1

 

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                       FOOD AND DRUG ADMINISTRATION

 

               CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

 

 

 

 

 

 

 

 

 

 

                     FOOD ADVISORY COMMITTEE MEETING

 

                     Advice on CFSAN'S Draft Report:

 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Wednesday, July 13, 2005

 

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

 

 

 

 

                            Greenbelt Marriott

                              6400 Ivy Lane

                              Grand Ballroom

                        Greenbelt, Maryland 20770

                                                                  2

 

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

 

       FOOD ADVISORY COMMITTEE STANDING MEMBERS:

 

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

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

       Patrick S. Callery, Ph.D.

       Dennis Gonsalves, Ph.D., M.S.

       Jean M. Halloran (Consumer Representative)

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

       Margaret C. McBride, M.D.

       Mark Nelson, Ph.D. (Industry Representative)

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

 

       TEMPORARY VOTING MEMBERS:

 

       Petr Bocek, M.D., Ph.D.

       Margaret Briley, Ph.D., R.D.

       Erica Brittain, Ph.D.

       Ciaran P. Kelly, M.D.

       Soheila June Maleki, Ph.D.

       David O. Oryang

       Marc D. Silverstein, M.D.

       Suzanne Teuber, M.D.

 

       FOOD AND DRUG ADMINISTRATION:

       Catherine Copp, J.D. - Senior Policy Advisor

       Food and Drug Administration, CFSAN

 

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

       Food and Drug Administration

       National Center for Food Safety and Technology

 

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

       Food and Drug Administration, CFSAN

 

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

 Food and Drug Administration, CFSAN

 

       Stefano Luccioli, M.D. - Senior Medical Advisor

       Food and Drug Administration, CFSAN

 

 Marcia Moore, Food Advisory Committee, Executive Secretary

 

       Jenny Slaughter - Director

       Food and Drug Administration Integrity and Ethics Staff

                                                                  3

 

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

 

       GUEST SPEAKERS:

 

       Rene Crevel, Ph.D. - Senior Scientist

 Unilever, Safety and Environmental Assurance Centre, United Kingdom

 

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

 Food Allergy Research and Resource Program, University of Nebraska

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

 CFSAN, FDA Assistant Professor, Georgetown University

 

       Anne Munoz-Furlong

 Director, Food Allergy & Anaphylaxis Network

 

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

 Food Allergy Research and Resource Program, University of Nebraska

 

       Robert Wood, M.D. - Professor

 Johns Hopkins University School of Medicine

                                                                  4

 

                             C O N T E N T S

 

                                                               PAGE

 

       Call to Order, Welcome and Introductions

       Charge to the Food Advisory Committee

                 Richard Durst, Ph.D., Acting Chairman            6

 

       Conflict of Interest Statement & Other

       Instructions

                 Jenny Slaughter, FDA                            10

 

       Welcome and Opening Statement

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

 

       Use of Food allergen Thresholds

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

 

       Introduction to Food Allergens

                 Robert Wood, M.D.                               23

 

       Patient Perspectives on Food Allergies

                 Anne Munoz-Furlong                              72

 

       Allergenicity:  Analytical Methods

                 Susan Hefle, Ph.D.                              99

 

       Question and Answer Session                              126

 

       Oral Challenge Studies:  Purpose, Design,

       and Evaluation

                 Stefano Luccioli, M.D.

                 Senior Medical Advisor, CFSAN, FDA             133

 

       Question and Answer Session                              161

 

       Threshold Modeling Approach

                 Rene Crevel, Ph.D.                             170

 

       Food Allergen Thresholds

                 Steve Taylor, Ph.D.                            189

 

       Overview of Approaches to Establishing

       Thresholds:  Allergens

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

                                                                  5

 

                       C O N T E N T S (Continued)

 

                                                               PAGE

 

       Public Comments:

 

                 Tracy Atagi                                    228

 

                 John Carroll                                   232

 

                 Diane Castiglione                              242

 

 

                 Will Duensing                                  247

 

                 Martin J. Hahn, Esq.                           250

 

                 Peggy Mockett                                  254

 

                 Kim Mudd                                       257

 

                 Kim Mulherin                                   260

 

                 Linda Webb                                     264

 

                 Jupiter Yeung                                  268

 

       Committee Discussion:

 

                 Panel Discussion with Guest Speakers

                 Thresholds for Food Allergens - Questions      272

 

       Adjournment

 

                 Richard Durst, Ph.D., Acting Chairman          414

                                                                  6

 

                          P R O C E E D I N G S

 

                CALL TO ORDER, WELCOME, AND INTRODUCTIONS

 

                  CHARGE TO THE FOOD ADVISORY COMMITTEE

 

                 CHAIRMAN DURST:  I would like to call the

 

       meeting to order.

 

                 Good morning.  I am Dick Durst, professor

 

       of chemistry in the Food Science and Technology

 

       Department at Cornell University.  I was asked to

 

       chair this meeting over the next two and a half

 

       days.  I would like to make a few announcements

 

       before we begin our meeting this morning.

 

                 I would appreciate it if everyone would

 

       turn off their cell phones, unless they are

 

       expecting a call of a super emergency nature.  I

 

       would also like to ask if the guest speakers could

 

       make themselves available for the discussion this

 

       afternoon, I would really appreciate it.  We may

 

       have some additional questions.

 

                 We have received a charge from the FDA to

 

       give our evaluation of the draft report prepared by

 

       the Threshold Working Group.  I assume all of the

 

       members have read that thoroughly.  In my opinion,

                                                                  7

 

       I it was fascinating.

 

                 It was an excellent article and I commend

 

       the Committee for coming up with it.  It was very

 

       educational.  Not being an expert on food allergens

 

       myself, it was extremely educational, and I was

 

       able to follow it quite clearly.

 

                 Our charge is to evaluate this report to

 

       determine whether the approaches that are presented

 

       in there are the only ones or the better ones,

 

       which of the ones that are in there might be the

 

       most appropriate.  This is the focus of our meeting

 

       today, both on the food allergens and on gluten.

 

 

                 Let me also begin by asking the committee

 

       members to introduce themselves.  We will start

 

       with Dr. Silverstein.

 

                 Marc, would you start it off?

 

                 DR. SILVERSTEIN:  Good morning.  My name

 

       is Marc Silverstein, and I'm a general internist

 

       and geriatrician at Baylor Health Care System in

 

       Dallas.

 

                 DR. TEUBER:  Good morning.  My name is

 

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

                                                                  8

 

                 MR. ORYANG:  Good morning.  I am

 

       David Oryang.  I am a risk analyst and agricultural

 

       engineer at the United States Department of

 

       Agriculture, Animal and Plant Health Inspection

 

       Service.

 

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

 

       gastroenterologist at the Harvard Medical School in

 

       Boston.

 

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

 

       scientist with the USDA.

