoid it completely.

This results in extremely limited diets with

significant impact on basic nutrition.

The precautionary labeling terms such as

\"may contained\" or \"processed on the same line\"

force families and patients to contact

manufacturers to try to gauge the risk of certain

foods or to avoid them all together. As a rule,

most of our patients and families decide on a zero

tolerance approach, resulting in even more dietary

restrictions.

If we are going to try to address the

current confusion in labeling with threshold

levels, we have a significant amount of serious

259

work to do. We do not have enough data to discuss

NOAELs or LOAELs. The studies that have been done

absolutely exclude extremely allergic subjects.

No one wants to do food challenges on

somebody with a history of anaphylaxis. If you

doubt this, ask yourself, \"Would you sign a consent

form that listed \'death\' as a possible risk?\"

Could you sign that form for your child and let me

feed that child, your food-allergic child, a food

that you know has caused anaphylaxis in the past?

If we do ultimately end up with threshold

levels, I need to know what to tell my patients and

my families. We know that the severity of reaction

and the dose required to elicit these reactions

varies from person to person.

We don\'t have the data to tell these

families what to expect. Food labels are the only

tools that food-allergic consumers have to keep

themselves and their children safe. If the

food-allergic consumer loses faith in the integrity

of these labels, they will be left with a very

dangerous practice called \"trial and error.\"

260

Thank you.

CHAIRMAN DURST: Thank you.

Any comments or questions?

(No verbal response.)

CHAIRMAN DURST: Thank you very much.

Our next speaker is Kim Mulherin from the

Food Allergy Anaphylaxis Network.

MS. MULHERIN: Good afternoon. My name is

Kim Mulherin, and I have an 11-year-old daughter

named Courtney who is severely allergic to milk

protein. Courtney\'s CAP/RAST test for milk is

greater than 100, always has been. Since her limit

exceeds the upper limits of the test, we cannot

determine the exact numerical measurement.

Scratch tests for milk cannot be performed

on Courtney, since the test itself poses too great

a risk for someone with such a high sensitivity.

The severity and the reality of my daughter\'s milk

allergy goes far beyond theoretical numbers

collected year after year.

Instead, her allergy is a very real

day-to-day struggle where the seemingly simple and

261

necessary act of eating presents continuous,

life-threatening dangers most people don\'t ever

have to experience.

The prevalence of milk products in our

society not only as the main ingredient but also as

a filler or flavor enhancer makes avoidance

especially difficult.

Since prepared foods and restaurant dining

is essentially off limits, the accuracy and clarity

of ingredient labels is critical for Courtney\'s

well-being and safety.

Despite our very best efforts to avoid

milk ingredients, Courtney has suffered severe

anaphylactic reactions from ingesting both

undeclared and minute amounts of milk protein.

In one instance, Courtney suffered an

anaphylactic reaction when she was given

turkey breast luncheon meat which, unbeknown to her

caregiver, contained a very small amount of

caseinate which was later discovered as one of the

last ingredients on the label.

On another occasion, Courtney suffered an

262

immediate and violent reaction when she ate simply

one bite of shrimp from a precooked package of

shrimp cocktail purchased in a grocery store.

There was absolutely no mention of milk protein on

the label.

When subsequent tests and patient history

ruled out the possibility of a shrimp allergy, the

remaining contents of the store-bought shrimp which

caused the severe reaction was sent for analysis to

Mount Sinai Hospital.

The analysis revealed that the shrimp

contained undeclared caseine and whey. To this

day, none of the parties involved in the chain of

production admit adding milk to the shrimp.

Just as Courtney\'s IgE level to milk

protein is too high for the CAP/RAST test to

measure with exactness, it is very possible that

her immune system is indeed more sensitive than any

laboratory test devised to predict a reaction.

Courtney\'s sensitivity to milk is so high that we

simply don\'t know what her safe threshold level is.

Without this knowledge, any minimum threshold level

263

established by the FDA is nothing more than a

statistical estimate.

Unfortunately, Courtney has already

learned the hard way that a statistical estimate is

far from a guarantee. Statistically speaking,

since 80 percent of the approximately 3 percent of

milk-allergic children outgrow the allergy by age

5, Courtney has managed to fall into the 6/10ths of

1 percent of children with a lifelong, anaphylactic

milk allergy.

It is simply unconscionable for the FDA to

ask such a person to bet her life on statistics

rather than facts. When I explained to Courtney

that the FDA was considering establishing minimum

threshold levels, she anxiously replied, \"Now I

won\'t need to use an EpiPen after almost every

meal.\"

Can you look her in the eyes and tell her

with absolute certainty that she is wrong? That is

the real minimum threshold level you need to

establish for Courtney and every other person with

severe food allergy.

264

Thank you.

CHAIRMAN DURST: Thank you.

Any comments or questions?

(No verbal response.)

CHAIRMAN DURST: Our next speaker is

Kim Sclarsky from the Food Allergy Anaphylaxis

Network.

(No verbal response.)

CHAIRMAN DURST: Our next speaker is

Linda Webb from the Food Allergy Anaphylaxis

Network.

MS. WEBB: Hello. I am Linda Gabel Webb.

Thank you for giving me this opportunity to talk to

you and for trying to do the right thing for people

with food allergies.

I have food allergies. They are not too

terrible, but I do have to avoid apples, pears,

onions and garlic so I don\'t have asthma all the

time. Naturally, they are my four favorite foods.

On a more serious note, my five-year-old

son is allergic to peanuts, nuts, shellfish, and

less so to seeds. His numbers are all way up high,

265

so that he actually can die from eating those

things as opposed to just being itchy or wheezing

like me.

The first time we figured out that he has

this problem was when he almost died when peanut

butter cookies were being baked in the house.

Thank goodness he didn\'t eat them.

Once we found out, which was when he was

about two, we have practiced complete avoidance to

the best of our abilities by reading labels, and so

on, cooking from scratch. We have been very

fortunate that he has not had any incidents since

then.

I actually am so strict that I don\'t even

allow these things into the house, and I don\'t eat

them myself, even though I\'m not allergic to the

same things because I want to be able to kiss him

without killing him.

I have really come to count on some of the

big food manufacturers who for a long time have

voluntarily done this labeling, and I think very

well.

266

I wish they would put \"May Be Manufactured

in the Same Plant\" way up top in huge letters

rather than at the bottom, but I really take that

to the bank.

We have been very fortunate, and we are

very grateful to them for that. I am looking

forward to labeling getting even better and more

thorough as it does become mandatory.

I have also tried to thank them, where

appropriate, when I call their 800 numbers and talk

to people and get further information about things

like flavors, like one of the other mothers

mentioned.

I am very grateful, and I don\'t buy their

product (laughter). It is kind of a mixed blessing

for them. However, I do have even greater

confidence when I see that same company\'s products

not having those ingredients listed.

One final note personally in addition to

the life-threatening aspects of his allergies, my

son, Charlie, who is five \-- I\'m not sure if I

mentioned that \-- also has a developmental disorder

267

that makes it very difficult for him to integrate

socially with his little peers.

You know, I can\'t tell you how much it

means that he doesn\'t have to be different in one

other way at school where mothers that want to

support him and support me can look at the list and

know that he can have this brand of Fig Newtons

and everybody else can have that, too, for a snack.

You know, it doesn\'t take away from the

fact that he is \"different\" or that he has got his

big, red emergency kit with him all the time, but

it is just one way for him to fit in.

I have complete faith that he is going to

continue to learn and grow and have a great life.

My main concern is keeping him alive. Obviously,

anything that the industry can do to make that more

possible I am very grateful for.

Thanks a lot.

CHAIRMAN DURST: Thank you.

Any questions or comments?

CHAIRMAN DURST: Okay. We will move on to

our next speaker, Jupiter Yeung from the Food

268

Products Association.

DR. YEUNG: Good afternoon. I am

Dr. Jupiter Yeung, and I serve as the principal

scientist for the Food Products Association in

Washington, D.C. FPA represents the food industry

on scientific and public policy issues.

Protecting the public from health risks

while maintaining a viable food industry in an open

society is a daunting task. The \"Draft Report\"

provides a reasonable perspective of pros and cons

of various options towards establishing allergen

thresholds and helps to keep the public informed of

the deliberative process.

While the report is a reasonable view of

conceptual options for establishing thresholds, FDA

should also consider the recent European Commission

directive of providing a temporary three-year

exemption for certain food ingredients derived from

major allergens such as fish gelatin.

This directive was based on the scientific

opinion of the European Food Safety Authority that

these food ingredients are extremely unlikely to

269

induce an allergic reaction.

While an avoidance diet remains to be the

most effective, too, for the allergic consumers, it

is generally that there are threshold doses for

allergenic foods.

Clearly, sufficient data are available to

conclude that thresholds for certain major

allergens are finite, measurable and above zero.

Hence, the assumption of zero tolerance for food

allergens places an unnecessary and unachievable

burden on the industry.

The declaration in labels of all

perceivable levels of major food allergens

including biologically insignificant amounts will

cause confusion to allergic consumers.

For example, small amounts of soy lecithin

can be used as a releasing agent during processing

but is not included in allergen labeling under the

current requirements. Some allergic consume who

previously had been safely consuming this product

will unexpectedly find the same allergen

declaration on this product as they expect to find

270

it in other soy-containing products.

Unfortunately, this is likely to put the

sensitive individual in the position of either

further restricting their food choices or choosing

to ignore the label information.

Risk management is vital to the protecting

the well-being of allergic consumers. Clearly,

decisions must be based on current available

knowledge, even with less than perfect and complete

information. Without information on thresholds, it

is difficult for the industry to optimize their

quality control efforts to protect allergic

consumers.

A reasonable certainty of no harm standard

should be applied towards establishing threshold

levels. It is not intended to ensure nor is it

possible to ensure safety with absolutely

certainty, and it does not mean that no individual

under any conditions would be protected from any

harm. Therefore, uncertainty factors that are

reasonable should be applied, and only when needed,

based on the relevance of the available data.

271

CHAIRMAN DURST: Your time is up.

MR. YEUNG: Pardon?

CHAIRMAN DURST: Your time is up.

MR. YEUNG: Can I make another minute.

CHAIRMAN DURST: Not another minute, but

one more sentence.

MR. YEUNG: Okay. For example, the

uncertainty factor is not necessary for

intraspecies for peanuts because more than 10 of

the studies were done in both male and female and

also in adults and children.

Neither should a standard uncertainty

factor of 10 be applied to the sensitive

populations, since children and sensitive subjects

were included in the clinical trials.

Since the lowest, not the mean, dose for

an objective symptom is being used to estimate

thresholds, an uncertainty factor of 2 may be

justifiable to give added protection to the highly

sensitive subpopulation.

Thank you very much.

CHAIRMAN DURST: Thank you.

272

Any questions or comments?

(No verbal response.)

CHAIRMAN DURST: Did we miss anyone as far

as the public statements?

(No verbal response.)

CHAIRMAN DURST: We are scheduled for a

break after the public comments. Even though we

are a bit early, we will take the break and

reconvene at 3:15. That will give us almost 20

minutes.

Thank you.

(Thereupon, from 2:55 p.m. to 3:15 p.m.,

there was a recess in the proceedings.)

COMMITTEE DISCUSSION:

REVIEW OF THE CHARGE AND QUESTIONS FROM FDA

CHAIRMAN DURST: I would like to reconvene

our session.

All right. This is the section of our

meeting today where the Committee can, I guess, ask

questions of any of the speakers that have

presented earlier, and also discuss any of the main

thrust of this. I would just like to establish a

273

couple of ground rules.

We had slightly gotten off track at one

point today where we had gotten into labeling.

This is not the purview of this Committee to decide

any issues on labeling nor is it the purview of the

Committee to try to come up with numbers as far as

threshold values.

We are here to basically assess the report

that the Threshold Working Group has put together

as far as approaches and give our learned opinions

on the report itself.

You have in front of you or everyone

should have the charge to the Committee. I will

just read the charge to begin with, and then we can

get into the actual discussions.

The Food Advisory Committee is being asked

to evaluate the \"Threshold Working Group draft

report, \"Approaches to Establish Thresholds for

Major Food Allergens and Gluten in Food.\" The

Committee should advise the FDA whether the draft

report is scientifically sound in its analyses and

approaches and whether the draft report adequately

274

considers available, relevant data on major food

allergens and on gluten. In addressing these

issues, FDA requests that the Committee consider

the following specific questions.

Now, again, for this afternoon, we are

going to focus on the allergens. Tomorrow, we will

be on gluten. You have in front of you some

general points that we should consider and then

some questions that the FDA would like our opinions

on.

At this point, I would like to open up the

discussions to the Committee, if there are any of

you that still have questions for any of our

previous speakers or would like to make some

comments or statements about your opinions on this.

Yes.

DR. BARACH: Yes. Jeff Barach with the

Food Products Association. I would like to commend

the presenters this morning, but I have questions

for Dr. Wood and Dr. Taylor. Both reported on the

composition of the challenge studies in a different

manner, and maybe they can clarify this a little

275

bit.

In Dr. Woods presentation, he said that

the most allergic patient was not in his studies.

Yet, Dr. Taylor reviewed many studies and said,

yes, the sensitive individual is included and had

an explanation of why. I thought that perhaps one

or both could address that issue?

CHAIRMAN DURST: Dr. Wood had to leave

early. I hope Dr. Taylor is around.

Yes.

DR. TAYLOR: Well, I think I can answer

for both of us because I think I understand Dr.

Wood\'s point of view as well. It is an individual

clinician decision as to which subjects in a clinic

would be subjected to diagnostic challenge trials.

In the United States, it has now become

the practice that only challenges will be done on

those patients who are below the 95 percent cutoff

level for the CAP/RAST, at least in some clinics.

That very well could be true in Dr. Wood\'s clinic

at Johns Hopkins, I am not entirely sure.

On that basis, he was correct in saying

276

that the most highly sensitive individuals would

not be subjected to challenge because in the U.S.

you cannot get by ethics forums.

In Europe the situation is different.

There are groups that challenge on a diagnostic

basis every patient that they encounter as part of

their standard diagnostic practice, at least that\'s

what they tell me. That seems true from the

publications that they have put in the peer

reviewed literature.

Consequently, I think it varies from

clinic to clinic, investigator to investigator, and

report to report making the work of your panel even

more difficult.

CHAIRMAN DURST: Yes.

DR. MALEKI: Dr. Taylor, Soheila Maleki,

USDA. Can you comment on the soy lecithin? We

heard a lot about that in the questions and

comments. I was wondering if you know of any

allergic reactions to that?

DR. TAYLOR: Yes, I have actually looked

pretty carefully at the clinical literature on soy

277

lecithin reactions. I should start by saying that

some highly respected clinicians like Hugh Sampson

do not advise their soy-allergic patients to make

any attempt to avoid soy lecithin.

Soy lecithin is acknowledged to contain

residual protein at levels that might be somewhat

debatable but probably in the range of 100 parts

per million.

You would use soy lecithin in direct

ingredient applications where it would appear on

the label anyway because it has a functional effect

in the finished product at 1 or 2 percent. You are

talking about 1 or 2 parts per million soy protein,

if you started with 100. In these processing aid

applications, the levels would be several orders of

magnitude below that.

There are two reports in the clinical

literature of allergic reactions to soy lecithin,

both of them involve both pediatric cases from

Europe, I think both of them are from Europe,

involving infants exposed to \-- I know in one case

it is soy formula and I think the other case is the

278

same.

Unfortunately, in my view, we don\'t know

the protein level of the lecithin because the

clinical investigators used an inappropriate

method. They attempted to determine the protein

level of the lecithin using the Kilnaught

(phonetic) procedure which would pick up the

nitrogen and the phospholate fractions. They got

huge numbers, but the numbers are not valid in my

opinion.

DR. MALEKI: All right, thank you.

CHAIRMAN DURST: Yes.

DR. KELLY: I just want to return,

briefly, to the issue of challenge studies, which

is important I think because they may well be used

to determine acceptable levels.

My question has to do with an individual

who doesn\'t need a diagnostic challenge study,

because the clinical presentation is so clear. Are

they included, in general, in the challenge

studies? Secondly, individuals with very severe

reactions, anaphylactic reactions, would they ever

279

be included in challenge studies or are they almost

by definition excluded?

DR. TAYLOR: I think that there are

clinicians in Europe who tell me that they

challenge every potential food-allergic patient

that crosses the threshold of their clinic. I\'m

taking it on faith that is true.

Certainly, if you look at the list of

symptoms that their patients present with when you

read their papers, that would appear to verify the

fact that their challenging everyone or nearly

everyone.

There definitely are clinicians in both

Europe and the United States who do not choose to

challenge subjects who have had life-threatening

reactions in the past.

As I alluded to in my comments, I think

that it would be very good to know what percentage

of the referral patients fall into that category.

I mean, we have heard from the parents of some of

those children this afternoon.

I have to respect the clinical judgment of

280

those physicians. If they don\'t feel comfortable

doing the challenge in their office, then that is

the way it ought to be.

It is only the specialized clinics that

challenge these severely affected ones. However, I

don\'t know what percentage, even of these referral

clinics, are excluded from challenge. That it

discoverable, it is just that the question hasn\'t

been asked.

CHAIRMAN DURST: Soheila.

DR. MALEKI: Just a quick comment. I

think there are still some clinics, of course like

you said it would be wonderful to know the

percentage, of the clinics that do this type of

work and the percentage of the allergic

individuals.

I do know some clinics and especially

hospital settings and research places that do

actually challenge people that do have anaphylactic

reactions as well. Particularly in like one of the

anti-IgE studies, I know that they used patients \--

(Simultaneous discussion.)

281

DR. TAYLOR: In the immunotherapy studies,

I should have pointed that out, were these anti-IgE

studies, the Tannock study and others. They have

tried to actually enroll people who have very

severe peanut allergy into those trials. They

wanted to find out if the therapy had any benefit,

and that would be the best group to make that

judgment.

CHAIRMAN DURST: Okay. Any more questions

for Dr. Taylor while he is up there?

(No verbal response.)

CHAIRMAN DURST: No? Okay.

Yes.

DR. BRITTAIN: I have just kind of a

big-picture question. Is that appropriate now?

CHAIRMAN DURST: Sure.

DR. BRITTAIN: It is going to more a

comment. It is really hard for me to think about

this without defining what the goal is of the

threshold is in very precise terms. Are we talking

about a threshold where only 1 in a 1,000 of very

sensitive people would react? Are we talking about

282

a threshold where 1 out of 100 all allergic

patients would react? Without specifying that, it

is really hard to talk about what the threshold

should be.

CHAIRMAN DURST: Yes. Well, there again

we are not talking about what the threshold should

be, it is how to best determine it.

DR. BRITTAIN: I don\'t see how you \-- I

don\'t mean the actually \--

CHAIRMAN DURST: Value?

DR. BRITTAIN: Yes, I don\'t mean the

value. Like, later on when we talk about

uncertainty factors, I don\'t see how you would go

through that exercise without establishing what

your goal is of the threshold, not what the

threshold value is. I don\'t know whether we should

ask the FDA that or\--?

CHAIRMAN DURST: Steve, can you address

that or\--? Steve is in consultation.

(General laughter.)

DR. BRITTAIN: It just strikes me that is

the first step.

283

CHAIRMAN DURST: Yes, in some ways this is

like a bootstrap operation. How do you get to a

level without knowing what the level is?

DR. GENDEL: This is Steve Gendel for the

record. I guess all I can say is we are not at a

position to really address the question that you

have raised.

In the terminology we use, that is

considered a risk management decision that would

take into account the scientific information and

the kinds of analyses in these reports and other

factors in making that decision.

Right now, we are simply interested in

trying to identify the approaches that could be

used. Once a decision is made on whether to

establish thresholds and which approaches to use,

then we would be in a position to get to the kind

of specifics that you are asking for.

DR. KELLY: Let me ask a related question,

then, if I may. Assuming that whatever

methodological approach one took, one would arrive

at a certain threshold level where it would be a

284

0.1 or a 0.01 percent risk of a significant event.

There will still be individuals who fall

outside because of being highly sensitive, because

of their situation at the time, unpredictable

events that are outside of the curve or at the very

far end of the curve.

Is there a mechanism to also accommodate

those events or to gather information about those

events in an anecdotal way? Can that ever be

considered to be part of the methodology? For

example, for drugs we have reports, very rare

events, of drugs.

People make reports, and at certain points

the reports mount to the level where there is a

pattern. We may only be talking about 12

individuals, but 12 individuals who died, and a

drug may be taken off the market. Have you

considered any approach like that?

MR. GENDEL: I think that is one of the

things that we have asked you to discuss, so I\'m

just going to turn that question back on to you.

(General laughter.)

285

MR. GENDEL: We would like your input on

how we should go about thinking about those

questions.

CHAIRMAN DURST: Yes. I think it is

farther down the line where we have to \-- and

probably this Committee won\'t do it \-- I believe

EPA, for example, uses the term \"acceptable risk,\"

an with these parents behind us I am sure none of

them would say that there is any acceptable risk,

that this has to be very safe for everyone.

In reality there is the economics and many

other considerations that come into this. Again,

this is not something that we have to consider

during our deliberations today, but we want to get

into the approaches that are. DR. GENDEL: The

one other point I think I would like to make, as I

mentioned, one of the things that we are trying to

do is to evaluate the advantages and drawbacks data

needs of each of the approaches. Clearly,

questions like that are relevant to making those

evaluations.

CHAIRMAN DURST: Carol.

286

DR. WASLIEN: Carol Waslein. I would

think any kind of approach should include a

mechanism for establishing new methods, new

guidelines once data becomes available \-- not just

saying once data becomes available but some kind of

mechanism that says \"Now data is available.\"

Whether that is effects or symptom reports

or it is the results of clinical trials that are

underway or whatever that is, it might be that our

stance or position here is to say \"Do this when

this becomes available, do this when this becomes

available.\" This would set up a system for

evaluating ongoing cases, for evaluating data that

must be available in the trials but was never

reported. That could be part of our approach.

Because the approach gives us a choice of

four, and I personally like choices of 1.5, 2.5 or

a combination thereof for the approaches because it

says go back and look at safety data.

Well, can\'t you set a standard based on

existing safety data now and not have to go back

and look at it, if safety data exists? You use a

287

combination of approaches and a mechanism that also

says at a given time we will go back and look.

When a certain amount of test data becomes

available, you go back and change it.

CHAIRMAN DURST: Yes, Suzanne.

DR. TEUBER: I actually have a question

for Sue, for Dr. Hefle, and this relates to the

fact that in the data that has been presented on

LOAELs and NOAELs, of course most of these

challenge studies were done in diagnostic settings

where, as you were pointing out, not all of the

patients with severe, severe, life-threatening

allergy would have been included at all; they would

have been excluded.

When you have been involved in some of

these threshold studies that are designed for this

purpose of safety assessment, some of the studies

that were mentioned like Dr. Wensing was the lead

author on, in those situations then the studies

were stopped with the subjective symptoms before

any objective sign.

This actually would bring up the fact that

288

the studies that you are involved in would add a

number five approach, because it would be a

modification of finding three of the safety

assessment approach.

Right now, it is written as a suggestion

to use objective signs for the LOAEL. The data

that you have, you have actually been able to

recruit more patients with a history of severe,

life-threatening reactions.

It seems to me that if we were to suggest

yet another approach, the one that you have

outlined may be very appropriate. I am wondering

if you can comment on the recruitment of these

patients to us? This might help address this great

concern that people with severe anaphylaxis aren\'t

included.

I\'m thinking that the adults that I know,

I have hundreds of adults with severe,

life-threatening tree nut allergy. They are eager

to participate in threshold challenges, if they

know that it would be stopped at their first

symptom of any tingling in the mouth. That is

289

their usual symptom in the real world. They would

be happy to participate. I think I would like to

hear more about your recruitment.

DR. HEFLE: Well, I have to give a lot of

recognition to my European collaborators, because

I\'ve got to say that this is way easier to do in

Europe.

They have patients beating down their

doors to do this that are severely allergic, even

parents offering their children up because they

have a greater sense of the greater good over there

in comparison to American people I think in the

later respects.

They will have a lot of recruitment. It

is easy to recruit because they are told exactly

what will happen and they are told exactly that

they will stop with these mild reactions.

Now, Dr. Wensing, they made a decision

that they were going to stop at that level, but not

every physician makes that same decision. I just

let the physicians make the decisions. I don\'t

have patients, so I\'m not qualified to make those

290

decisions as to when to quite a challenge.

Actually, the people that do participate,

we have found in the last couple of years that they

find thresholds beneficial to their day-to-day

maintenance.

Carsten Bindslev-Jensen will give talks

about how he uses thresholds in educating his

patients. He says he has two patients with the

same IgE levels and things, same size skin tests,

one can eat half an egg and one can\'t have any at

all. The advice you give is much different and the

restrictions you can have in one versus the other

are much different.

We see more and more people actually

seeing if they can be in these challenges and

wanting to do them and feeling pretty comfortable.

Now, that is not to say it is necessarily really

easy to go find 300 people to do this and

especially for soy and some of the other allergens

where we have a challenge.

However, we have gotten some fairly

severely allergic people to participate. They felt

291

comfortable but they have to feel comfortable with

their physician and comfortable that the right

precautions are taken. I can understand why

someone would not want to do this.

Yes, it is really individualistic as to

when the physician is going to stop. As a

physician, I\'m sure you can understand when you

make that kind of judgment call, too. It is based

on years of experience and thousands of challenges,

and not everybody is comfortable doing that.

I hope I\'ve kind of addressed your

question. As I said, it is a lot easier to do this

in Europe. They seem to take the whole population

in there versus the United States.

Here, it seems much more difficult to get

people to do this, to make them feel comfortable

that this is going to be okay, and that they will

be able to go through it and not experience really

adverse reactions.

DR. TEUBER: I think it would be actually

easy to get people here. Like I said, I have

hundreds of people who have expressed interest in

292

this sort of thing with severe, severe allergy, but

it wouldn\'t be for a diagnostic challenge. It

would have to be in the research setting.

DR. HEFLE: Right.

DR. TEUBER: Therefore, it would be laid

out that it would be stopped at the most mild

symptom. This brings up another point, then. If

you stop at that mild symptom, can you trust the

results?

I believe in those studies they used two

active and two placebo for each. Are you familiar

with any data that that has not been a correct

assumption for stopping a challenge?

DR. HEFLE: I am not aware of any other

data that is an incorrect assumption. That was

their approach, and I decided to let them go with

it because they know better than I do.

Perhaps, other physicians with other

research would approach it a different way, but I

am not aware of any other data that would impact on

that or would show that is, indeed, the right way

to do it.

293

DR. TEUBER: I would just note for the

record, for those of you not involved with food

challenges, Dr. Allan Bock wrote an office manual

on food challenges that was published back in, I

think, 1978. In there for subjective symptoms, it

was suggested that multiple challenges be done to

make sure that it was a \"real reaction.\"

During the same setting period, once

somebody has had, say, a symptom of itching in the

mouth, then it would be blinded as to whether the

next challenge they had was again an active one or

placebo, but you would repeat this several times.

In practice, we use this for instance when

somebody is concerned that a headache may be

triggered by food, or it can be used in this

setting of coming up with a threshold. For

something like headache, it would have to be done

on multiple days.

Rather than just doing one active and one

placebo, there are multiple given. I am, again,

hopeful that the multiple challenges that were done

you could get more people as you did with severe

294

reactions to help establish a threshold.

DR. HEFLE: It would be nice. At our last

threshold conference in Majorca we had 20

clinicians who do this from around the world

sitting around. A lot of them felt that if you had

a subjective reaction, you actually should go to

the next one to get an objective reaction because

they are usually pretty mild at that point, too.

They felt as a group not every single time

that it might be a necessary thing to actually go

beyond the mild, subjective reaction when you are

trying to get a threshold study done. That was

kind of the consensus of the clinicians.

DR. TEUBER: Thank you.

CHAIRMAN DURST: Marc.

DR. SILVERSTEIN: I have a couple of

issues that I think are important to clarify our

thinking, but I\'m not sure how they would

specifically be addressed, so let me mention the

issues and then maybe you can see. It is related

to the whole issue of testing.

In clinical medicine, we often use tests

295

that are not perfect, but they are pretty good.

Some of the tests we use, the tests themselves are

not a gold standard.

If we want to test for anemia, we would

test for a hemoglobin and say we know what anemia

is because we define it by the absolute value of

the test. However, there are many other tests

which are for conditions that have some other

criteria for the diagnosis.

We can set a threshold for the test, and

we often do set a threshold. When we set the

threshold low, the test may be more sensitive and

less specific; and when we set the threshold high,

it may correspondingly differ.

It seems to me we have a choice with using

symptoms, subjective findings, and signs, objective

findings. With a symptom, we may be more sensitive

and less specific; and with a sign, we may be less

sensitive. Did we get that correct?

DR. TEUBER: Mm-hmm (affirmative

response).

DR. SILVERSTEIN: It may be less sensitive

296

and more specific. I believe that there is some

inferences we can make from the existing literature

about how a food challenge may perform as a

diagnostic test for the presence of food allergen.

The caveats and questions there, though,

Does the test perform in the general population the

same way it performs in the studies that are

published? Of course, it may or may not perform as

well, depending on whether there is some selection

bias.

To the extent to which published

literature tells what the selection was or the

reviewers for the report can provide that

information, we would be able to be more or less

confident that the tests and the inferences about

the thresholds are strong.

In that regard, some guidance might come

from the study I believe the Agency for Healthcare

Research and Quality funded a study to evaluate

systems for evaluating the strength of evidence.

I think Kathy Lohr and the Research

Triangle Institute was responsible for that. They

297

set sets of criteria questions to ask when looking

at a question that would be answered by a

randomized control trial, by a case control study,

a cohort study, or a diagnostic test.

I think the report might be strengthened a

bit if we could look at some of the criteria that

was proposed by that study for looking at

diagnostic tests.

As I looked at it, most of the issues that

they covered were considered by the FDA in the

report, but it might be useful to look at that,

which is out in the literature. It has been out

now for a couple of years.

The second thing I want to do is to

clarify our thinking from how a test may perform to

diagnose the presence of food allergy so that a

clinician and a parent or a patient can together

decide what is a course of treatment, from the

prognostic value of what would happen in the future

in the real world when the patient\'s family or the

patient tries to adhere to dietary restrictions.