 

                 DR. BRITTAIN:  Erica Brittain, I am a

 

       statistician at the National Institute of Allergy

 

       and Infectious Disease.

 

                 DR. BRILEY:  Margaret Briley, University

 

       of Texas at Austin, nutritionist.

 

                 DR. BOCEK:  Good morning.  I am

 

       Petr Bocek, medical officer in NIH's National

 

       Institute of Allergy and Infectious Diseases.

 

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

 

       the FDA as the executive secretary of the Food

 

       Advisory Committee.

 

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

                                                                  9

 

       nutritional epidemiologist at the University of

 

       Hawaii.

 

                 DR. McBRIDE:  I am Margaret McBride.  I am

 

       a child neurologist at Akron Children's Hospital.

 

                 DR. CALLERY:  I am Patrick Callery, a

 

       pharmaceutical scientist from West Virginia

 

       University.

 

                 DR. GONSALVES:  I am Dennis Gonsalves, a

 

       scientist with USDA in Hawaii.

 

                 DR. HEIMBURGER:  I am Doug Heimburger, a

 

       physician and nutrition specialist at the

 

       University of Alabama at Birmingham.

 

                 DR. BARACH:  Jeff Barach with Food

 

       Products Association, vice president for special

 

       projects and regulatory affairs.

 

                 DR. NELSON:  Mark Nelson with the Grocery

 

       Manufacturers Association responsible for

 

       regulatory and scientific policy.

 

                 MS. HALLORAN:  Jean Halloran from the

 

       Consumers Union where I am director of food policy

 

       initiatives.

 

                 CHAIRMAN DURST:  Thank you very much.

                                                                 10

 

                 One other item is that we may have some of

 

       our members leave early on Friday, depending on the

 

       amount of time we can spend.  What I propose is

 

       that today and tomorrow that we anticipate having

 

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

 

       that we have enough time for all of our

 

       discussions.

 

                 Okay.  Let me introduce our first speaker.

 

       This will be Jenny Slaughter, director of Ethics

 

       and Integrity Staff at the FDA, to describe the

 

       "Conflict of Interest Statement" and other

 

       instructions.

 

                      CONFLICT OF INTEREST STATEMENT

 

                          AND OTHER INSTRUCTIONS

 

                 MS. SLAUGHTER:  Well, good morning and

 

       welcome.  The Food and Drug Administration is

 

       convening today's meeting of the Food Advisory

 

       Committee under the authority of the Federal

 

       Advisory Committee Act of 1972.

 

                 With the exception of the industry

 

       representatives, all members of the Committee are

 

       special government employees or regular Federal

                                                                 11

 

       employees from other agencies subject to Federal

 

       conflict of interest laws and regulations.

 

                 FDA has determined that members of this

 

       Advisory Committee are in compliance with Federal

 

       ethics and conflict of interest laws including, but

 

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

 

       354.

 

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

 

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

 

       applicable to only FDA, Congress has authorized FDA

 

       to grant waivers to special government employees

 

       who have financial conflicts when it is determined

 

       that the Agency's need for particular

 

       interventional services outweighs the potential

 

       conflict of interest.

 

                 Members who are special government

 

       employees at today's meeting including special

 

       government employees appointed as temporary voting

 

       members, have been screened for potential financial

 

       conflicts of interest of their own as well as those

 

       of their spouse, minor child, and employer, which

 

       are related to the discussions of today's and

                                                                 12

 

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

 

       Draft Report: Approaches to Establish Thresholds

 

       for Major Food Allergens and for Gluten in Foods."

 

                 These interests may include investments,

 

       consulting, expert witness testimony, contracts,

 

       grants, research and development agreements, public

 

       speaking, writing, patents, royalties, and primary

 

       employment.

 

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

 

       full waivers have been granted to the following

 

       participants, Dr. Suzanne Teuber and Dr. Soheila

 

       Maleki, please note that all of the interests in

 

       the firms that could potentially be affected by the

 

       Committee's decisions.

 

                 A copy of the written waiver statements

 

       may be obtained by submitting a written request to

 

       the Agency's Freedom of Information Office, Room

 

       12A-30 of the Parklawn Building.

 

                 In addition, the following individuals are

 

       participating as FDA's invited guest speakers,

 

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

 

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

                                                                 13

 

       Dr. Robert Wood.

 

                 The following individuals will be

 

       participating as FDA invited guest speakers

 

       tomorrow, July 14th: Dr. Pekka Collin,

 

       Dr. Alessio Fasano, Dr. Donald Kasarda,

 

       Dr. Cynthia Kupper, and Dr. Joseph Murray.

 

                 Lastly, I would like to report that

 

       Dr. Jeffrey Barach and Dr. Mark Nelson are serving

 

       as the industry representatives on the Committee at

 

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

 

       regulated industry.

 

                 Dr. Jeffrey Barach is employed by the

 

       National Food Processors Association and

 

       Dr. Mark Nelson is employed by the Grocery

 

       Manufacturers of America.

 

                 A copy of this document will be placed on

 

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

 

       it.  I thank you.

 

                 CHAIRMAN DURST:  Thank you very much.

 

       We will now go on to the welcome and opening

 

       statement by Dr. Michael Landa, the deputy director

 

       for Regulatory Affairs at CFSAN, the FDA.

                                                                 14

 

                 Mike.

 

                      WELCOME AND OPENING STATEMENT

 

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

 

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

 

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

 

                 (General laughter.)

 

                 MR. LANDA:  Thanks again.  Good morning to

 

       everyone.  Welcome to the members of the committee,

 

       to the guest speakers, to members of the public who

 

       have joined us today, and to my fellow FDA

 

       employees.

 

                 I would like to give a special thanks to

 

       the Committee members for your willingness to take

 

       time from busy schedules to help us with your

 

       expertise for a meeting that will be several days

 

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

 

       chunk of Friday.

 

                 Let me just add that Dr. Brackett had

 

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

 

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

 

       some portion of the meeting.  He was called

 

       downtown for a meeting this morning.

                                                                 15

 

                 I am going to refer to a couple of points

 

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

 

       apply to celiac disease as well.  It is just less

 

       cumbersome to start with the food allergens.  The

 

       agenda has been making, I think, an opening

 

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

 

       that.

 

                 There are just a few points I want to make

 

       as you go into your inquiry today.  The first is

 

       virtually every FDA speaker makes at this kind of

 

       proceeding which is what we do really is based on

 

       science.

 

                 We talk about being a science-based

 

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

 

 

       In that context, I am going to paraphrase what may

 

       be a rather obscure 19th century Senator, Karl

 

       Shrews from Pennsylvania.

 

                 The paraphrase essentially is, Our science

 

       correct or incorrect, when it is correct, help us

 

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

 

       correct it.  That is as much as anything else what

 

       we want from you here in terms of your expertise in

                                                                 16

 

       the science.