The question we would have is, What is the

298

prognostic value of a positive or a negative food

challenge test? If, for example, we were to accept

either symptoms or signs as our threshold, in those

patients who are positive in symptoms or signs

reproduced and a diagnoses of food allergy is made

and the clinician says, \"This is what you should do

for your diet,\" what is the future risk and

occurrence of subsequent episodes of anaphylaxis,

since we know some of those patients will indeed

experience episodes?

In the patient who is reassured that, no,

they don\'t have a food allergy because they did not

react positively to a food challenge test, do we

have literature about how reassuring that is? In

other words, does the negative food challenge test

provide sufficient assurance of future risk for

those patients?

I suspect there is very sparse literature.

However, if there were some literature that looked

at long-term outcomes in food challenge test

positive and food challenge test negative

individuals, we might know whether the thresholds

299

used in the test for those individuals could be

used to set policy.

DR. TEUBER: I can partially answer that.

In terms of if somebody has a negative challenge,

you are getting back again to using food challenge

as a diagnostic measure not for risk assessment in

somebody you already know has an anaphylactic

sensitivity to foods. It is really kind of a

separate thing.

In that situation, we would do an open

challenge with the food as they would normally eat

it because what was used in the challenge setting,

and Steve Gendel did write about this, may not

reflect what is really consumed by the patient.

For diagnosis, it is still different than

having someone you already know who has anaphylaxis

to food. That is where I\'m thinking that the

possibility of using the subjective symptoms for

your LOAEL may be very reasonable, because we also

talked about how there are other factors that may

influence somebody\'s reactivity on a particular

day.

300

Asthma I think was brought up, alcohol,

inflammatories, exercise, even the time of year.

Some people may have more histamine-releasing

activity in terms of their mastocytes and basophils

after the spring pollinosis season, if they also

are highly allergic to pollen. Those factors could

go into that uncertainty factor.

If you then say that you are only going to

accept objective symptoms from the data, that means

a lot of Wensing\'s data on threshold would actually

have to be thrown out, because only 5 patients out

of the 29 or so actually had gone up to objective

signs.

This was one of the few studies where

because these patients were told, \"We\'re going to

be extremely safe, extremely careful, and we\'re

going to stop before you have anything severe,\"

they were able to recruit the people with

anaphylaxis that we want to protect by recommending

a safety assessment approach here.

I mean, that is why I keep bringing up

this issue about can we accept that for the issue

301

of safety assessment, if you have blinded

challenges that are repeated.

I think it is a really different issue

than diagnosis and different than the performance

of food challenges as how reproducible they are.

I\'m not enough of an epidemiologist or a risk

assessment person to go into that. I\'m looking at

this from the patient care viewpoint. Does anyone

else want to elaborate? Actually, anyone out there

can, too.

DR. SILVERSTEIN: Well, so let me ask,

then, if we were to use symptoms, which is more

sensitive, and you had an individual whose parents

and the physician recommended a food challenge and

the food challenge test was negative, no reaction

or symptoms, and you knew what the threshold was,

then that would be sufficient to make

recommendations, or then the person might get an

open food challenge?

DR. TEUBER: I\'m sorry, that person would

actually not have a negative challenge because,

again, to be included in a database that would be

302

adopted by the FDA for determining a threshold, the

person who had a negative challenge in the studies

would not be included.

See, you have to be getting up to a

response, either a subjective response that is

reproducible or to something objective, lip

swelling or nausea or vomiting or something else.

You wouldn\'t even include that individual in your

evaluation.

DR. SILVERSTEIN: There would be a

population of food allergy patients who may have a

negative test but might yet have the diagnosis of

food allergy?

DR. TEUBER: Again, they may be someone

who has developed tolerance now, and so they would

be challenged openly for food as they would

normally eat it. If they can eat that, then they

no longer have a food allergy. Or, they may be

somebody with a special situation such as

exercise-induced anaphylaxis that is food

associated where they only have a reaction in a

certain context.

303

CHAIRMAN DURST: Comment?

MS. HALLORAN: I think that Dr. Teuber,

though, is getting to an important issue, which is

a concern that I had listening to all of this

testimony, which was that the repeated issues as to

questions that the data on LOAELs and NOAELs just

is not that good.

It is better for peanuts and eggs and

milk. However, in the other categories, though,

everybody was saying that the data is really not

sufficient. I\'m interested in Dr. Teuber\'s

suggestion of actually recommending to FDA that

possibly they could conduct some research to

establish NOAELs and LOAELs. She proposes a

methodology that appears to possibly get around

some of the medical issues.

DR. TEUBER: None of this is my proposal.

This is all proposed by people already doing it.

Again, a lot of these studies are underway right

now. I take absolutely no credit. You are looking

at some of the people over there who are doing

these studies.

304

It is just that the studies designed

specifically for this issue, there area a few that

have been mentioned that were done in this way or

they are underway right now.

There hasn\'t been any funding to do them.

For instance, for tree nuts there is only one on

hazelnut, and none of the other nuts have been

addressed at all. We see Dr. Hefle nodding her

head over there.

Again, just to be recommending some

approaches right now, I think a hybrid approach of

a 3.5 of accepting the LOAELs for some of these

subjective reactions might be very reasonable, but

then I guess some other methods will have to come

in for those foods not covered at all.

MRS. MOORE: I\'m sorry, I want everybody

to remember to say your name.

DR. TEUBER: Oh, I forgot to say my name.

Suzanne Teuber.

MS. HALLORAN: Jean Halloran, sorry.

MRS. MOORE: Okay. For the transcriber,

she can probably pick it up with the voice. Okay,

305

do you remember to say your name.

DR. TEUBER: I\'m sorry.

DR. KELLY: Just a follow up briefly.

CHAIRMAN DURST: Your name?

DR. KELLY: Ciaran Kelly, sorry. A brief

question about this issue of positive result on

challenge or maybe more specifically a negative

result on challenge. Then, it is frequent that

there would be a real life challenge with regular

food?

DR. TEUBER: Yes.

DR. KELLY: How often would the real life

challenge would be positive where the laboratory

clinical challenge was negative?

DR. TEUBER: That sort of data is, indeed,

in the literature and in some of the literature

that Dr. Gendel has cited here, some of the

follow-up studies by the Johns Hopkins group.

Unfortunately, that statistic is not on

the top of my head, so I would be venturing, but

certainly there are folks \-- and in Dr. Bock\'s

series as well \-- who tolerated the dehydrated food

306

in challenge and then reacted upon eating the real

deal. I can\'t give you a percent.

Again, those folks would not be included,

their data would not be included for this sort of

risk assessment that we are really trying to decide

on approaches for them here today.

DR. KELLY: It clearly speaks to the

validity of one of the tests that they\'ve used to

establish a threshold.

DR. TEUBER: Again, the people that would

be used \-- this is Suzanne Teuber again \-- the

people who would be, hopefully, enrolled in studies

to establish a threshold would be those who very

clearly have had anaphylactic reactions or a range

of reactions that very clearly is to the food in

question and where a diagnosis has already been

established. It would not at all be to use just

data from diagnostic challenges.

A diagnostic challenge, I think most

people would want to go to an objective sign when

you are trying to figure out a difficult case,

like, is it sesame or was it the peanut in the

307

Asian food in this 34-year-old who has a new onset

of allergy?

You think it\'s probably sesame, because

most peanut allergy has its onset in childhood, but

you would really want to be sure because that

really determines which food is this person going

to avoid, sesame or peanut.

In that case, as a physician, I would want

to go for a mild, objective sign rather than

stopping for a symptom. Again, that is a different

issue than trying to give advice to the FDA of

which approach to choose for labeling.

CHAIRMAN DURST: Yes.

DR. MALEKI: Soheila Maleki here. It

seems to me like with all of the methodologies that

have been outlined in this report that everybody

seems to be looking at or interested in the

threshold of those studies.

I think it is pretty much a consensus out

there that the threshold dose studies need to be

done, and that would be the practical approach to

go about determining this somewhere down the line.

308

That seems to be the most important I think to

establish as far as the patients go.

On that line, I would like to ask

Dr. Hefle if she could tell us how they would go

about this and how long does it take?

I think it seems like, and of course this

is my opinion in this case, that before you can

take any methodology to determine, say, \"Okay, this

is the limit of detection of our analysis,\" well,

our technology is so high that our limit of

detection can be down to 1 molecule.

In other words, you can probably find

peanut dust on this (pointing) tablecloth, if you

wanted to. Therefore, at this level we can\'t say

the limit of our detection is going to be what is

going to establish this. It is going to have to be

human studies.

DR. HEFLE: You are asking about your

average threshold study? How long does it take?

What is required?

(Simultaneous discussion.)

DR. MALEKI: Yes, how long does it take

309

and how much money.

DR. HEFLE: Yes.

DR. MALEKI: How do you get the money?

what do you do? what is limiting? and so forth.

DR. HEFLE: Nowadays, 29 patients for an

allergen you can find pretty easily like peanuts,

at least \$200,000 U.S. dollars. That primarily is

clinic cost and hospital cost.

The hospitals are charging more. They

have costs. They have to have a crash cart ready;

they have to have nurses ready; they have to have a

lot of things ready. Therefore, in most cases, we

do this in research centers, so a lot of that is

clinical cost. That is the vast majority of it.

We have to make standardized materials and

send these to everybody. We have to find the

patients and make sure they are the right kind of

patients.

For something like soy, it is one of the

\"Big 8\" allergens and there are a lot of kids out

there allergic to soy, but they are all mostly

infants.

310

To find 29 soy-allergic people, which we

are trying to do right now, for our soy threshold

study is pretty daunting and we have to go to the

ends of the earth to try to do that.

It can take from concept to actually

getting the challenges done and getting through the

ethics board, maybe two years. Depending on the

ethics board you are dealing with, they might take

six months to get an approval; it is very

individualistic.

Denmark has got two ethic boards they have

to go through, so if we hope to get any patients in

Denmark, they\'ve got to go through twice as much

and get translated in Danish and all sorts of extra

things.

But even just developing the food vehicles

in a double-blind manner and doing the sensory

analysis in the studies we need to make sure that

it is truly blinded and available to clinicians.

To test 29 patients can take easily 6 months to a

year to develop the correct vehicle, choose the

right representative food to use. It can easily

311

take two years even for a really great allergen we

can find lots of patients for.

Then, the funding, there is no

governmental funding for this to date. All of the

funding to date for threshold studies, I\'ve gotten

a little bit of USDA. Steve and I have gotten a

little bit of USDA funding out of this. The food

industry has paid for the majority of these studies

to date because they really want the answers, so

that is where the funding comes from.

It is kind of difficult for them to

identify funding for this, too, rather than just

throw \"May Contain\" labeling on the products. You

know, what is the choice here? For some companies,

it is easier to say, \"I\'m not going to cough up

\$50,000 to help you. I\'m just going to put

labeling on my products.\"

We have gotten a lot of support from the

food industry, and we are moving ahead as best we

can. It has been kind of slow in getting this data

out. We need a consensus protocol before we can

move ahead.

312

There are some centers in Europe that are

choosing to go ahead and do some threshold studies

and kind of work that in, if we provide the

materials, as they can without having a huge amount

of financial support from us, as they can work it

into their patients, if they are truly interested

in it.

For a specific study, it probably will

take at least two years for any one allergen and at

least \$200,000. Those costs are just going to

continue to go up. One clinical investigator that

I like to use a lot in Europe just told me that now

they are required to have insurance for the study,

and that is only going to be \$10,000 U.S. dollars

for this one study. And that is only for about

three patients. We will have to do another \$10,000

the next time we want to do a threshold study. It

is getting more and more costly to do.

CHAIRMAN DURST: This is Dick Durst. I

would just like to pick up on one comment that

Dr. Maleki made concerning the sensitivity of the

analytical methods. It is true that for a great

313

many of the allergens we are talking about, we can

get down to very low levels.

We don\'t want to get into the situation

that we had with the Delaney clause with

carcinogens. At one point you set a level based on

the state of the art, which may have been parts per

million, and the law says, \"Well, as much as you

can trace or detect, that is the limit.\"

The analytical methods got better and

better, and it got to parts per billion and

trillion and quadrillion. Therefore, the

analytical methods, per se, probably are not the

way we want to establish a threshold. However, you

do need the analytical methods, then, to verify

that the foods that the thresholds are set on

actually conform to it.

I think, again, we have to keep going back

to these challenge methods, you know, the actually

biological studies to set the threshold, and then

the analytical methods can provide the validation.

DR. MALEKI: Soheila Maleki. I agree with

you a hundred percent that we definitely need the

314

analytical methods once the thresholds are

established or a range is established in order to

determine if we can comply with that \-- in other

words, compliance \-- but I don\'t think that alone

they could be used in that way. Since, as you

instructed, we are supposed to be evaluating some

of these methods, that is the point I was making.

CHAIRMAN DURST: Marc.

DR. SILVERSTEIN: Marc Silverstein. I

would like to follow up on the \"N\" equals 29

patients for a modest size study. That would be

assuming that the hypoallergenic formula, or a

percentage of 10 percent, was an appropriate

prevalence of a reaction in the population of

generally allergic individuals that you are

testing.

However, I think we need to say \-- it is

different for us to say that we believe that only

10 percent or fewer than 10 percent of patients

like those tested will go on to experience an

episode of food allergy, which could be of very

different severity even if only a third were

315

severe.

I think we need to say the sample size in

power calculations to have meaningful assessments

are as a risk that is probably important to

patients would be much greater, orders of magnitude

greater.

In Dr. Luccioli\'s handout, there is a

slide where the top row is 10 percent, which then

equals 29 for a 95 percent confidence interval.

The bottom line, as I can read it, is \"1/5,000\" or

\"1/10,000.\" We might want to have very high levels

of confidence, more than 95 percent, if the true

rate may be less than 1/1,000 or 1/10,000 who would

have such an event. I do think that you are being

very optimistic, and even so will just be confident

about a rate of 10 percent.

CHAIRMAN DURST: Okay. Petr and then

Margaret.

DR. BOCEK: Petr Bocek. I have actually

one question and one comment. Regarding the

analytical methods, I absolutely agree that we do

need them. We talk about 1 part per billion or

316

million. What is that part?

I would like to know the analytical

method. Does it relate to the major allergen,

let\'s say, RH1/RH2, polyclonal serum ELISA? What

is the physiological relevance? I\'m missing that

point as far as the analytical methods.

DR. HEFLE: Well, the analytical methods

were not originally designed to find the allergens.

That wasn\'t the purpose of the food industry. They

wanted to find out, Do they have peanut, or do they

not have peanut? It is claimed? Is it not

claimed? In that case, then, it is not necessary

and when we are designing these to look for the

allergen specifically.

In addition, not every allergy is known

for every food yet, either. If you target just

one, you could miss the rest of them. The approach

that has been very successful is to use polyclonal

serum, a more crude extract in general, and they

seem to work very well at picking up peanut/no

peanut.

The parts per million varies from kit to

317

kit as to what it really means. It can mean parts

per million peanut, which is the whole food. What

does that mean? It can mean peanut butter or

whatever.

In some cases, the companies will say that

means part per million peanut protein. What that

means is the soluble proteins from the peanut that

can be detected in an aqueous situation. That is

one of the debates about what these numbers mean

when they are crunched out at the end. What is it

expressed in? How do you relate that to other test

kits? That is a challenge. However, they are not

specific for the allergens.

CHAIRMAN DURST: Petr.