 

                 If with respect to the threshold in the

 

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

 

       know from you that we have gotten it right.  We

 

       want your help in keeping it right.  If we have

 

       gotten it wrong, we want your help in getting it

 

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

 

       not considered an approach that we should have

 

       considered, we want to know that from  you.

 

                 The third point I will make is that

 

       Americans suffer from food allergies, particularly

 

       children.  There is some evidence that the number

 

       is increasing.  If you add to that family members,

 

       you really have tens of millions of folks who are

 

       involved.  At the moment their principle means of

 

       protection really is exquisite attention to the

 

       food label.  That is their pathway to safety I

 

       suppose.

 

                 We are hoping that eventually thresholds

 

       will provide another path to safety.  This is the

 

       beginning of the inquiry into thresholds, that is,

 

       the approaches that are outlined in the report.  It

                                                                 17

 

       is the first step in a very important process.

 

                 The last point I will make is just that

 

       this is as much as anything else for members of the

 

       public, the docket is going to remain open until

 

       about the middle of August.

 

                 If people have comments, based on what

 

       they have heard today, for example, they should

 

       feel free to submit those comments to the docket.

 

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

 

       precise date, but it is the middle of August.

 

                 In that connection, I should say we are

 

       especially interested, as I think is always the

 

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

 

       outlined in the report.

 

                 Thank you.

 

                 CHAIRMAN DURST:  Thank you, Mike.  Since

 

       Mr. Landa didn't want me conferring a doctorate

 

       degree on him, I will not do it with Catherine

 

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

 

       FDA, who will discuss the use of food allergens

 

       thresholds.

 

                     USE OF FOOD ALLERGENS THRESHOLDS

                                                                 18

 

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

 

                 (General laughter.)

 

                 MS. COPP:  Thank you, Dr. Durst.

 

                 Good morning.  As you know, the focus of

 

       this meeting today and tomorrow and the discussion

 

       on Friday is the Draft Report of CFSAN's Threshold

 

       Working Group:  Approaches to Establish Thresholds

 

       for Major Food Allergens and For Gluten in Food.

 

                 I have been asked to provide a context for

 

       the Draft Report in terms of CFSAN's programmatic

 

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

 

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

 

                 (Slide.)

 

                 MS. COPP:  Last August, Congress enacted

 

       the Food Allergen Labeling and Consumer Protection

 

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

 

       awkward acronym "FALCPA."

 

                 This new law amends the Federal Food, Drug

 

       and Cosmetic Act, the principle statute

 

       administered by FDA by requiring that the label of

 

       a food product that is or contains an ingredient

 

       that bears or contains a major food allergen

                                                                 19

 

       declare the presence of the allergen as specified

 

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

 

       in "consumer friendly" terms.

 

                 FALCPA defines a "major food allergen" as

 

       one of the eight foods or food groups or a food

 

       ingredient that contains protein derived from one

 

       of these foods.  Those are listed on the bottom of

 

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

 

       nuts and crustacean shellfish, which were

 

       identified by Congress in the law.

 

                 (Slide.)

 

                 MS. COPP:  The possible existence of

 

       threshold levels for food allergens is an important

 

       scientific issue, as Mr. Landa has pointed out,

 

       associated with our implementation of FALCPA.

 

                 Although the law does not require FDA to

 

       establish thresholds for any food allergen, there

 

       are three possible ways, which are listed on this

 

       slide, that such thresholds could be used to

 

       implement the new law, these are: administering the

 

       petition process provided for in FALCPA,

 

       administering its notification process, and

                                                                 20

 

       addressing the issue or the occurrence of

 

       cross-contact.

 

                 (Slide.)

 

                 MS. COPP:  FALCPA provides two processes

 

       by which an ingredient may be exempt from the

 

       FALCPA labeling requirements, a petition process

 

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

 

       own slides (laughter).  No, okay.

 

                 Under the petition process, an ingredient

 

       may be exempt, if the petitioner demonstrates that

 

       the ingredient does not cause an allergenic

 

       response that poses a risk to human health.

 

                 Given this language for the petition

 

       exemption standard, we believe it will be very

 

 

       important for us to both understand food allergen

 

       thresholds and to have a sound scientific framework

 

       for evaluating the existence of such thresholds.

 

                 Under the notification process, an

 

       ingredient may be exempt, if the notification

 

       contains scientific evidence that demonstrates that

 

       the ingredient does not contain allergenic protein,

 

       or, if FDA has previously determined under the food

                                                                 21

 

       additive approval process that the food ingredient

 

       does not cause an allergenic response that poses a

 

       risk to human health.

 

 

 

                 (Slide.)

 

                 MS. COPP:  Given this language for the

 

       notification exemption standard, we also believe

 

       that it will be very important for us to understand

 

       food allergen thresholds and to have a sound

 

       scientific framework for evaluating the existence

 

       of such thresholds.

 

                 (Slide.)

 

                 Finally, the FALCPA directs FDA to prepare

 

       and submit a report to Congress.  This report will

 

       focus principally on the issue of cross-contact of

 

       foods with food allergens and is to describe the

 

       types, current use of, and consumer preferences

 

       with respect to so-called "advisory labeling."

 

       Processed in a facility that also processes tree

 

       nuts is an example of such labeling.

 

                 Cross-contact may occur during food

 

       production when residues of an allergenic food are

                                                                 22

 

       present in the manufacturing environment and are

 

       unintentionally incorporated into a food.  Because

 

       the food is not intended to contain the allergen,

 

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

 

       label.  In some cases, however, the potential

 

       presence of the food allergen is declared by a

 

       voluntary advisory statement.

 

                 We also believe that understanding food

 

       allergen thresholds and developing a sound

 

       scientific framework for evaluating the existence

 

       of such thresholds may also be useful to us in

 

       evaluating and addressing food allergen

 

       cross-contact and the use of advisory labeling.

 

                 Thank you.

 

                 CHAIRMAN DURST:  Thank you very much.

 

                 Does the Committee have any questions or

 

       discussion of this presentation?

 

                 (No verbal response.)

 

                 CHAIRMAN DURST:  If not, I think we will

 

       proceed.

 

                 The next speaker is Dr. Robert Wood,

 

       professor at Johns Hopkins University School of

                                                                 23

 

       Medicine, who will give us an introduction to food

 

       allergens.

 

                      INTRODUCTION TO FOOD ALLERGENS

 

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

 

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

 

       provide an overview of food allergens and food

 

       allergy leading into the discussion that is going

 

       to go on over these next couple of days.

 

                 (Slide.)

 

                 DR. WOOD:  The beginning of this, any talk

 

       about food allergy really requires that we have

 

       some common definition that we can all agree on.