DR. BOCEK: Petr Bocek again. There was a

comment, which was a clinical comment, which

relates to point number three on the food allergens

of the charge, which is basically asking whether if

we have any specific data for one of the major

eight allergens, if it can be easily transferrable

to others.

Obviously, that is not an easy answer, but

318

we know from clinical studies as far as development

of tolerance, outgrowing actually a food allergy,

there are significant differences between these

eight groups, specifically peanut stands out.

Frequently, kids who outgrow peanut

allergy, which current studies show it is up to

about 20 percent, still retain their high levels of

specific IgE, which is absolutely not true for milk

and egg.

At least as far as development of

tolerance we can be certain there are differences

between these eight allergenic groups, and it may

also apply to thresholds of these eight allergenic

groups.

CHAIRMAN DURST: Erica.

DR. BRITTAIN: Hi, this is Eric Brittain.

Back to the sample size. I guess obviously there

is a concern with the 29. You are very limited in

the statistical conclusions you can draw. I think

the presentation that talked about the modeling may

be the way to go if you are wanting to rule out

very, very small rates of reactions. I don\'t see

319

any other way to allow very, very small risk.

CHAIRMAN DURST: David.

MR. ORYANG: Yes, David Oryang. Can you

stay there, please?

(General laughter.)

MR. ORYANG: Yes, I\'m just going to back

to this just briefly. You mentioned that detection

levels should be tied to threshold levels in your

presentation earlier. Until the threshold levels

are determined, we need to know what the detection

levels are in order to determine threshold levels.

However, this analytical methods-based

approach I am just wondering whether there have

been any studies that have looked at the detection

levels, taken the detection level, let\'s say,

2.5 parts per million for peanuts and then taken

it, whether it is peanut butter or a whole peanut,

and at that detection level maybe looked for a

specific protein within the peanut that an

individual reacts to?

You take that detection level and you

design your study and challenge people at that

320

really low level and increment from that point as

opposed to increment from a much, much higher

level. I don\'t know whether there are any studies

that have done that and whether there have been any

results that have shown any positive results?

DR. HEFLE: There have been no studies

that have started out at a detection level for a

commercial study and then decided to challenge at

those levels. That decision has not gone from that

aspect of it.

When we sat around and thought about the

consensus protocol, the levels were designed to try

to incorporate what we felt were good starting

levels and lower starting levels than normal.

When you calculate from those levels \-- we

came up with starting at 10 micrograms or starting

at 100 micrograms, which 100 micrograms is kind of

a magic number that has been used out there for

subjective symptoms reported as causing subjective

symptoms in peanut-allergic people \-- when you

calculate what you can detect, then 100 micrograms

is appropriate in the detection limit of the

321

assays, around 10 parts per million or so.

Where those subjective symptom numbers

lie, the test kits can easily do that level. Right

now, actually they are better than that. However,

no one has designed a study to actually see if the

detection limits are protecting human health at

this point. We think that they are lower than what

they need to be, but we\'ve never designed a study

that way.

MR. ORYANG: Okay. David Oryang again.

Just following up on that, I see the

analytical-based approach at least beginning to set

some of those lower limits. If industry has

already looked at these things, there is some value

in at least starting there and then adding on with

some of the other methodologies the challenge test

to really find out whether people react and

starting to understand the dose response.

Why I\'m talking about these analytical

methods-based approach, I think it has implications

on other allergens that have cumulative effects as

an example.

322

DR. HEFLE: I\'m sorry? Other allergens\--?

MR. ORYANG: That have cumulative effects.

DR. HEFLE: I\'m not as good a person to

ask that question of. I guess I would point to one

of the physicians.

DR. TEUBER: Suzanne Teuber here. Yes, in

a situation of disorders like chronic atopic

dermatitis, there may certainly be effects from

small doses ingested.

(Simultaneous discussion.)

MR. ORYANG: Small doses?

DR. TEUBER: Yes, you have exacerbation.

Some of the challenge studies that are in the

literature, actually symptoms don\'t show up for

three days to seven days. That is also true with

some of the gastroenterological disorders, it may

take a little more time.

CHAIRMAN DURST: Yes.

DR. NELSON: Mark Nelson. I just wanted

to make sure we understand what we are talking

about when we mention the analytical approach or

the analytical method.

323

As I read it, it reads that we would set a

threshold based on whatever we can measure in a

validated way, and then next week if we can measure

something 1/10th of that, then that is the new

threshold. It is not necessarily connected with a

reaction or a lack of reaction.

MR. ORYANG: Yes. David Oryang. Yes,

that is true, and that is why I am not saying that

they should be used to set the threshold levels.

I\'m just saying that this should be a starting

point I believe that will enable more studies to be

done, the challenge tests, and so forth. I think

it is a good starting point, if that is the only

thing that one has.

DR. NELSON: This is Mark Nelson again.

That raises a question I wondered, Sue, if you

could clarify. You mentioned 100 micrograms was

the magic number for a challenge test, and then it

was equated at 10 ppm in the test. Was that 100

micrograms of peanut, or 100 micrograms of peanut

protein versus 10 micrograms of peanut, or 10

micrograms of peanut protein?

324

DR. HEFLE: I\'m going to pass that. I\'m

going to pass that to Dr. Taylor.

(General laughter.)

DR. TAYLOR: When we published the

\"Threshold Paper One,\" 10 parts per million is

10 milligrams per kilogram. If we then assume that

the serving size for the food is 100 grams, and we

could have a whole day\'s debate on serving sizes

for food, but if we did that, then that is one

milligram.

DR. NELSON: Gotcha.

DR. TAYLOR: If we look at the clinical

threshold trials that have been done, 1 milligram

is in the neighborhood of where the most sensitive

individuals that have been reported have the onset

of these mild, objective reactions.

Therefore 100 micrograms, where the

subjective reactions have started in some of these

studies equates to 1 part per million, which is

about the lower detection limit of some of the

analytical methods.

That is why we think that the analytical

325

methods are pretty much in the order of magnitude

of sensitivity that they need to be because of what

we do know about threshold doses.

If you get below the limit of detection in

one of these analytical methods, you can be

reasonably certain as a food industry that you

don\'t need to declare the presence of milk or

peanut or whatever it is on the label of that

product.

CHAIRMAN DURST: Doug, did you have

something?

DR. HEIMBURGER: Yes. Doug Heimburger. I

don\'t know if this will shift the discussion, it is

a little bit related but not entirely. With regard

to the question raised by Ms. Atagi, the first

person that made public comment, urging FDA to

consider sensitization as a possible endpoint of

concern, how much is known about sensitization?

Are there levels that can be associated with

sensitization as opposed to not? This may be for

Suzanne or anyone else. I don\'t know, maybe you

can dispense with it quickly, and say we know

326

nothing.

(General laughter.)

DR. TEUBER: Yes, you see my smile and I\'m

shaking my head. Oh, gosh, there is a vacuum here.

There is great concern that there is sensitization

via breast milk. There is concern that in some

cases because of first-exposure reactions as a

neonate with first feeding that there has been

sensitization in utero.

There is concern about cutaneous

sensitization. This is an area of tremendous

research right now of just the environmental

presence of peanuts causing sensitization

transcutaenously in kids who do have atopic

dermatitis or some breakdown in the skin barrier.

In terms of the amount that causes that \--

oh, my goodness, yes, I can say that we just are

not there at all to be able to make that an

endpoint.

DR. HEIMBURGER: Okay.

DR. TEUBER: It is a wonderful point that

she raised, but I don\'t think we have the science

327

to be able to do that. Again, this is Suzanne

Teuber.

CHAIRMAN DURST: Petr.

DR. BOCEK: Petr Bocek. Just a comment.

Probably if you draw blood on all of us sitting

here and do a RAST for the eight major allergens, a

number of us will have, I don\'t know, 3 kilo units

per liter to various allergens.

We eat those foods, and we are completely

fine, but we are sensitized. It is very difficult.

That is why the RAST is always something what has

to be considered with the clinical picture.

The \"sensitization,\" first of all, how do

we define it? We define it by level of specific

IgE, if we talk about immunohypersensitivity.

Then, we have to go what is the level when we say

that we are sensitized? Is that more than zero of

the CAP/RAST that Pharmacia has, let\'s say.

Sensitization is not really practical, I think.

DR. BOCEK: It is not practical?

DR. TAYLOR: It is not because if you

define it a RAST to some extent without any

328

clinical histomorphology, what does it mean?

DR. HEIMBURGER: Right. Doug Heimburger

again. Are you saying that because we would find

that all of us had specific IgE to various ones of

these allergens but we wouldn\'t have had any

knowledge of how much exposure we\'d had, therefore

we wouldn\'t know what doses had been required or

what exposure levels had been required to create

the sensitization that you pick up in the RAST

test?

DR. BOCEK: Petr Bocek again. Well, as

far as the exposure levels, anybody with a regular

diet is exposed to tons of major allergen groups.

DR. HEIMBURGER: Right. Right, so you

couldn\'t set a threshold in that case because we

have been exposed to a lot and perhaps we have

developed a little bit of specific IgE.

DR. MALEKI: Again, Soheila Maleki. There

are still theories out there about low-dose

exposure kinds of sensitization at an early age and

others say high-dose exposure is protected.

High dose frequently is protected, and low

329

dose at low frequency or intermittent, that is

sensitization. Right now, all of this is being

challenged, and it is all theory, so there is

really not much speculation about determining a

threshold for sensitization because we really have

no idea how it happens in the first place.

CHAIRMAN DURST: Petr.

DR. BOCEK: Petr Bocek again. Just in

connection to that, there were current reports by

Gideon Lack\'s group from the Royal College for

London where they looked at kids in Israel and kids

in England and looked at peanut allergy.

Surprisingly, there is about more than an

order of magnitude lower peanut allergy in Israel

than in Europe. One of the possible reasons, which

is now being intensely investigated, is the fact

that Israeli children, Jewish children, have early

exposure to high doses of peanut protein through a

snack called Bamba, which basically since most of

them starting at six months of age start sucking on

it and eating it and eat basically 2 full grams of

peanut protein a week.

330

There is certainly high-tolerance probably

happening, and it is currently in a clinical trial

by Gideon Lack in London looking at that.

DR. BRITTAIN: I haven\'t really heard

anybody talk about this, but just because something

is a serving size doesn\'t mean somebody is going to

eat just one serving size. Someone might eat 20

cookies. It seems like that should be taken into

account. If something is labeled essentially by

the absence of saying it has peanuts in it or

whatever, people may think it\'s safe and then they

eat 10 servings worth. That should be taken into

account.

CHAIRMAN DURST: David.

MR. ORYANG: Yes, David Oryang. Just

going back to methodology, just briefly, the

analytical methods-based approach. The issues that

FDA has put before us here that need to be

considered when using analytical methods-based

approach.

Just touching on one of those issues, I

don\'t know whether Dr. Taylor could comment on

331

this, if anything has been done, but someone had

earlier brought up the issue of sensitivity and

specificity of the methods and of the kits, the

fact that there were varied kits and a lot of them

hadn\'t been specifically validated. Are there any

that you know the specificity of and the

sensitivity? Is this standard published before you

start using the kits?

DR. HEFLE: Well, these are proprietary

products, but when people ask questions

manufacturers are glad to provide things that

aren\'t apparently trade secrets. They will provide

manufacturers and others with information on

cross-reactivity.

You can get tables from them. They have

done all of this. If you ask for it, you can get

the data. It is not something they put in the kit

inserts that the average person pulling off the

shelf can read about all of the cross-reactivity,

so they test out with a matrices.

There is specificity and sensitivity known

and cross-reaction amongst things, but I guess you

332

have to call the manufacturer and ask the

questions. Some people aren\'t willing to do that.

They expect it to be out there and everywhere.

That has been one of the hurdles in getting people

to just call and ask.

For most of the companies that I know of,

they are willing to share this information with

somebody that is truly interested and not just

looking for trouble. That information should be

available from the manufacturers, to my knowledge,

and be available from the government, too.

MR. ORYANG: The methods have been

validated by the manufacturers?

DR. HEFLE: Yes. By the manufacturers,

yes.

MR. ORYANG: Okay.

DR. HEFLE: The only validation that

hasn\'t really been done in a lot of cases is in an

interlaboratory kind of trial to make sure that it

performs the same way in different \-- that is

pretty much the way I understand the validation

that needs to be done.

333

MR. ORYANG: I see. Is there any move to

do that or\--?

DR. HEFLE: There are lots of efforts

going on around the world not so much at FDA right

now, although I know they have been working on as

best they can, given the budget that they have.

Yes, if we could get past this validation,

I think everybody could be comfortable that we

could use the methods for a lot of different

things. It is already being used and being

validated in other parts of the world. Germany has

their own system.

They do their own validations. They do

ring trials to get it done, and they use it. I

think we just need to get some more of these

international trials done. There are efforts.

Again, that takes money and time and

materials and reference materials, too, which is

why some of this has not been done yet. There is

no funding available to do these. That is a pretty

substantial amount of funding to run one of these

and coordinate one of these, so that is not

334

inconsequential.

CHAIRMAN DURST: Pat.

DR. CALLERY: Pat Callery. To follow up

on that, it looks like there will probably be some

good advancements in this area. The concern about

sensitivity and specificity comes in part from the

comment I think I heard a few minutes ago, that in

fact this test is related to peanuts rather than

the allergen itself. The specificity might very

well be to deal with the specific allergen.

In our writeup that we were given, in the

preliminary information, there is one reference by

Shefcheck that is on the confirmation of the

allergenic peanut protein, Ara h 1, in a model food

matrix using liquid chromatography/tandem mass

spectrometry.

This is a technique that is incredibly

sensitive and specific, and if they can look for

the specific protein, I think that there will be

great advancements. I think the method was not

supported much in the writeup, because it is a

potentially expensive, time-consuming method, but

335

it has a chance of providing the information that

we are after.

DR. MALEKI: Soheila Maleki. One,

manufacturers as well as consumers wouldn\'t really

necessarily care if there was a specific allergen

in there. They just want to know if that food is

in there. Particularly, the different allergens

and the different proteins interact with different

processing in different ways.

For example, Ara h 1 becomes highly

insoluble in the case of roasting. You can\'t test

it if you are just testing for that. You have a

much better chance of detecting peanut protein or

something in there if you are actually targeting

the peanut protein, in other words, you have much

more sensitivity. You have really high specificity

to detect small amounts.

Now, if you had large amounts of something

else in there that it possibly would cross react

with, then you would get a non-specific response.

However, when you have small amounts and you are

trying to detect trace amounts, in that case

336

cross-reactivity is very rare. I don\'t know if

that helps.

DR. CALLERY: Pat Callery. If you are

trying to set a value, it is best to look for a

single entity that is not going to be changed from

matrix to matrix.

DR. MALEKI: That is a good idea, but it

won\'t work because those individual allergens will

change from within one matrix to another. Like I

said, you have a much better chance of detecting

them, if you can detect multiple proteins rather

than just one.

That way if it is there, you will always

know. Even if Ara h 1 doesn\'t go in the solution

or Ara h 2 falls out of the solution or is broken

down, you still have a chance to say, yes, there is

peanut there. There is less chance of error,

actually. That is pretty much well known within

the industry and the manufacturers.

CHAIRMAN DURST: Yes.

DR. KELLY: That brings me to another

comment or question.

337

CHAIRMAN DURST: Name?

DR. KELLY: Ciaran Kelly.