 

       This is something that is not as easy as it might

 

       sound and often generates a lot of confusion.  The

 

       reality is that a lot of what is called food

 

       allergy is really not food allergy and may fall

 

       under more of a food intolerance category.

 

                 When we are talking about food allergy,

 

       there are a couple of key ingredients.  One of them

 

       is that there is an immunologic component to the

 

       reaction.  The reaction is typically to the protein

 

       component of the food as opposed to a food

                                                                 24

 

       intolerance that is more often related to the

 

       carbohydrate component of the food.  Importantly to

 

       this meeting, exquisitely small amounts may cause a

 

       reaction and that these reactions can be severe and

 

       even life threatening.

 

                 (Slide.)

 

                 DR. WOOD:  The pathophysiology of the

 

       allergic response is sort of very schematically

 

       diagramed here.  What we are thinking about is a

 

       process that begins with exposure and with most

 

       allergy, probably all allergy, you have to have

 

       some prior exposure to develop your sensitivity.

 

                 (Slide.)

 

                 DR. WOOD:  There is a genetic

 

       predisposition that makes some people particularly

 

       more prone to develop allergy in general, whether

 

 

       it be food allergy or respiratory allergy, than

 

       others.   There are some people who no

 

       matter what, how, when and where they are exposed

 

       they will never develop an allergy, and others who

 

       with very trivial exposure may develop a severe

 

       allergy.

                                                                 25

 

                 If you are in this group who is

 

       genetically predisposed, your immune system then

 

       goes through a process we will refer to as

 

       sensitization.  Sensitization is most often

 

       involving the production of IgE antibodies.  We

 

       will talk about this in a little bit more detail

 

       about some different food allergy syndromes.

 

                 However, it is also important to note that

 

       not every food allergy involves IgE and that there

 

       may be differences in the types of reactions and

 

       the doses of food required to induce a reaction in

 

       those patients that have IgE versus

 

       non-IgE-mediated food allergy.

 

                 Once you have become sensitized, then

 

       reexposure to this food will lead to symptoms.

 

       These symptoms may be abrupt, they may occur within

 

       seconds of eating the food, or they may be very

 

       low-grade and chronic.  This is another concept

 

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

 

                 With some patients it will be very easy to

 

       determine a threshold, and in some patients it will

 

       be virtually impossible to determine a threshold

                                                                 26

 

       because their symptoms will not appear in a

 

       challenge test.  They may take days or weeks of

 

       chronic exposure and then develop very significant

 

       disease based on that chronic exposure.

 

                 (Slide.)

 

                 DR. WOODS:  The prevalence of food allergy

 

       is substantial.  The numbers that we would be most

 

       comfortable with would be 5 to 7 percent of young

 

       children; 2 to 3 percent of adolescents and adults;

 

       at least 10 or 11 million Americans affected.

 

                 We do believe that the prevalence is

 

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

 

       food allergy.  There has been a substantial rise in

 

       asthma and other allergic diseases as well as food

 

       allergy.

 

                 Now, the reason that these numbers change

 

       between childhood and adolescence and adulthood is

 

       because a large proportion of food allergy is

 

       outgrown over the first five to seven years of

 

       life.

 

                 (Slide.)

 

                 DR. WOOD:  There is a long list of

                                                                 27

 

       potential food allergens out there.  At least 200

 

       foods have been identified and characterized as

 

       truly food allergens, but there is a relatively

 

       shorter list that are focused upon because they are

 

       responsible for the vast majority of food allergy

 

       that occurs.

 

                 The list on the left-hand side

 

       representing what is most common in young children:

 

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

 

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

 

       older children, adolescents and adults and is

 

       dominated by peanuts, tree nuts, fish, and

 

 

       shellfish.

 

                 The reason that this list changes from

 

       childhood to adulthood is because four of these

 

       most common food allergens in your children --

 

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

 

       outgrown.

 

                 Eighty to 90 percent of children will

 

       outgrow those food allergens and not carry them

 

       into adolescence or adulthood, whereas the peanuts,

 

       tree nuts, fish and shellfish are significantly

                                                                 28

 

       more difficult to outgrow, less commonly outgrown,

 

       and tend to persist into adulthood and actually

 

       through the patient's entire lifespan.

 

                 (Slide.)

 

                 DR. WOOD:  Now, the signs and symptoms of

 

       food allergy are highly varied.  They may be

 

       chronic and low grade as I mentioned, they may be

 

       acute and life threatening.  What I want to run

 

       through in the next couple of minutes are just some

 

       examples of allergic reactions that will point out

 

       a number of things about not only the kinds of

 

       reactions, but the exquisitely small amounts of

 

       food that induce these reactions we are going to

 

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

 

       patients with food allergy are facing.

 

                 (Slide.)

 

                 DR. WOOD:  The first couple of patients I

 

       am going to show you have urticaria or hives.  This

 

       is a total body hive reaction that this boy is

 

       experiencing, a patient I have known since he was

 

       an infant.

 

                 He is school age at this point.  This

                                                                 29

 

       reaction occurred when he was in the grade school

 

       cafeteria, was being teased about this food

 

       allergy, another child blew a straw full of milk

 

       across the table into his face, and he had this

 

       really significant reaction.

 

                 (Slide.)

 

                 DR. WOOD:  This baby here was identified

 

       with milk allergy in the first few weeks of life.

 

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

 

       allergy until they are two or three or four years

 

       old, while there are others who are really

 

       demonstrating food allergy in the first days of

 

       life.

 

                 This was a baby who was so allergic that

 

       he would react very acutely if his mother, who was

 

       breast feeding him, ingested any milk protein.  She

 

       was on a very strict avoidance diet after we

 

       identified his milk allergy, but on the occasion of

 

       her birthday ate a piece of cheesecake, breastfed

 

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

 

       hive reaction.

 

                 (Slide.)

                                                                 30

 

                 DR. WOOD:  Now, when we are thinking about

 

       urticaria or hives, there are patients that may

 

       have chronic urticaria.  Food allergy is rarely a

 

       cause of chronic urticaria.

 

                 However, when someone shows up with an

 

       acute episode of hives, the chance that it is food

 

       allergy becomes higher.  Again, we are looking a

 

       relatively short list of foods that are most

 

       commonly implicated: peanut, nuts, eggs, milk,

 

       fish, and shellfish.

 

                 Importantly, these reactions are usually

 

       very quick in their onset.  Ninety percent of them

 

       or thereabouts will have an onset within 30

 

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

 

       and virtually all of them, within 2 hours.

 

                 When a patient has this type of reaction,

 

       it is often very easy to identify the culprit food

 

       because of the abrupt association of the ingestion

 

       of that food with the onset of these hives.

 

                 Then, in more severe episodes, there may

 

       be swelling or angioedema or associated

 

       gastrointestinal or respiratory symptoms.  That is

                                                                 31

 

       moving into more of a systemic reaction that we

 

       would refer to as "anaphylaxis."

 

                 (Slide.)

 

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

 

       is having an anaphylactic reaction.  When you look

 

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

 

       you see her front, though, she is having swelling

 

       and breathing difficulty.

 

 

 

                 (Slide.)

 

                 DR. WOOD:  This is a patient who was

 

       having a reaction in the midst of a food challenge

 

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

 

       dose of egg protein, she went into this very

 

       severe, anaphylactic reaction.

 

                 (Slide.)

 

                 DR. WOOD:  This boy here is someone who is

 

       having a dramatic episode of swelling.  His

 

       reaction occurred.  Most patients, we should say,

 

       who are having severe reactions know about their

 

       food allergy and are making efforts to avoid it.

 

                 He was shellfish allergic -- he is

                                                                 32

 

       shellfish allergic.  He was making efforts to avoid

 

       shellfish, and he had been reaction-free for

 

       several years.

 

                 Then, on another birthday occasion, he ate

 

       chicken in a restaurant and the chicken had been

 

       fried in the same oil as shrimp had been fried.

 

       With that cross-contact, this severe reaction.

 

                 (Slide.)

 

                 DR. WOOD:  Anaphylactic reactions are

 

       defined as a systemic allergic reaction,

 

       involvement of multiple organ systems.  These have

 

       an abrupt onset typically.  They are related to IgE

 

       antibodies.

 

                 You can identify these by doing a skin

 

       test or a blood test looking for IgE.  The

 

       manifestations are not always severe.  There is an

 

       impression that all anaphylaxis is

 

       life-threatening.  Some episodes are relatively

 

       mild, but others progress rapidly to

 

       life-threatening or fatal reactions.

 

                 We think that there are at least 150

 

       deaths in the United States each year due to fatal

                                                                 33

 

       food-induced anaphylaxis.  That number is probably

 

       a substantial underestimation, but we would be very

 

       comfortable saying that it is well identified of

 

       100 to 150 deaths per year.

 

                 There are different types of reactions:

 

       some are single phase and some have two phases,

 

       where a patient may look better and then two or

 

       three or four hours later have an even more severe

 

       reaction than they had initially, some of those

 

       lead to the worst outcomes.

 

                 (Slide.)

 

                 DR. WOOD:  This is a patient with one of

 

       the more chronic forms of food allergies, the

 

       patient with severe itching due to his eczema.  In

 

       Eczema, a food allergy is often underappreciated

 

       because there is not an obvious cause and effect.

 

                 This is one where it is more of a

 

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

 

       harder for a patient or a family member to identify

 

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

 

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

 

       reaction where you don't see these direct

                                                                 34

 

       relationships between ingestion of the food and the

 

       outcome being their eczema or atopic dermatitis.

 

                 It is also a condition where food allergy

 

       is underappreciated by physicians and where

 

       patients may be treated with a variety of different

 

       creams and lotions and only later on find out that

 

       it was really a food allergy that was driving the

 

       eczema.

 

                 Overall, 40 to 50 percent of patients with

 

       severe atopic dermatitis and 20 or 25 percent with

 

       less severe cases have an underlying food allergy.

 

                 The same list of foods: egg allergy being

 

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

 

       and fish.  These six foods account for the vast

 

       majority of food sensitivities seen in atopic

 

       dermatitis.

 

                 From our standpoint, it makes it

 

       relatively easy to screen patients and find which

 

       of them are allergic by testing for a relatively

 

       short list of foods.

 

                 (Slide.)

 

                 DR. WOOD:  Now, the last category that I

                                                                 35

 

       want to mention is something that we will lump

 

       together as gastrointestinal food hypersensitivity.

 

       There are a variety of conditions that fall under

 

       this umbrella.

 

                 There are some that are in the immediate

 

       hypersensitivity category.  This would be part,

 

       say, of an anaphylactic reaction where someone ate

 

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

 

       abdominal pain, or other gastrointestinal symptoms.

 

                 There is another condition called "oral

 

       allergy syndrome" where patients have reactions

 

       that are confined to their mouth or throat or lips,

 

       particularly related to fresh fruits and

 

       vegetables.

 

                 There is another group of conditions that

 

       are lumped under a category of eosinophilic

 

       disorders of the GI tract.  There is a specific

 

       condition, eosinophilic esophagitis, where only the

 

       esophagus is involved.  As most people in the

 

       audience know, the eosinophil is a type of white

 

       blood cell that is most affiliated with allergic

 

       reactions.

                                                                 36

 

                 If you take someone who is having a bad

 

       hay fever day outside today and look at their nasal

 

       secretions, their nasal secretions will be loaded

 

       with eosinophils.  If you take someone that is

 

       having difficult asthma, their bronchial mucosa

 

       will be loaded with eosinophils.

 

                 By the same token, if you have allergic

 

       eosinophilic esophagitis, the lining of your

 

       esophagus is loaded with eosinophils.  It may be

 

       isolated to the stomach, it may be more diffuse

 

       where we would call it "allergic eosinophilic

 

       gastroenteritis."  This is somebody who may have

 

       disease anywhere in their GI tract, and oftentimes

 

       very diffusely.

 

                 There are some other conditions,

 

       enterocolitis syndrome and dietary protein

 

       proctitis, that are much more common in very young

 

       babies.

 

                 The importance of presenting these

 

       different syndromes here is that some of these

 

       syndromes are IgE mediated and some of them are not

 

       IgE mediated, some of them are very acute and some

                                                                 37

 

       of them are very chronic.

 

                 It turns out that those syndromes that are

 

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

 

       any acute symptoms, don't present with any clear

 

       cause and effect of eating the food and having

 

       increased gastrointestinal symptoms are going to

 

       be, potentially, the most difficult for this

 

       Committee to grasp.  That is because these patients

 

       are often reacting to remarkably small exposures.

 

                 I will come back at the end to sort of

 

       give a couple of examples of the dilemma that kind

 

       of patient is going to present to us as we really

 

       try to figure out what is safe and what is not

 

       safe.

 

                 It also turns out in the same vein that

 

       the non-IgE conditions in general are probably

 

       going to be most difficult to deal with, both

 

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

 

       symptoms, and because they are predominantly

 

       mediated by a different part of your immune system

 

       that can recognize even smaller degrees of these

 

       food proteins that identifying thresholds are going

                                                                 38

 

       to be much more difficult.

 

                 (Slide.)

 

                 DR. WOOD:  Now, when we are trying to

 

       approach a patient with a food allergy, one of the

 

       real difficulties is making an accurate diagnosis.

 

       The diagnosis, as in most everything we do, begins

 

       with a history, talking about the foods they

 

       suspect are causing problems, whether we think the

 

       symptoms are consistent with food allergy, whether

 

       this is something that may not be food allergy at

 

       all, or whether it may be a food intolerance rather

 

       than an allergy.  We are going to be interested in

 

       the timing of the symptoms and the reproducibility

 

       of reactions.