(General laughter.)

DR. KELLY: Ciaran Kelly. That is, the

issue when we are talking about validation of

assays, we also need to consider standardization of

assays. They are not quite the same. Someone may

have done a lot of work to validate and demonstrate

that their assay measures what they say their assay

measures.

However, we also want to be in a world

where if different assays are being used, they can

be cross referenced. I think that is very

important.

There are also important methodological

considerations there, particularly when we are

talking about polyclonal reagents. That is

something that I think also needs to be addressed,

because ultimately it is likely that those assays

will be used to measure whatever threshold levels

are being used.

CHAIRMAN DURST: Dick Durst. Along

338

similar lines, the matrix effect is one of the most

serious problems I think with these assays. The

assays in buffer solutions, and so on, can show

tremendous specificity, sensitivity, and so on.

However, when you have the matrix effect,

that can greatly affect the extraction of the

protein that you are interested in and cause

interferences, and so on. That is where a lot of

the problems come in. A lot of work also has to be

done in the development of protocols for extracting

the active ingredient, the allergen that we are

interested in.

DR. MALEKI: Soheila Maleki. Just in

answer to Dr. Callery, again, to reference what you

are talking about between standardizing between the

kits, that has come up a lot.

It is an issue that I think is going to be

addressed in developing some type of standard by

maybe one manufacturer that can allow all the kit

manufacturers to standardize their kits, so that

later that can be related to actually what the

threshold doses are, which is what they are

339

determining now. That is one thing.

As far as the matrix effect, there is

really not a whole lot you can do with that except

as technology increases. Right now, the extraction

methods are getting better and better.

Better buffers are being used and better

treatments, whereas you are getting a lot more

consistent results between the kids and by the kids

themselves. Therefore, when you do the

experiments, you are getting more, essentially,

consistent results, and so forth.

CHAIRMAN DURST: David first and then

Ciaran.

DR. KELLY: Ciaran Kelly. This is on a

different topic, so I don\'t know if there is

another question on the same topic.

CHAIRMAN DURST: Okay. David had his hand

up.

DR. KELLY: You might want to continue.

MR. ORYANG: Well, it is similar, about

the sensitivity again. I just wanted to follow up

with Dr. Taylor or anyone else, again, just

340

highlighting this analytical methods-based. What

allergens have, let\'s say, caused a response in

individuals at the levels of detectability of some

of these methods? Do we have a list of that so

that at least we can begin to say, okay, the

analytical methods-based approach could be used on

these things, because right now we know that the

level of detectability is similar to\--?

DR. TAYLOR: Well, when we worked to

develop the detection levels of these tests, it was

absolutely our goal that no patient would react at

the limit of sensitivity of the test. I am

actually quite hopeful that I will never find that

case, because we were trying to be conservative.

If you get a negative result on this test,

you are going to advise the food industry to go

forth and not label this product. Why? All of

these people are going to buy this product and you

don\'t want their children to react to it. We don\'t

know that anyone reacts to reasonable serving sizes

at those levels, limits, of detection.

MR. ORYANG: Okay. The follow up, what

341

allergens react to, let\'s say, hundredfold levels,

a hundred times the level of detection?

DR. TAYLOR: Again, that is kind of a hard

question to answer.

(General laughter.)

DR. TAYLOR: Help me work through this

analytically, 2.5 parts per million, a hundredfold

higher than that, 250 parts per million. Two

hundred and fifty parts per million would be

250 milligrams per kilogram, 25 milligrams.

If I looked at all of the data, and again

I\'m assuming a 100-gram serving size \-- a heck of

an assumption, but we will go with that because the

math I can do in my head in the late afternoon \--

if we look at all the data on all of those studies,

I would say that a relatively modest percentage of

the challenge patients with published data would

react at 25 milligrams to peanut, milk and egg.

We have almost no data on wheat and

soybean and fish and crustacean shellfish. In

fact, there wouldn\'t be any data out there, limited

as it might be, on soybean to suggest that 25

342

milligrams of soybeans is hazardous to anyone.

MR. ORYANG: Thank you. I just wanted to

get some kind of reference point for the

applicability, direct applicability, of the

analytical methods-based approach.

DR. TAYLOR: Yes, I mean, I see what

you\'re driving at. It would be my view that if you

use the 2.5 part per million level as your interim

threshold level, that would be a very conservative

approach.

Like I said, I hope I never meet the

person that would react at that level, because it

was the intent for that level to be safe for

virtually everyone, if not everyone.

DR. KELLY: Ciaran Kelly. Actually,

Dr. Taylor, you may want to address this question

also. I wanted to return to the question of the

sensitivity of the challenge studies, particularly

the question as regards whether symptoms or signs

are used.

I am a physician also and I reiterate

Marc\'s comment that for a physician about objective

343

symptoms versus subjective symptoms. It burns a

hole in our \--

(General laughter.)

DR. TAYLOR: I usually call them

\"reactions,\" so I guess I get away with it either

way.

DR. KELLY: In any event, can you give us

a sense of where the field is at present? Because

the objectives may be different in terms of clearly

signs are going to be much more objective and much

more specific, but we perhaps would have a greater

desire to have sensitivity in identifying

thresholds that may cause an allergic reaction.

Are you aware of any studies that are

specifically looking at that, looking, for example,

at what is the difference in dose between a symptom

but then goes to a sign? Is that being looked at,

or has the field sort of abandoned symptoms?

DR. TAYLOR: Well, I don\'t know if they\'ve

abandoned, maybe neglected it. Dr. Teuber made

this point earlier, and she is absolutely correct.

Many of these studies that I referred to and that

344

Rene Crevel used in drawing his curves are actually

diagnostic challenge trials.

If you are trying to diagnose a patient to

determine if they actually have a given food

allergy, you want to see signs. Almost all of

those clinicians, I think, would proceed to

actually physically observable symptoms.

However, that doesn\'t mean they wouldn\'t

pay attention to subjective symptoms that might

occur along the way as they are increasing the

doses and the person says, \"My mouth itches\" or \"My

stomach hurts.\" I think you would pay attention to

that because it would alert you to the fact that

the guy might have a more significant event the

next dose.

There have only been a limited number of

studies where people have done threshold trials

where they actually went through the subjective

symptoms and got to the objective signs.

The study we did with Jonathan Hourihane

and others on peanut thresholds published in 1997

was one of those. Admittedly, it was modest. It

345

was the first threshold trial that ever got done.

It was 14 subjects, 2 of them reacted with

subjective symptoms at 100 micrograms. They got

several doses after that, and one of those

individuals first developed mild, objective signs

at 2 milligrams and the other at 5.

As you wrestle with this, in my view,

whether you use signs or symptoms, it is a question

of how much uncertainty you assign to those

numbers, how big the uncertainty factor is.

As I alluded to this morning, I would

advocate using a smaller uncertainty factor if you

go with subjective symptoms than you would if you

went with objective signs.

Although, it is still not even that

simple, because if the person had objective signs

at 500 milligrams in a diagnostic trial, I am real

concerned about what might happen at levels far

below that.

DR. KELLY: The consensus protocol, how

does that address this issue?

DR. TAYLOR: The consensus protocol that

346

we published last year, the consensus was to go to

objective signs in these threshold trials, but to

pay attention to subjective symptoms and record

them, record the doses at which they occurred.

I mean, these studies cost a lot of money.

I believe in capturing every conceivably

significant data point, because I don\'t know how

regulators are going to use this information, so

let\'s give it all to them and let the wisest people

decide what to do.

DR. KELLY: Ultimately, I guess that is my

point, that these data, hopefully, will be gathered

and it will be possible to look at subjective

symptoms as a secondary endpoint and see how it

relates.

DR. TAYLOR: Yes. Another point I didn\'t

make is that I am convinced that even though

clinicians have only reported LOAELs in their

studies, that many of these clinicians have NOAEL

data on their charts. They just haven\'t taken the

time and effort.

In fact, I asked Dr. Sampson that question

347

last week and he said, \"Yes, I have more than a

thousand charts. If you\'d like to send me some

money so I can have someone sit down and look at

these charts, I would be able to give you the

individual NOAELs for all of the patients who did

not react at the first dose. I have never

published that data; I have never collated it; I\'ve

never computerized it. It is all on paper charts.\"

CHAIRMAN DURST: Okay. One more question

from Marc, and then I would like to move on to the

specific questions that FDA has asked us to

address.

Marc, do you want to just finish up?

DR. SILVERSTEIN: I wanted to ask the

scientific rationale for an uncertainty factor? Is

it just giving you a wider range to be right about

the prognostic value, that is, the likelihood that

in those who are positive or negative their

subsequent events, whether it be anaphylaxis or

other food allergy related events?

Is the scientific rationale for

uncertainty factors just being careful, or is the

348

scientific rationale based on what we saw earlier,

intraspecies individually between species and

within individual variations, or is it between

symptoms and signs? What is your best judgment

about the rationale by which you can provide the

uncertainty factors?

DR. TAYLOR: I think uncertainty factors,

the old standard \-- I went to school in toxicology

\-- was this hundredfold uncertainty factor. It was

tenfold for extrapolating from mice or rats to

humans and tenfold for interindividual variations

among humans. That is mostly very arbitrary.

Although I was told in graduate school, and never

went back to look it up, that it actually has a

basis in fact.

It came about from some famous drug

contamination episode called the \"elixir of

sulfanilamide episode,\" back in the 1930s, where

they actually had animal data and they actually had

human data from the poor, unfortunate souls that

succumbed to this contaminated drug. It has some

basis in fact, but it is a lot of expert judgment

349

not so much biologically based in some cases.

DR. SILVERSTEIN: Let me comment, then,

and again highly relevant to the FDA with that

historical example, this would be inferences drawn

from toxicologic studies where live proportions of

the population might be susceptible to some range

of exposure?

In contrast, though, in allergic diseases

we are dealing with not a large proportion of the

population but a substantial fraction of the

population that might have within individuals much

more range in terms of sensitivity.

What I\'m leading to is I might want to be

more cautious about taking from a toxicologic

exposure to an allergic disease mechanism the same

range of uncertainty.

DR. TAYLOR: Yes. It is hard to address

that point, because most of our experience with

uncertainty factors deals with toxicologic

exposures where the whole entire population is

conceivably at risk. Here, admittedly, we have a

smaller proportion of the population that is at

350

risk.

Conceptually, I don\'t have a problem with

using uncertainty factors, because the goal is

still the same: Protect a fraction of the

population or protect the whole.

I think I\'m bringing you back to what Rene

said about using the models and then doing a better

job of documenting whether the decisions that are

made are appropriate by attempting to validate

whether the model is correct or not.

We actually have a lot of data now

accumulating very rapidly from all of these

analytical determinations that are being done in

industry and in academic laboratories and

government laboratories about levels of allergens

in products that do not have adverse reactions

associated with them.

Now, you could probably get even better

data if you could analyze what some of these

consumers have actually eaten that did not make

them sick. Based on my experience, I am almost

sure that they eat tiny, tiny amounts of milk and

351

egg periodically, even though they don\'t know about

it. That would help you determine whether the

numbers you selected were achieving the goal you

wanted to reach, and I don\'t know how to determine

that otherwise.

DR. SILVERSTEIN: Dr. Crevel is not here.

Could I follow up with one question about the

modeling approach?

CHAIRMAN DURST: Okay.

DR. SILVERSTEIN: I found that modeling

approach very interesting. He selected an ED10 and

ED1. Is there a rationale for having the ED1,

which for me would be saying we\'re looking to see a

threshold that would affect 1 percent of the

population?

DR. TAYLOR: One percent of the allergic

population?

DR. SILVERSTEIN: Yes.

DR. TAYLOR: Yes. Well, the ED10, your

model should predict that because if you\'ve got 29

observations, you\'ve got the ED10. If your model

doesn\'t predict an ED10, it is truly a lousy model.

352

The ED1, I can\'t remember the binomial

distributions, but you\'ve got to have a lot of

participants to get to the ED1, so you have to

extrapolate.

I\'m not much of a statistician, but you

are going to get a lot more variability in guessing

ED1, and you get even more variability if you tried

to surmise what the ED 0.1 is.

But then if you used one of those, my

argument is you could see what the experience is of

the allergic individuals in the population. If you

choose well, then all of the allergic individuals

stay well; and, if you don\'t choose well, some of

them are going to get sick. That is why I think it

is important to follow this up and see whether we

chose well enough.

CHAIRMAN DURST: Okay. Thank you very

much.

I think, as I mentioned, we really do have

to address some of these questions put to us by the

FDA, since our time is going to be limited

tomorrow. We will be focused on glutens, and then

353

Friday will probably be a somewhat truncated

session. Hopefully, we can get through a number of

these questions before 7:00 or 8:00 tonight.

(General laughter.)

CHAIRMAN DURST: I think the general

questions probably can wait until we\'ve had the

gluten discussion because they probably address

both aspects, but, specifically, the food

allergens. Why don\'t we just take these questions

one by one, and, hopefully, come up with some kind

of conclusion or consensus for the FDA.

The first one: \"Are there distinct

subpopulations of highly sensitive individuals

within the allergic population for each of the

major food allergens?\"

Would anyone like to address that?

(No verbal response.)

CHAIRMAN DURST: My goodness, what

happened to that talkative group?

(General laughter.)

DR. HEIMBURGER: This is Doug Heimburger.

Clinically, anecdotally, yes, people do respond,

354

allergic people within the subpopulation. There

are subpopulations who respond both more severely

and at lower levels, but it sounds like we really

don\'t have nearly enough data to be able to say

just how we identified those people; is that

correct?

DR. BRITTAIN: Erica Brittain. Yes, I

don\'t know how you would distinguish between a

subpopulation versus a continuum. I mean,

obviously there is variability and sensitivity,

that\'s for sure.

DR. HEIMBURGER: Yes.

DR. BRITTAIN: Whether it is a continuum,

I certainly don\'t know.

DR. MALEKI: Soheila Maleki. I think that

Dr. Wood, who unfortunately isn\'t here, really

addressed that question fairly well this morning,

showing the range of the reactions and the

populations.

However, I also think the answer to that

is, yes, that there are individuals that are highly

sensitive that can be set apart from the rest of

355

the group in some ways.

Generally, I think if we go back to that

presentation that it would be very sufficient in

explaining the percentages as well as the range of

reactions going from IgE-mediated to

gastrointestinal and other types such as celiac

disease.

CHAIRMAN DURST: Does the Committee feel

that this applies to each of the allergens or\--?

DR. MALEKI: I think so. I mean, I think

even, for example, in some cases when egg and milk

are outgrown as an infant, there is a severely

allergic population that will not outgrow it.

There are always the exceptions or the highly

allergic. Maybe Sue or one of the clinicians may

be able to address that.

DR. HEIMBURGER: Doug Heimburger. The

fact that they grow some of those means that they

are at some points in their lives more sensitive

than they are at other points in their lives. The

answer is, yes, there are definitely more sensitive

and less sensitive.

356

DR. MALEKI: Yes, I agree.

DR. KELLY: Ciaran Kelly here. Sorry to

disagree and maybe pick on words, but are there

distinct subpopulations? How can we identify these

individuals?

If there are individuals who at one point

in their life are very sensitive and later less

sensitive, then to me they are not distinct; they

merge one into another.