 

                 It turns out that when you do a very

 

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

 

       will be correct in the acute reactions, where you

 

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

 

       scrambled eggs for the first time last week, and he

 

       had hives all over."

 

                 "She took her first bite of peanut butter,

 

       and developed hives within 2 minutes."

                                                                 39

 

                 It is very likely that the history will be

 

       born out when you do further testing.  However,

 

       when you look at the bulk of patients with food

 

       allergies, many of them will have these more

 

       chronic conditions like eczema or the

 

       gastrointestinal disorders.  When you are looking

 

       at those patients, you will only verify the history

 

       when you do further testing about a third of the

 

       time.

 

                 (Slide.)

 

                 DR. WOOD:  The next set of tests we do

 

       after taking a history would typically either be

 

       skin testing or serologic testing.  A RAST test,

 

       "radioallergosorbent test," is the most common

 

       serologic test that is used.

 

                 These tests have some value and they also

 

       have some problems.  The problems they have is that

 

       there is a relatively high rate of false-positive

 

       tests.  They do not have a terribly good positive

 

       predictive accuracy.

 

                 They are generally accurate when they are

 

       negative.  Although, they will only be active when

                                                                 40

 

       they are negative when you are convinced this

 

       patient has an IgE-mediated condition, because both

 

       of these tests rely on the presence of IgE

 

       antibodies to identify the specific food allergy.

 

                 An example would be if a patient develops

 

       hives or anaphylaxis, which typically are

 

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

 

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

 

       likely that they have that allergy.  If you get a

 

       negative test back, then you need to keep looking.

 

       It was not likely that food that caused that

 

       reaction.

 

                 However, if you have a patient with

 

       something like the allergic eosinophilic

 

       gastroenteritis where there may not always be IgE

 

       antibodies, you cannot stop with a negative test

 

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

 

       allergy."  That is something that happens all the

 

       time, but it is often going to lead to a

 

       misdiagnosis and mismanagement of that patient.

 

                 The bottom line is that we need to

 

       carefully interpret our tests in the context of the

                                                                 41

 

       overall clinical picture, and that we need to rely

 

       on oral challenge tests as the more accurate tests,

 

       so that we will say that they are not completely

 

       definitive.  They are more definitive but not

 

       completely definitive.

 

                 Again, they are going to be less

 

       definitive in the patients that have more delayed

 

       type reactions or more chronic conditions where

 

       they won't react in that four-hour observation

 

       period of your food challenge.

 

                 (Slide.)

 

                 DR. WOOD:  You are going to hear more

 

       about food challenges this afternoon, but I will

 

       just mention a couple of issues here in terms of

 

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

 

       down as open challenges where both the patient and

 

       the person administering the challenge knows what

 

       is being given.

 

                 A single-blind challenge is where the

 

       patient is blinded but the person administering the

 

       challenge knows the food that is being

 

       administered, whereas a double-blind,

                                                                 42

 

       placebo-controlled challenge is regarded as the

 

       most accurate test because it eliminates the bias

 

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

 

       may be feeling a great deal of anxiety about this

 

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

 

       may have their own biases about this patient's

 

       allergy and might overinterpret or underinterpret

 

       symptoms.

 

                 We would say that these are going to be

 

       the most accurate tests for the diagnosis of food

 

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

 

       results don't provide a clear diagnosis.  That is

 

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

 

       that may not be accurate and laboratory tests that

 

       may not be completely accurate.

 

                 Then, we also do them very commonly to

 

       determine when an allergy has been outgrown.  This

 

       would be a patient who has been known to be

 

       allergic to a food, and we would be monitoring them

 

       with some regularity in determining at some point

 

       that it is worth trying to retry that food.

 

                 We would typically do it in a controlled

                                                                 43

 

       setting, just because even in some patients you

 

       don't expect to react at all there may be

 

       significant reaction.  Consequently, we have to do

 

       these with considerable caution.

 

                 (Slide.)

 

                 DR. WOOD:  I think I pretty much mentioned

 

       this.

 

                 (Slide.)

 

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

 

       briefly, a study that we published last year

 

       looking at the risk of oral food challenges.  What

 

       we have presented in this paper were results on

 

       almost 600 challenges, 253 of which were failed

 

       challenges.  The patients reacted in the challenge,

 

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

 

       other 57 percent, the patients had no symptoms, so

 

       it was a risk-free challenge once they might have

 

       gotten over the anxiety of being there.

 

                 We collected a lot of information on

 

       demographics, other atopic disease, symptoms during

 

       challenges, treatment needed, doses at which

 

       reactions occurred.  Even though there is a lot

                                                                 44

 

       said about safety of food challenges, there has

 

       been very little published before this paper on

 

       what really occurs.

 

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

 

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

 

       front here, that these results are not

 

       representative of the general population of food

 

       allergy.

 

                 These patients that are being challenged

 

       in this either had an unclear diagnosis, so it

 

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

 

       thought to have potentially outgrown their allergy

 

       and were being challenged to potentially prove that

 

       their allergy was gone.

 

                 We are really looking at very low-risk

 

       population, and it is not representative of the

 

       whole population of food allergy patients that are

 

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

 

       times looking at the specific data.

 

                 (Slide.)

 

                 DR. WOOD:  Now, whenever we are doing this

 

       sort of analysis, we try to break things into

                                                                 45

 

       categories.  One of the tough categories to decide

 

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

 

       literature some different definitions that have

 

       been used.

 

                 We chose to create our own for a series of

 

       studies that we were doing, and talked about mild

 

       reactions that were skin and/or oral symptoms only.

 

       Oral symptoms is just at itching or they will often

 

       have an obvious hive-like reaction in their mouth

 

       or pharynx when they are having one of these

 

       localized reactions.

 

                 A "moderate reaction" was described as

 

       upper respiratory and or GI symptoms only or any

 

       three systems.  When we are talking about systems,

 

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

 

       lower respiratory and cardiovascular.

 

                 Then, severe reactions were those that

 

       were that were potentially life threatening, where

 

       they have lower respiratory and/or cardiovascular

 

       symptoms or any four systems were involved.

 

                 (Slide.)

 

                 DR. WOOD:  When we broke things down into

                                                                 46

 

       these different systems which were involved in

 

       which challenges, you will see here that when we

 

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

 

       total in this paper we reported on milk, egg,

 

       peanut, soy and wheat.

 

                 The greatest number of failed challenges

 

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

 

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

 

       that skin manifestations were most common, 78

 

       percent.

 

                 This is actually similar to what we have

 

       seen and what is in the literature in terms of

 

       reactions that happen out in the real world.

 

       Eighty percent of food reactions, 80 percent of

 

       anaphylactic reactions involve the skin, but about

 

       20 percent do not.