I think my clinical experience is that it

is a continuum, that there is not a group of

individuals who are highly sensitive, a different

group who are moderately sensitive and another

group who are not sensitive at all. There is a

whole population. I don\'t think we can subdivide

them into subpopulations.

DR. WASLIEN: Carol Waslien. Can you

divide them on the basis of how many epitopes they

are sensitive to? Some are sensitive to only one

of the proteins in peanut protein, some are

sensitive to two, some are sensitive to three, and

some are sensitive to soybeans as well as peanuts.

357

There is that kind of subpopulation, and

those are not on a continuum. Those are distinct

characteristics. There is that kind of

differentiation on the basis of some of the

differences.

DR. HEIMBURGER: Doug Heimburger.

(Simultaneous discussion.)

DR. MALEKI: Soheila Maleki. Oh, I\'m

sorry.

I was just going to say that right now,

they are doing microarray analysis on

individualized epitope mapping in relation to what

relationship that has to the type of reactivity

that these individuals are having. They have

identified specific dominant epitopes that are more

likely to occur \-- their IgE is more likely to

recognize, if the individuals have severe

reactions.

Again, going back to what you were you

were saying \-- and I would like to hear from the

clinicians, maybe Suzanne Teuber, about the fact

that, yes, there are definitely subpopulations that

358

are severely allergic. Does anybody else have a

comment on that?

CHAIRMAN DURST: Petr.

DR. BOCEK: Petr Bocek. Well, I think the

question is posed in order to then actually follow

with the uncertainty factor. It is not whether we

can define this subpopulation by a specific

biomarker, but it is asking whether the eight major

food allergy groups, are there people with severe

allergy? The answer is yes.

It is basically asking within the

population of people who are allergic to these

foods, what is the range, what is the factor we

apply in order to be safe? I think the simple

answer to the first question is yes.

DR. MALEKI: I agree.

CHAIRMAN DURST: Okay. David.

MR. ORYANG: Yes. Just following up on

Dr. Bocek \-- David Oryang \-- I think the sensitive

individuals, the allergic population, has already

been divided up. The children react differently

from adults to a lot of the allergens, so there is

359

already those subpopulations.

Beyond that, maybe there are even

subpopulations within that. Right now, are the

safety factors to be applied to children the same

as the safety factors to be applied to adults or

not? That is the question. Should they be the

same? I don\'t know.

CHAIRMAN DURST: By the \"safety factors,\"

are you talking about these uncertainty factors?

MR. ORYANG: The uncertainty factors,

right. Yes, the uncertainty factors.

DR. HEIMBURGER: Severity of response

factor as well.

DR. MALEKI: Soheila Maleki here. I think

that one, not all, but maybe some of the allergenic

substances for adults and children will be the

same. However, there are specific allergens that

are adult allergens that are not child allergens,

for example, egg and milk. I don\'t think we should

consider the safety of a child more than we should

consider the safety of an adult. I think life is

precious.

360

MR. ORYANG: That\'s true.

DR. MALEKI: I don\'t think that is the

term to subdivide it. If you were going to divide

it into anything, it might be the different foods

to consider. Even in that case, I don\'t think we

should make that distinction. I think everybody

should be protected or that\'s who we should

consider.

MR. ORYANG: You are saying we shouldn\'t

divide it into any subpopulations?

DR. MALEKI: Well, I think severe reaction

versus non-severe reaction but not, like,

separating children versus adults or men versus

women, and so forth.

MR. ORYANG: That\'s an example. If there

is a real difference in their reaction or an adult

response, and so forth.

DR. MALEKI: Oh, I see.

MR. ORYANG: I mean, if there are major

differences, if you can break the whole population

up into different ways in which they react to the

same dose, a child versus an adult, are they going

361

to react the same? Then, also, the exposure maybe

also needs to be considered and all those things.

The safety factor I think in children\'s

food, isn\'t there a much higher safety factor for

some of those kinds of things than other

commodities? I don\'t know whether some of the

industry people can respond to that.

CHAIRMAN DURST: Okay. Suzanne and then

Doug.

DR. TEUBER: I had a specific question. I

was just going to bring up that between children

and adults, for instance, most of the deaths are

caused by peanuts and tree nuts and then seafood

for a smaller percent, at least that is in our

culture.

As time goes on, Sicherer in that

Johns Hopkins group and now Mount Sinai have shown

that in follow-up interviews for many of the kids

who have peanut/tree nut allergies, the reactions

actually became more severe with time, but we don\'t

know what happens to the thresholds. I don\'t think

we have that kind of age data, and I don\'t know if

362

anybody is studying that right now.

DR. HEIMBURGER: Doug Heimburger. To

point back to the question again, as Petr did, the

question is not asking us to identify

subpopulations; the question is asking us is 10

times 10 equals 100 a sufficiently wide range.

That is a different question from can we identify

them.

CHAIRMAN DURST: What is the answer?

DR. MALEKI: Soheila Maleki. I just

wanted to add a comment to Suzanne\'s comment, that

they have actually identified, they have

determined, that individuals between 11 and 33 are

more likely to suffer anaphylaxis and have fatal

anaphylaxis, because that is when they start

experimenting with food. That is the age range, if

that was a question. Again, the bottom line answer

to this is pretty much yes.

CHAIRMAN DURST: Yes?

DR. BRITTAIN: Well, are you asking to

answer the factoring question.

(General laughter.)

363

CHAIRMAN DURST: Yes, the statistician,

please.

DR. BRITTAIN: Well, to me it feels really

arbitrary. It goes back to the question I posed at

the beginning of the discussion. I mean, I don\'t

know if we are aiming at \-- we want to make sure

there are almost no reactions in the most sensitive

population. If that is our goal, that affects how

we would choose the uncertainty factor.

We would want a bigger uncertainty factor

if we are really trying to focus on the

supersensitive patients. If we are just trying to

say something about all allergic patients, then you

might not need as big an uncertainty factor.

It also depends on what data you used

amongst the studies. Are you only including those

studies in allergic patients? That is all part of

it, too. It is sort of hard to answer this

question in isolation.

CHAIRMAN DURST: She asked and answered

it.

DR. BOCEK: Petr Bocek. Well, I think at

364

least what I\'m hearing is we agree that the safety

assessment-based approach is good and valid and it

is fine. The concern I have, and we have already

addressed that, whether the current data is

targeting the right population.

At least in this country even considering

the more aggressive approach in Europe, we\'re still

certainly missing the most allergic patients

because we are doing diagnostic challenges, the

majority of them.

If you want to base the uncertainty factor

on that, on the LOAEL determined from these

studies, and you think about, let\'s say, 2,500

milligrams being the LOAEL in these studies \-- I\'m

just pulling a number \-- and then you have a

patient, anecdotal evidence of kids anaphylaxing

and adults anaphylaxing just to the peanut powder

when somebody opens a bag of peanut, and there are

case reports of that, that certainly is more than

100, less milligram exposure than 100 milligrams in

those challenges.

I\'m not sure, you may not like me, but I

365

think the hundredfold, if I were thinking about the

current data from the current double-blind

challenges, I don\'t think it is sufficient.

DR. BRITTAIN: Yes. Adding to that they

mention there is one millionfold, the previous

statistic today, one-millionfold range in

sensitivity, so I don\'t see how the hundred address

that.

CHAIRMAN DURST: Anything else on this?

DR. MALEKI: Soheila Maleki. Just to

comment, yes, there is a range of one-millionfold

of sensitivity. On the other hand, just like zero

levels of a particular allergen in a food is

virtually impossible for the industry and

manufacturers, I think to set your statistics on

zero tolerance, that nobody is ever going to have a

reaction, is also unachievable.

You want to determine threshold levels,

that means the most severe reactors, and then pick

a level severalfold below that, and that might

increase the safety factor.

With the knowledge and what we have today,

366

I don\'t think it is possible to say we have to pick

a level of a millionfold less. I know, I

understand why you\'re saying it, that it is

probably because of the range that is different.

However, if you pick the lowest level then \--

DR. HEIMBURGER: Then, a hundredfold

uncertainty factor applied to that, then perhaps it

is sufficient.

DR. BRITTAIN: If you had the right data?

DR. HEIMBURGER: If you have the data on

who is the most sensitive person and who is that at

one millionth of the other person, and then you

have a hundredfold uncertainty factor. The

question is, Is that a sufficient uncertainty

factor? It is sounding a little more sufficient, I

think, if you phrase it that way.

DR. MALEKI: Soheila Maleki. Just one

comment again. Being able to test these people,

most of the data that has been shown or is

available is based on diagnostic challenges.

The threshold studies that are actually

going to be valid for the first time or some that

367

have been done, maybe there are two studies, this

is a beginning type of study going on.

Right now, there may not be all of that

data available, but I think they are going up the

right track where they are picking the most severe

reactors and they are treating them and waiting and

recording subjective and then objective data. That

is going to give us the closest we can get with the

funds and opportunities and what we know available.

CHAIRMAN DURST: Suzanne.

DR. TEUBER: Again on that, I would hate

to see some of the subjective symptoms thrown out

of the analysis. There are going to be individual

physicians who are involved in these threshold

studies who are not going to go above that, at

least this is what I had heard. They are going to

be more comfortable if they have a reproducible,

subjective symptom in stopping.

Again, if we talk about the safety

assessment as it is written, it would throw out all

that data and throw out these patients who may be

exceedingly sensitive, and this is some of the

368

population that we want.

I think this just keeps coming up as a

concern for the FDA in evaluating what approach is

to be used and how the future data comes in to be

evaluated.

CHAIRMAN DURST: Okay. Anything else?

Erica.

DR. BRITTAIN: Erica Brittain. I guess I

just wanted to make a general comment about the

report. The report seemed to me, if I understood

it, the recommendations in the report seemed to be

feeling that the modeling approach wasn\'t really

ready for prime time, if I understood the

conclusions they drew.

I guess I\'m a little confused why this,

which seems, you know, just like a very vague

standard or just finding some uncertainty factor,

why that would be preferable to the modeling, even

if it hadn\'t been completely validated. I just

wanted to make that comment.

CHAIRMAN DURST: Is there anything else on

this?

369

(No verbal response.)

CHAIRMAN DURST: I guess we\'ve answered it

to their satisfaction.

Yes.

DR. BARACH: Jeff Barach. I have one

comment to add to it. I think it is probably a

little bit premature that we should start to set

values for these uncertainty factors of tenfold or

whatever.

We heard from Steve Taylor that he was

looking at uncertainty factors of maybe one or two.

I think that reflects the fact that if we go with a

10 and 10, we are using a standard approach that

has been used for pesticide residues in the food

system for a while, so there is some comfort level

associated with that.

However, I don\'t think we really have the

comfort level from the data and the population

studies and the challenge studies to really pin

down these numbers.

I would say that using uncertainty factors

will be a benefit, but I don\'t think we are really

370

quite ready to even identify the magnitude of those

uncertainty factors is at this point.

CHAIRMAN DURST: David.

MR. ORYANG: Yes, David Oryang. I concur

with Dr. Barach in a sense, but I add that I think

more work could be done to try different safety

factors and apply it in the context of the model

that evaluates how many people might come up with

symptoms, if the safety factor was a certain value

for a specific allergen, given people\'s reactivity.

We can begin to capture the outliers, in

other words, those highly reactive people. I think

there is some data which indicates the percentage

of people that would probably react up to the

million times more than the average person.

DR. TEUBER: There is that, that is what

has been brought up.

MR. ORYANG: Okay. There is that data, so

I think some modeling probably could be done to

find out, to determine, how many cases would come

out of setting a safety factor at a specific level,

if the appropriate models were developed to do

371

that. That is where the risk assessment-based

approach is.

I think we can begin to start doing some

of that, if we put in the distributions even the

safety factor, but the NOAEL could be put in as a

distribution as opposed to a point value, as an

example, and you can then run a model to determine

how many cases there would be of reaction at a

specific safety level.

I think that is the kind of thing that FDA

could do to take this a little bit further as

opposed to just deciding.

I mean, it is impossible to decide just

like this, to say, well, is a hundredfold good

enough? There has to be a basis for saying that it

is good enough.

The basis might be, well, we\'ve reduced

the number of cases tenfold or reduced it a

hundredfold or we\'ve reduced the number of cases to

less than one in a million, or whatever the case

is, and then you can decide that you have taken it

to the right level.

372

CHAIRMAN DURST: Okay.

DR. WASLIEN: This is Carol Waslien.

Maybe because there are so many studies, it sounds

like they are almost ready to be reported. Using

some of the kind of data that we would need to set

uncertainty factors, maybe we can say that, yes,

there may very well be differences, but we can\'t

tell what they are right now.

However, when that data becomes available,

we should be able to say what they are and make

those calculations for differences using subjective

and objective, using prognostic information.

Therefore, we should then use the correct

scientific approach to determine uncertainty

factors in something besides pesticide residues

that all of us are sensitive to.

CHAIRMAN DURST: Erica.

DR. BRITTAIN: I think you would also want

to think about maybe doing both approaches, both

modeling and uncertainty factors, and hope to see

some kind of agreement in the approaches. I want

to emphasize for both you need the right data.

373

CHAIRMAN DURST: Jean.

MS. HALLORAN: Yes. I think very good

comments have been made here about that. This type

of uncertainty factor is very different from

pesticides. For one thing, we are not

extrapolating from rats to humans. We are working

with human data to start with.

Another one we are not dealing with sort

of variability from an average person. We are

trying to start with the most sensitive person and

set a safety factor for them.

It is a really different task, but it is

also a task for which we don\'t have the data that

you need to start with, which is the number for the

most sensitive person.

Perhaps, as a principle, we could suggest

to FDA something like what Steve said, which is

basically: the better the data, the less of an

uncertainty factor you may need; the worse the

data, perhaps the bigger the uncertainty factor

that should be built in.

DR. MALEKI: Soheila Maleki. I just want

374

to ask, I know the Food Allergy and Anaphylaxis

Network has helped in a lot of research studies

because they have 27,000 members of food-allergic

people.

I wonder if anybody has done, or are there

any studies done to divide up highly severe to

moderate to low allergic individuals? It seems

like that is one of the questions that David was

asking.

MS. MUNOZ-FURLONG I have not done that

with our membership. I\'m not aware of any studies.

I will tell you from the fatality registry and the

fatality studies that have been published, there

have been a number of people who have died who had

only previously had mild reactions.

I\'m not sure we are ever going to be able

to put people in neat, little boxes that says,

\"You\'re a mild reactor, and you will always stay

there.\" This seems to move and nobody can predict

when or why.

CHAIRMAN DURST: Margaret.

DR. McBRIDE: Margaret McBride. As I

375

listen to all of this, a couple of things come to

mind, and one is that we really are looking at

risk. No matter how you define the range of

sensitivity there is going to be an outlier or

there are going to be outliers of that very

sensitive end.

In a sense, that is what people have been

asking, What are we aiming for? We really know

that we can\'t set something that will be truly safe

for everyone.

The other things is, if understand again,

LOAELs, if we in fact we could test everyone, we

would get a LOAEL and we wouldn\'t need any safety

factor.

The safety factor is because we can\'t test

everyone and because we are assuming that we are

not testing the most sensitive individual. Does

anybody want to comment on that?

I mean, what we are trying to say is easy

to say. I would certainly agree that we don\'t have

the data to set a safety factor, but remember that

we are setting a safety factor because we can\'t

376

test everyone or because, understandably, the most

sensitive people won\'t sign up for the testing.