 

                 Oral symptoms occurred in about a quarter,

 

       upper respiratory in a quarter, lower respiratory

 

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

 

       thankfully, had no cardiovascular reactions in this

 

       population.

 

                 Now, why would that be the case?  It would

                                                                 47

 

       be for two reasons.  The biggest reason is that

 

       cardiovascular reactions are not that common in

 

       children.

 

                 The cardiovascular system of a child is

 

       really sturdy enough to put up with the insult of

 

       an allergic reaction without necessarily becoming

 

       involved.  Cardiovascular reactions are much more

 

       common in adults, and this population was entirely

 

       childhood.

 

                 The other reason that we might have seen

 

       the absence of cardiovascular reactions would be

 

       that we were dealing with a relatively low-risk

 

       population.

 

                 When we break it down into those three

 

       severity classifications -- mild, moderate and

 

       severe -- you will see that the numbers are

 

       relatively similar for each food.  When we look at

 

       the total category, they broke pretty close to a

 

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

 

       severe.

 

                 When you look across the specific foods,

 

       the most important point that came out of this is

                                                                 48

 

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

 

       this kind of setting is more dangerous than

 

       another.

 

                 It turned out that the greatest number of

 

       severe reactions occurred with egg challenges.

 

       This was important information we thought to get

 

       out to get out to people doing challenges.

 

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

 

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

 

       I'm not touching a peanut challenge because they

 

       are really dangerous.  However, I will do egg and

 

       milk challenges out in my office any time."

 

                 The message there is that really all of

 

       these foods have a potential to have severe

 

       reactions and need to be done in a setting where

 

       you are really equipped to deal with that potential

 

       for a severe reaction.

 

                 (Slide.)

 

                 DR. WOOD:  When we looked at the RAST test

 

       score or the median IgE level for these different

 

       challenge results, we found that there was really

 

       no strong association between their IgE level and

                                                                 49

 

       the reaction severity.

 

                 Now, this is an example of where this

 

       population is not a good one to look at for this

 

       data.  The reason is that we were essentially only

 

       challenging people that had relatively or very low

 

       levels.

 

                 We were not challenging people with very

 

       high levels where they were extremely likely to

 

       fail the challenge.  There is no reason in most

 

       instances to prove that they are allergic.  When

 

       you know with, say, 99 percent certainty that they

 

       are allergic, we would not put that patient through

 

       a challenge.

 

                 Consequently, if you went out in the real

 

       world where the RAST test levels range anywhere

 

       from zero to 100, you would typically see

 

       escalating reaction severity with levels that are

 

       higher.  We have that data for peanut allergy where

 

       the group of patients that had levels at 100 did

 

       have more severe reactions when they had accidental

 

       exposures.

 

                 (Slide.)

                                                                 50

 

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

 

       present from this study is whether reaction

 

       severity was correlated or related to the percent

 

       of food ingested in these challenges.  It turns

 

       out, if anything, it is inversely correlated.  The

 

       more severe reactions, and none of these were

 

       statistically significantly, but if you look at the

 

       general trends, you will see here that the more

 

       severe reactions occurred with milk and eggs.

 

                 As you can see, the severe reaction for

 

       milk is 15 percent and 30 percent for eggs.  When

 

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

 

       percent and 30 percent.

 

                 (Slide.)

 

                 DR. WOOD:  What is the reason this

 

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

 

       have your more severe reactions with smaller

 

       exposures?  The reason we think it happens is

 

       because it is just identifying the more reactive

 

       patients.

 

                 It is picking out those that even though

 

       our test scores said that they are not so allergic

                                                                 51

 

       that they should do this, it is picking out those

 

       that react more abruptly and have more severe

 

       symptoms early in the challenge just because they

 

       were higher risk patients.

 

                 Now, we have come up in our studies about

 

       some decision making about when we would do food

 

       challenges.  This is purely for clinical purposes.

 

       These are for those reasons of when we are trying

 

       to decide if they are truly allergic or when we

 

       think that the food allergy might have been

 

       outgrown.

 

                 What we would say is that we would do food

 

       challenges based on their history of reactions.  If

 

       they have reacted recently, we wouldn't feel the

 

       need to do a food challenge.

 

                 We would base it on their laboratory

 

       testing, the skin testing and the RAST testing.

 

       Then he would base it on the importance of the food

 

       to the diet.  There are some foods that are

 

       obviously much more important to the diet.

 

                 A family may never care whether that child

 

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

                                                                 52

 

       may elect to never have a pea challenge done, but

 

       they may be jumping to do a milk or what challenge

 

       at the first opportunity, because milk or wheat

 

       back in the diet would make such a dramatic

 

       difference in their day-to-day life.

 

                 Then, we have come up with some

 

       recommendations based on RAST testing of when we

 

       would recommend doing challenges.  These cutoffs

 

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

 

       greater than 50 percent chance of passing the

 

       challenge, if you have levels below that range.

 

       For other foods, it has been harder to determine

 

       cutoffs, and we would challenge at higher levels

 

       for things like wheat and soy.

 

                 (Slide.)

 

                 DR. WOOD:  Just to go through an algorithm

 

       of how we approach diagnosis, then, because it does

 

       impact on the discussions that are going to happen

 

       here, we would first take our history.

 

                 Based on the history, we would make some

 

       distinction whether we think this is consistent

 

       with an IgE type reaction or whether we think that

                                                                 53

 

       it is consistent with a non-IgE type reaction.

 

                 If it is IgE-mediated in all likelihood,

 

       then a skin test or a RAST test will help identify

 

       whether that food that was suspected to cause a

 

       reaction probably did or probably didn't.

 

                 If the test is negative, because the

 

       negative predictive accuracy is so high, we would

 

       feel that you could stop worrying about that food

 

       at that time.  If the skin test is positive,

 

       because there are false-positive tests that occur,

 

       we need to do something more.

 

                 We might do a trial on an elimination

 

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

 

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

 

       would arrive on the specific elimination diet

 

       recommended for that patient.

 

                 If it falls into a non-IgE category, the

 

       situation is much more difficult because we can't

 

       rely on a simple screening test to weed out those

 

       patients.

 

                 They are going to need some combination of

 

       challenges -- endoscopy, if it is a

                                                                 54

 

       gastrointestinal symptom; elimination diets,

 

       rechallenges, maybe a reendoscopy -- so there is a

 

       much more difficult plan on this side of the screen

 

       to sort out those patients.

 

                 (Slide.)

 

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

 

       with a couple of conclusions and present a couple

 

       of dilemmas.  The conclusions are that food allergy

 

       is very common.  This is a remarkably worthwhile

 

       initiative that is going on here, and that right

 

       now avoidance is the only treatment plan.