We have a conundrum, but we still have

folks who need to read labels. I mean, I\'m a

clinician, so it is easy for me to live with some

uncertainties because I\'m forced to every day when

the data isn\'t available.

DR. BRITTAIN: Yes, this is Erica

Brittain. That brings up something that I keep

thinking about. There really isn\'t a safety

threshold overall so much as each person has their

own threshold.

This is a totally different way of

thinking about it. However, if you could label the

food by the quantity instead of saying yes/no it is

above some magic line, is that a solution, that

people would know their own tolerability?

DR. McBRIDE: It may change over time, you

know, maybe we need to look at yearly threshold

testing or something.

DR. MALEKI: Soheila Maleki. Exactly, as

Anne just mentioned, you don\'t even know the

377

reactors much less the threshold levels for each

person changing. You can just choose a population

that you believe to be the most reactive and

determine what you best can determine.

Maybe technology will improve with time,

and you an do a lot better, or more people can be

tested in that way. Yes, that is a nice thought,

but I don\'t think most people know what their

thresholds would be.

CHAIRMAN DURST: Okay. Shall we move on?

(No verbal response.)

CHAIRMAN DURST: As far as the second one,

we touched on it a little bit the LOAELs and

NOAELs: \"Is the initial objective response seen in

a clinical challenge study always an adverse effect

that poses a risk to human health?\"

DR. TEUBER: I find this question a little

bit ambiguous. An objective response in one

person, so, yes, that particular response in many

of these studies has been an extremely severe

response, but not in the studies that were designed

as a true threshold study.

378

They are just saying clinical challenge

study. Since so many of these studies were

diagnostic, there were so many people who reacted

on the first dose. Yes, it could be a

life-threatening reaction; but in the

well-performed threshold studies, the first

objective reactions have not been life threatening.

It could still be clinically significant. You

would want to account for that with the uncertainty

factor going down below that.

DR. MALEKI: Soheila Maleki. Just an

addition, the dosage again that Steve also

mentioned before, the dosage with a clinical

challenge study is very different than the dosage

that use for threshold doses. For a threshold, you

are obviously trying to determine a threshold.

With a clinical challenge, you want to have a

clinical reaction to say, yes, this person is

allergic.

Am I correct, Suzanne?

DR. TEUBER: Yes. They could have chosen

lower doses to start with, but I think people are

379

now choosing far lower doses to start with, even in

diagnostic challenges. However, there had to be

something to start with in the literature, and that

is what we have.

CHAIRMAN DURST: Marc.

DR. SILVERSTEIN: Marc Silverstein. If I

were to try to operationalize a question like that

for an epidemiologic study or a clinical study, the

words that I would be focused on is \"always\" and

\"risk.\"

For me \"always\" might be 90 or 95 percent.

An attorney might say it is 50 percent or greater.

There would be some, \"Well, what is always?\" It

would be some large number. For us in the clinical

realm, we might say it is 80, 90, 95 percent.

Then, risk to human health? Well, if the

outcomes of an allergic reaction could include

death among the spectrum of anaphylaxis, then we

might be thinking of risks that were weak risks.

Low risk would be clinically important risk.

In an epidemiologic study, we might say

even those variables where the risk ratio was less

380

than two might be important, or we may say we are

going to consider large risks that might be risk

ratios of four or greater.

As I try to answer some of these

questions, other than an absolute no risk and

never, I would try to operationalize them in terms

of magnitude knowing that in the real world

clinicians and policymakers have to make some

decisions.

Having said that, my subjective

inclination would be to say I would think that

clinicians caring for patients and policymakers

would make assume that if a patient reacted

positively in a diagnostic challenge with objective

symptoms, that patient is at risk probably to the

point where they would translate it into a

recommendation for patient and the family with

regard to diet.

With regard to that, I would say it seems

to me that it is reasonable to say, yes, objective

symptoms would be tantamount to saying essentially

risk would be of sufficient frequency and

381

sufficient magnitude to answer this question yes.

That would be the way I might approach it.

CHAIRMAN DURST: Petr.

DR. BOCEK: Petr Bocek. I think the

remainder of the paragraph is actually looking at

the subjective response and the objective response.

I understand this first question as if you do a

challenge study and your stopping point would be

the initial objective response, it is asking, does

it always impose this risk to human health?

Well, my answer is no. Because if you do

a challenge study, a clinical challenge study, and

your endpoint is the first initial objective, most

of the time it is not life-threatening.

The data we have, how many people actually

die during the challenge study? It is usually

cutaneous manifestation, hives, or something like

that. To me that doesn\'t pose a risk to human

health. That is how I understand the question.

CHAIRMAN DURST: Yes.

DR. NELSON: Mark Nelson. Yes, I was

trying to understand the question as well. It

382

struck me as ambiguous. I guess I have a question

of the clinicians. Is the objective of a clinical

challenge to try to get a response to see?

As Petr said, following on the subsequent

questions, I think my interpretation of the

questions it that they seem to be asking us whether

the clinical challenge approach is really the best

way to try to set a threshold as opposed to use it

as a diagnostic tool.

DR. TEUBER: Suzanne Teuber here. Again,

in interpreting this question, I am trying to

figure out if they mean should they be throwing out

the data of people who reacted on the first dose in

the diagnostic challenge studies; and, if so, we

know that they really have to have a lower LOAEL

level than that.

The next question is, Is it scientifically

sound to use this response to determine a LOAEL?

My answer to that would be no. Again, the question

is ambiguous of what was intended. Again, I would

throw out data on people who are first-dose

responders because they really would probably react

383

at lower levels. Is that what it is asking?

CHAIRMAN DURST: Steve, would you be able

to address that ambiguity?

DR. GENDEL: Let me get back to you on

that.

CHAIRMAN DURST: I beg your pardon?

DR. GENDEL: Let me get back to you on

that.

(General laughter.)

CHAIRMAN DURST: Jean.

MS. HALLORAN: Yes. My reading was that

they were trying to get at how you interpret data

from clinical challenges where you\'ve got LOAELs in

the absence of NOAELs. I think all of our experts

have said that if you only have a LOAEL and not a

NOAEL, then you don\'t know what the NOAEL is.

(General laughter.)

MS. HALLORAN: Then, the third question

for the safety-assessment approach, Is a proposed

uncertainty factor of tenfold sufficient and

appropriate to use in the absence of a NOAEL?

I don\'t know what others think, but from

384

what I\'ve heard it seems to me like the answer is

not necessarily. You just can\'t necessarily guess,

because there is no standardized procedure.

DR. HEIMBURGER: It would be much more

than tenfold.

MS. HALLORAN: Yes.

DR. HEIMBURGER: The difference between

the LOAEL and what you did and the NOAEL \--

Doug Heimburger \-- so I think the answer to that

question is no.

DR. MALEKI: Soheila Maleki. I think the

answer to the first three questions is no, no, no.

(General laughter.)

CHAIRMAN DURST: That was easy. I wish

they were all that easy.

(General laughter.)

CHAIRMAN DURST: Margaret.

DR. McBRIDE: Margaret McBride. Just

along the same lines, really the issue of the

increment, even if you are doing a threshold study,

is important.

CHAIRMAN DURST: Sure.

385

DR. McBRIDE: Probably that\'s something

that needs some standards.

DR. MALEKI: Soheila Maleki. I think the

better question would have been that instead of a

clinical challenge study to ask us about a

threshold dose study, and then all of these

questions would be relevant. In a clinical

challenge study where you usually use higher doses,

and again you don\'t know the NOAEL, then it is not

relevant to ask the question.

DR. HEIMBURGER: Doug Heimburger. The

overarching thing here is, Should data from

clinical challenge study be used to set these

levels?

DR. MALEKI: It is no.

DR. HEIMBURGER: The overarching answer is

no.

DR. MALEKI: Soheila Maleki again. If you

actually change that question to what I believe

might have been intended as some clinical

challenges for threshold dose studies, then you can

answer some of these questions or address them.

386

Because most of the data that is in the

literature is clinical challenge studies, the

question was actually intended to see if \--

(Simultaneous discussion.)

DR. HEIMBURGER: Should we answer the

question after changes those words and then

re-answer it?

(General laughter.)

DR. MALEKI: Actually, I think they might

have been to look at the literature. Since most of

the literature is on clinical challenges, they

wanted to know if they can use that data in order

to answer these questions. It is actually an

appropriate question, and the answer is again no.

DR. HEIMBURGER: No.

(General laughter.)

CHAIRMAN DURST: Yes.

DR. KELLY: Ciaran Kelly. I agree with

the second two numbers, but I would like to revisit the

first numbers. The question is, "Do objective responses

in clinical challenge studies always have an

adverse event that poses risk to human health?" I

387

agree absolutely with Petr, that these are not

life-threatening responses.

On the other hand, are they acceptable

responses? Would an individual experiencing this

response at a meal consider that they\'d had a

healthy meal?

I think if you look at it in that way the

answer would be, yes, these are significant to risk

human health, if you have a broad sense of health

and well-being. Although, I agree that they are

not by any means a risk to life \-- probably no risk

to life.

DR. BOCEK: Petr Bocek. They are asking

about clinical challenge, and I don\'t think anybody

is having a happy, healthy meal doing clinical

challenges.

(General laughter.)

DR. KELLY: Yes, but the question as I

understand it is \-- Ciaran Kelly again \-- if an

individual has that level of symptomatology, would

that be considered an allergic reaction in everyday

life? I think the answer to that is yes, I

388

believe.

CHAIRMAN DURST: Marc?

DR. SILVERSTEIN: Marc Silverstein. I

would like to just clarify. My thinking would be

that if clinicians would translate a positive

response to a clinical challenge or a food

challenge test into a recommendation for dietary

modification, that basically is affecting the

patient\'s care and that is affecting their health.

To me that is a simple-minded but very realistic

issue.

Does it mean that the patient will have a

risk of dying? Yes. How big of a risk? Maybe 10

or 15 or whatever percent is graded by the risk

ratio. What proportion of patients may have it?

Some proportion of the population. What would you

do as a clinician based on that?

If it is a sufficient threshold for

clinicians to change the management, I think it

would be a sufficient threshold for parents and

individuals to say that would affect what they

would like to see in labeling. That is why I think

389

I couldn\'t say no.

DR. TEUBER: Suzanne Teuber. This is

again why I did not say no to that, either. I said

yes, if you have an objective response. You have

to remember there is an uncertainty factor, and I

don\'t know the right term to apply, but that

applies to that individual based on the multiple

factors that have been discussed: whether their

asthma is under control, time of year, time of day,

circadian rhythm, other medications, exercise. I

think if you have an objective response at a dose,

it certainly could pose a risk in another

circumstance with that same dose.

DR. GONSALVES: I think we are doing a lot

of talking here, but it seems like Dr. Taylor said

that he is convinced that if you go back and look

at the clinical data, you could get the NOAEL

response there.

It seems to me that one would want to go

back and put this on a more scientific basis, once

you go back and look at those data and see where

you come to your NOAEL reactions.

390

DR. TEUBER: Suzanne Teuber here again.

Again, this would be going back to clinical data

that was mainly on diagnostic challenges in

populations that do not reflect all of the

extremely sensitive people that folks are most

concerned about, whereas the threshold studies have

been really trying to recruit these extremely

sensitive people.

The NOAEL data that might be obtained from

funding, say, the Johns Hopkins group and the

Mount Sinai group to go back might not give the

levels that you would get from a new prospective

challenge study that is really recruiting these

people.

CHAIRMAN DURST: I think we have kind of

moved into the third question there with some of

these comments concerning the thresholds

established for the major food allergens, so I

guess we will continue on along those lines.

\"Is it scientifically sound to use the

threshold established for a single food allergen as

a threshold for all major food allergens?\"

391

Suzanne?

DR. TEUBER: Suzanne Teuber. I would say

no, because we have the examples from soy, at least

from the data that we have, that the thresholds are

higher. It is actually again very, very difficult

to obtain people with lasting soy allergy.

CHAIRMAN DURST: Does anybody disagree or

support that?

Soheila?

DR. MALEKI: Soheila Maleki. I don\'t know

if I would say I agree or disagree, because I\'m not

a clinician, but I actually have a question to add

to that, to anybody that can answer it.

Is there a particular food \-- again, like

they say, for example, peanut \-- that is the most

sensitizing, that if you picked that, you would

pretty much cover the thresholds for the rest,

Suzanne, or somebody that might want to answer

that?

CHAIRMAN DURST: David?

MR. ORYANG: It would seem from the safety

perspective, the public health perspective, it says

392

here, \"In the absence of specific data,\" okay. Is

it scientifically sound to use a threshold

established for a single food allergen?

Yes, if you get the one that more people

react to or react most adversely to and use that as

a safety factor, you know that the other ones that

people don\'t react as much to will be covered.

Wow, I see all of these looks.

(General laughter.)

CHAIRMAN DURST: Okay. Mark?

DR. NELSON: This is Mark Nelson. I guess

the concern I have is that to use a single number,

one wouldn\'t be basing it on the science because we

do have some evidence that there are different

thresholds or different sensitivities for the other

allergens.

Also, then, objectively from a policy

standpoint, if you are going to label everything in

terms of the most sensitive or the most adverse

allergen, then you are going to be ending up

labeling incredible parts of the food supply, which

would hamper the choices of the allergic

393

population.

MR. ORYANG: David Oryang. I would add to

that and say, yes, in the absence of specific data

and if the allergen has data and it can be

compared.

I mean, if you know what to apply to a

specific allergen, then I think you use what is

applicable because you have the data. However, if

you don\'t have the data, and you know that people

react to it, where do you set the level? Maybe you

tie it to something that you believe is rather

similar or more reactive, and you know that you\'ve

covered it in the absence of data.

CHAIRMAN DURST: Okay.

DR. KELLY: Ciaran Kelly. I have two

difficulties with this approach. The first is

exactly what Mark mentioned, and that is, that

would be setting an unnecessarily low level. For

example, soy would have to be reduced to the level

of some far more generally allergenic compound such

as tree nuts or peanuts, that\'s the first.

The second is there is a fallacious

394

assumption here that somehow you can know which is

the most allergic without knowing the level, the

threshold level, for each. In order to choose the

most allergic, you have to know which is the most

allergic.

(General laughter.)

DR. KELLY: Basically, when you work

through it, you can\'t do it.

CHAIRMAN DURST: Marc?

DR. SILVERSTEIN: Mark Silverstein. We

often use epidemiologic studies to make inferences

about individuals. We may make an inference based

on the prevalence in a population or the severity

of a condition in a population about what that may

have as an impact for individuals.

However, that usually assumes homogeneity

in the population when we are going from population

data to individual data; and, similarly, going from

specific allergen, we are basically assuming some

homogeneity in the response.

I think we have enough evidence from other

areas to say that it is this homogeneity assumption

395

that we are uncomfortable with. I think there is

reason to believe, because we have some insight

into the nature of allergic responses, how variable

it is across allergens and individuals, that maybe

the assumptions going from allergens to rather

specific allergens wouldn\'t be valid; and,

similarly, going from population studies to

individual studies might not be met.

CHAIRMAN DURST: Dick Durst. I would just

like to comment that to me this approach is very

arbitrary. To me it is similar to the statutory

approach. It seems to be a one-size-fits-all type

of approach.

I think we have probably in the literature

enough data to see that is not really a realistic

way of going about it. We certainly need more data

to nail these thresholds down. From what\'s out

there even now, I think it is not the best approach

to use.

Marc? Oh, I\'m sorry, either Marc or Mark.

DR. SILVERSTEIN: I was just going to ask,

Is Catherine Copp likely be here tomorrow?

396

MRS. MOORE: Yes. Yes, she is here right

now.

DR. SILVERSTEIN: Oh, she is? May I ask

her a question. What I found was interesting was

the paradigm for the statutory approach under an

exemption would say \"Demonstrates that ingredient

\'does not cause an allergic response that poses a

risk to human health.\'\"

I was wondering whether there is some

regulatory precedence for what degree of risk,

either in terms of severity or proportion of

population affected that operationalizes that: no

fatalities, no hospitalizations, or is just less

than some amount in a population? Are there

precedents? What would you use to accept a

position that said that there would be no risk?

MS. COPP: Well, I think in a way

Steve Gendel answered your question when it was

posed in a more general way, and that is, we are

asking you to give us guidance on how to, for lack

of a better term, do risk assessment evaluation,

lower case risk assessment.

397

I\'m sorry, I didn\'t put my name on the

record, Catherine Copp. It seems to be a problem

with all of us this late.

(General laughter.)

MS. COPP: In terms of applying what is

the statutory standard, that would involve risk

management, which could involve and likely involve

more factors than simply the scientific

information, so that is one piece of the answer.

The other piece is in implementing this

statute we would seek to implement Congress\'

intention. I\'m not in a position \-- I am not

counsel to the Center anymore, I was, some of you

know that. We need to think about that along with

what does that statutory language mean.

There are, just as a general rule \-- and

we have counsel here but I don\'t think he is going

to answer the question any more than I am \-- the

general tools that we use for statutory

construction would be available to us. I know that

is not a specific answer, but that is really

because we are not there really yet.

398

Do you want to ask a follow-up and see if

I can avoid that one, too?

(General laughter.)

DR. SILVERSTEIN: No, I would just like to

reserve the right to ask a follow-up. I need time

to think about this.

(General laughter.)

DR. SILVERSTEIN: I guess I will make the

inference that there isn\'t a lot of guidance in

terms of high the risk might be or the nature of

that risk?

MS. COPP: To the extent that there is

guidance, maybe I can answer it this way. To the

extent that there is guidance, I think as a

scientist you would not find it very specific. Is

that a fair response?

CHAIRMAN DURST: Mark, I think you had

your hand up?

DR. NELSON: I just wanted to respond to

your comment, Mr. Chairman, about the arbitrariness

of the statutory approach, and to some extent it

is. It is based on the scientific expertise of the

399

U.S. Congress.

(General laughter.)

DR. NELSON: I think also as pointed out

here and I think the results of the Threshold

Working Group\'s report this would give us a

starting point to deal with some of the allergens

potentially as we gather information, gather more

data to deal with the others. I think it is a

starting point from an operational and a policy

standpoint.

DR. KELLY: A related question. To my

mind, the statutory approach isn\'t so much an

approach as almost a loophole or a back door method

to set a relatively arbitrary threshold.

My impression is that the intent was to

say since there is no negligible allergen present

in the oils and since they are widely used, that

you could continue using them, not to say that the

level that might be present inadvertently in some

is safe.

That is another approach that hasn\'t been

discussed, and that is to take foods which are

400

currently well tolerated by individuals with

allergies and determine what the levels of

contaminating allergens are and use that

information as a mechanism to approach what are

currently well-tolerated levels.

That is an approach that perhaps hasn\'t

received sufficient consideration because that is

an approach, for example, that we will be hearing

about tomorrow in relationship to celiac disease.

It is an approach that has been taking patients who

are currently taking foods with trace levels of

gluten but are doing very well clinically.

CHAIRMAN DURST: Soheila?

DR. MALEKI: Soheila Maleki. I kind of

want to \-- well, it maybe semi-controversial \--

follow up what Marc, too, said. Yes, it may seem

like a box, kind of loophole type of thing again.

Actually, I posed the question originally, but I

never made any comments on this.

Anne, if you have any comments on this,

well, feel free to make them because I don\'t want

to speak for the consumer.

401

However, I do know that consumers know

there is, for example, milk in this product, I

don\'t care how long you tell them it is they are

never going to eat it, if it is labeled that way.

I don\'t really see a harm in picking the

lowest maybe for now. For example, right now the

thresholds for peanut are being worked on, so I

don\'t really see the harm in picking the lowest and

using that as a guidelines just to start with until

we have better methods.

If you tell a consumer, I mean, \"Yes, it

has caseine\" or don\'t label it at a higher label,

it doesn\'t matter because they are still not going

to eat a product that has that. They would much

rather know it is at the lowest possible level and

avoid it than to not label it because it is going

to limit their choices. They wouldn\'t have eaten

it in the first place anyway. They just want to

know that it is in there, if that makes any sense.

MS. MUNOZ-FURLONG: Right.

DR. MALEKI: It would be preferable to

just have the lowest possible limit you have and

402

then say \--

DR. BRITTAIN: Do you mean the limit of

detection? Is that what you mean?

DR. MALEKI: Like, right now we know

peanuts \-- Soheila Maleki \-- and, again, whether

you want to consider the most severe food or the

more prevalent food, that is a question that comes

up.

In this case, threshold levels for one of

the most severe food allergic reactions, which is

peanuts, is being determined. We are pretty close

to that. Could that actually be used for other

foods?

I know it seems like a cookie-cutter type

of choice, but, on the other hand, I wonder if the

food-allergic consumer wouldn\'t much rather have

that than wait around for another 8 to 10 years

until they figure out what the thresholds for the

other foods are. That is just a comment.

CHAIRMAN DURST: Jean?

MS. HALLORAN: Actually, this is a

question for FDA, but I\'m not sure FDA has the

403

option to wait around for 8 or 10 years. I think

it has to put out rules in the interim.

Their final question here is if you don\'t

use peanut as your threshold for other categories

like soy where you don\'t have much data, is there a

more appropriate method to use? That is their

final question to us. I am having a hard time

thinking of a better alternative, so I agree with

Dr. Maleki. DR. MALEKI: Soheila Maleki.

I agree. Again, we have pretty much, just based on

discussion that has come out said you can\'t really

set a method because you don\'t have the data. You

can\'t do modeling because you don\'t really have the

data. Right now, Dr. Hefle and Taylor are working

on organizing a group or have already started doing

the first real valid threshold dose studies that

are happening. This is data that is going to be

available, hopefully, soon.

At least it is something to go on versus

waiting around like she said, because there is no

funding, it takes a year, it takes \$200,000 or so

to do it. Do we really want to wait for that to

404

happen?

CHAIRMAN DURST: Dick Durst. That is

certainly erring on the side of security and

safety. The other side of the coin, though, is now

you are going to be limiting people\'s abilities to

get foods that would be perfectly safe for them,

but it has now fallen into this threshold level

that, you know, says, \"Oh, no, if there is

something in there, don\'t touch it.\"

I\'m not sure, maybe a person with an

allergy would rather not have to try and have

access to some of these other foods, if there is

even the slightest chance of an allergen being

present.

DR. MALEKI: If I can answer that real

quick. As of now the detection kits that can

detect, for example, a product like this, that says

there is soy product in this candy bar or whatever,

that kit can detect a very, very low limit. The

industry is already labeling that as \"may contain.\"

They are already not going to eat that product.

Do you see what I\'m saying? As far as the

405

level of detection of the kit is below what they

would touch anyway. I don\'t know if it would limit

their choices. I think they would rather know.

DR. NELSON: This is Mark Nelson. I

don\'t think that is an accurate generalization

about the label.

DR. MALEKI: Okay. Go ahead.

DR. NELSON: No, I was just going to say I

don\'t think that is an accurate generalization

about the label.

DR. MALEKI: I\'m sorry? I don\'t

understand.

DR. NELSON: Just because a kit detects

it, depending on the sensitivity of the kit, it may

not necessarily be labeled if it is below a certain

level.

DR. MALEKI: Soheila Maleki. Can you

comment on that a little further? What do you mean

by that?

DR. NELSON: I think it refers to the rule

of thumb that Steve Taylor was talking about

earlier, that a lot of the industry has been using

406

in the absence of specific regulation.

DR. WASLIEN: Which is what?

DR. NELSON: It depends on the company,

what they use. Some of them use 10, some of them

use 5.

DR. WASLIEN: Okay.

CHAIRMAN DURST: Okay.

DR. MALEKI: Soheila Maleki. I agree with

you, but the level still is pretty low is it is

higher than 10 parts per million or 2 parts per

million.

DR. NELSON: Yes, it is.

DR. MALEKI: We are not talking \-- it is

not like the ingredient is there.

DR. NELSON: Right.

DR. MALEKI: All the \"may contains\" now

will be based on new label rules that will say

\"contains.\" It is no longer to be \"may contain.\"

DR. NELSON: Exactly, but there is an

ingredients label.

CHAIRMAN DURST: Okay.

Jeff?

407

DR. BARACH: Jeff Barach. I do agree with

the Chair and his comment about the fact that if

the level is set at the lowest possible level for

all allergens that we will see a proliferation of

labels that do contain information on allergens,

and that will limit the food choices for the

allergenic population.

To get to the last part of the question

that was brought up earlier, is there a more

appropriate method to use? I don\'t really

subscribe to that method, but if we are forced into

a box and we have to choose that type of method, I

would say that there is a possibility of grouping

some of these allergens together. That may be to

an advantage.

The levels of, say for instance, soy and

wheat are much higher than perhaps for peanut

protein, so there may be some opportunity to group,

say for instance, nuts, peanuts and soy and wheat

together to set levels rather than choose the

lowest for everything, which would cause a lot of

problems.

408

CHAIRMAN DURST: Okay.

DR. MALEKI: Just real quick. Soheila

Maleki. Again, it is in the absence of data, so

you can\'t group things together when there is no

data for the rest of the groups. Of course, that

is assuming you want an answer soon.

CHAIRMAN DURST: Okay. I would just like

to suggest the Chair has arbitrarily set 6 o\'clock

as our deadline, so why don\'t we just quickly

discuss, we have 15 minutes left to discuss the

last part, which we touched on already, these

highly refined oils. Would anyone like to make

some comments on the questions in there?

Petr?

DR. BOCEK: Petr Bocek. Well, we know

that there are allergens which the epitopes are

confirmational. They are epitopes which are

linear. Some preliminary data from Hugh Sampson\'s

lab are showing that people who are allergic to the

linear epitopes are actually more prone to the more

severe reactions.

I don\'t really know what the construction

409

entails, but I would be really concerned about the

denaturing of the protein and losing some of the

epitopes which would be allergenic in the protein

in the oils. That may be a reason that just the

level of the protein and the allergenicity of the

extracted oil may not be very well correlated. I

would have a problem with that.

CHAIRMAN DURST: Anyone else on that

topic? That was a good point.

DR. WASLIEN: You know, there is also the

question of oil level itself influencing the

absorption of allergens. If you are using

high-extraction oils as a standard, you are sort of

giving yourself an added safety factor, not safety

but a protective factor for setting limits or too

high a limit because of that oil protection or oil

interference with absorption. You may be using

protection when I shouldn\'t be using protection,

but that factors in there, too.

> DR. MALEKI: Soheila Maleki. I would like to refer that to one of the
> panel members, either Steve or Sue, which have done

studies with oil, or do you have anything to say

410

with that as far as can the oils be used, the

protein level in the oil being used, to determine

the thresholds?

DR. TAYLOR: (No microphone.) Since I

have absolutely zero confidence in the protein

levels that have been published in oil, I wouldn\'t

presume to use this approach to write regulatory

standards.

(General laughter.)

DR. MALEKI: Steve, I knew I\'d get an

answer out of you on that one.

DR. TAYLOR: (No microphone.) It\'s late

in the day.

CHAIRMAN DURST: Yes. Dick Durst. As

Petr said, I think that would probably give an

erroneously high threshold because of the fact that

you are looking at total protein, and it may be

that a lot of it has been denatured to the point

where you still detect it as a protein, but it does

not have the allergenic effect any longer. I think

that was a good point.

Yes?

411

DR. KELLY: Ciaran Kelly. Could that

problem be overcome or reduced by using an enzyme

immunoassay for detection? Have any studies like

that been done, or has it always been totally

protein?

MS. MUNOZ-FURLONG: (No microphone.) No,

no study has been done using ELISA. I don\'t trust

those either for oil substances, using it in

not-risk kind of situations. I don\'t trust the

data any more if you have the ELISA test. IgE

levels have been used in some cases, too.

DR. KELLY: Are there any circumstances

where antigenic activity was identified in these

oils.

MS. MUNOZ-FURLONG: Yes.

DR. TAYLOR: (No microphone.) Yes, there

are \--

MRS. MOORE: Excuse me. If you don\'t talk

into a mike, it might not make it into the

transcript, so I\'m going to have to ask you to go

ahead and repeat, because we\'ve gotten in trouble

for that in the past.

412

(General laughter.)

MRS. MOORE: Just summarize what you just

said.

DR. TAYLOR: Traces of IgE-binding

proteins, allergens, are present in oils, that is

for sure. The problem is there is so little

protein there and it is so hard to extract it out

of the oil into an aqueous environment so that you

can use aqueous testing systems.

The results are probably somewhat below

the lower limit of sensitivity of the testing

systems that have been used. Frankly, I don\'t yet

trust any of the data that exists on protein levels

of oil.

That opinion is the same as the European

Food Safety Authority\'s expert panel in reviewing

data on soybean oil and peanut oil. They said they

trusted the clinical data that was done, but they

didn\'t trust the protein data. They are making the

industry in Europe go back and develop actually a

better protein method, which I hope they will be

successful.

413

DR. NELSON: Steve \-- this is Mark Nelson

\-- there is data from a clinical standpoint about

soy oil and its reactivity?

DR. TAYLOR: No. We finished the soy oil

clinical challenge trial using that famous 29

subjects.

(General laughter.)

DR. TAYLOR: None of them reacted to

highly refined soybean oil. We took 30 soybean

oils from 30 different facilities around the world,

and we tested them for protein.

We made an oil challenge vehicle out of

the three oils that tested highest for protein

using the method that I don\'t trust, but it was as

good as we could do.

Highly refined peanut oil has been

suggested. Jonathan Hourihane did a study with 58

people, there have been at least another 20 or 30

challenges in other trials, and nobody has ever

reacted to peanut oil in any of these controlled

clinical challenge trials.

Usually, with cumulative doses up to 15 or

414

16 milliliters of oil, which would be equivalent to

about the maximum amount you would likely get in a

meal.

I think the oils are safe, but if you ask

me how much protein is in them, I\'ve got to dance

around that. At the moment, I don\'t think anybody

quite knows. It\'s not enough to provoke a

reaction, but there is some there.

CHAIRMAN DURST: Well, the Chair is

feeling generous and tired.

(General laughter.)

CHAIRMAN DURST: Unless Marcia has some

final comments\--? No?

MRS. MOORE: No.

CHAIRMAN DURST: Well, I would like to

thank everybody for participating today. I think

we start at 8:30 tomorrow morning. Thanks to all

of the speakers for their contributions also.

(Whereupon, at 5:50 p.m., the meeting was

adjourned, to reconvene at this same place on

Thursday, July 14, 2005, at 8:30 a.m.)

\- - -