 

                 We really hope in the next 5 or 10 years

 

       that there are going to be other treatments for

 

       food allergy.  It may be enough so that even if

 

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

 

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

 

       have these meetings, that small exposures won't

 

       even be relevant.  We are not even close to their

 

       yet, so avoidance is the only option.

 

                 Strict avoidance is essential to prevent

 

       reactions obviously, but we also think that in many

 

       patients it also helps to promote the outgrowing

                                                                 55

 

       process.

 

                 Here is where we may have very different

 

       thresholds.  We may have a threshold that this

 

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

 

       fact that they can eat this bread that has whey as

 

       the tenth ingredient and never have a symptom.

 

       They are perfectly fine with it.

 

                 What we have found that getting that bread

 

       on a regular basis may keep their immune system

 

       more revved up to maintain the allergy so this

 

       thing that is way below their threshold for

 

       reacting acutely may still drive the immune system

 

       to maintain the allergy and prevent them from

 

       outgrowing the allergy.

 

                 The next conclusion is that food

 

       challenges are a useful means to diagnose food

 

       allergy and a useful means to determine threshold

 

       doses.  There are going to be some limitations of

 

       challenges, and one of them is that as opposed to

 

       the study that I presented that Dr. Perry did with

 

       me, you have to include in a threshold type study

 

       the most allergic patients.

                                                                 56

 

                 Doing the kind of patients that we are

 

       studying on the lower end of the spectrum has

 

       nothing to do with thresholds.  It is irrelevant

 

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

 

       looks like a threshold because we are not including

 

       in those kinds of studies those highly allergic

 

       patients."

 

                 The greater dilemma, and this one is

 

       solvable, there are plenty of real allergic

 

       patients out there.  They won't necessarily want to

 

       undergo these studies, because it is not a pleasant

 

       thing to have allergic reactions, but that part is

 

       potentially solvable.

 

                 The more difficult thing is a

 

       determination of the threshold doses that I

 

       mentioned for the chronic allergic conditions,

 

       especially those that are not IgE mediated probably

 

       isn't possible.

 

                 To give a couple of examples, if we take,

 

       say, milk allergy, the most common food allergy of

 

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

 

       formula, there are a bunch of different options we

                                                                 57

 

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

 

       them are also allergic to soy.

 

                 Some would go on to a formula like

 

       Alimentum or Nutramigen, which is a formula where

 

       the milk protein has hydrolyzed to a small enough

 

       fragment that in 98 or 99 percent of kids with milk

 

       allergy.  It completely solves the problem.  They

 

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

 

       protein that remains in that formula.

 

                 That other 2 percent, though, may react

 

       severely to that.  They are typically the patients

 

       with the gastrointestinal disease.  They are

 

       typically very sick; they are typically not

 

       growing; they are typically malnourished.

 

                 They are a group of patients who aren't at

 

       risk for the acute dangerous reactions, but they

 

       may be at very high risk for chronic disease from

 

       their food allergy.

 

                 Those patients will typically respond

 

       dramatically to a formula that is based in a single

 

       amino acids as a protein source, and that is a

 

       formula like Neocate and Elecare.

                                                                 58

 

                 Now, when you take that population, and

 

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

 

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

 

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

 

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

 

       react severely to it.

 

                 We know that because of their

 

       gastrointestinal biopsies, their biopsies that are

 

       taken from their esophagus or stomach or intestinal

 

       tract still show evidence of severe allergy.

 

                 What we think those patients are reacting

 

       to would be either the absolutely trivial amounts

 

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

 

       that is the eighteenth ingredient in Neocate, or

 

       the trivial, trivial amounts of protein that may be

 

       left in the safflower oil that is used as a fat

 

       component of Neocate.

 

                 When we switched those patients off of

 

       Neocate we can prove, and we have 15 patients now

 

       who we have proven, that taking them off Neocate

 

       resolved their food allergy.  In this supposedly

 

       non-allergenic formula, they were still reacting.

                                                                 59

 

                 Now, whether the direction this Committee

 

       needs to focus on is this very unusual patient or

 

       not is sort of a separate debate all together, but

 

       it is safe to say that there are going to be

 

       patients out there who break all rules.  No matter

 

       what rules are established, there will be patients

 

       who completely break them and make all of our lives

 

       difficult from that standpoint.

 

                 I would be delighted to take any questions

 

       from the Committee or otherwise.  Thank you for

 

       your attention.

 

                 CHAIRMAN DURST:  Thank you, Dr. Wood.

 

                 Are there questions for discussion?

 

                 Suzanne.

 

       QUESTION-AND-ANSWER SESSION

 

                 DR. TEUBER:  This is Suzanne Teuber.  I

 

       had a question about your patients with the Neocate

 

       sensitivity in terms of what the company reported

 

       for the soy lecithin, did they have any values that

 

       you could report back as to a chronic ingestion

 

       threshold?

 

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

                                                                 60

 

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

 

       have that data on the protein content of their soy

 

       lecithin.  They say it is zero.  These kids when

 

       they were switched to Neocate One Plus, which has

 

       no soy lecithin, their disease went away.  We have

 

       to assume that there was enough there to drive that

 

       process.

 

                 CHAIRMAN DURST:  Yes.

 

                 MS. HALLORAN:  Jean Halloran.  Could you

 

       say something about the process about growing

 

       allergies?  How does that work?  What actually

 

       happens?

 

                 DR. WOOD:  Well, that is a very good

 

       question.  There are a number of things that we

 

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

 

       is that in the majority of patients we think that

 

       outgrowing is most related to the immune system

 

       gradually forgetting about that concern that it

 

       earlier had.

 

                 That is where we think that strict

 

       avoidance is likely to promote the outgrowing

 

       process, and with a prolonged period of strict

                                                                 61

 

       avoidance for many of these foods, the immune

 

       system has a memory that isn't long enough to

 

       maintain the allergy and that it will gradually

 

       wane and then full tolerance will be accomplished.

 

       There are probably lots of other mechanisms going

 

       on immunologically that are not well understood.

 

                 The other question with this that we have

 

       no great explanations for, lots of theories but no

 

       great explanations, is why you can take a food

 

       allergy like milk, which in early infancy can be

 

       every bit as severe as a peanut allergy, and have

 

       most kids outgrow that allergy, while very few kids

 

       outgrow the peanut allergies.  There is something

 

       very different about the immunologic memory of one

 

       food allergen versus another.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. KELLY:  Ciaran Kelly.  I wanted to

 

       come back to the issue of challenging individuals

 

       with severe allergies as a method for determining a

 

       threshold.  I would like to hear your comments as

 

       regards the feasibility and safety and whether that

 

       would be ethical to perform?  I guess my concern is

                                                                 62

 

       that once the threshold is crossed, whatever that

 

       threshold might be, isn't there a potential for

 

       severe allergic reaction?

 

                 DR. KELLY:  Yes.  Absolutely.  There have

 

       been threshold studies done for the biggie, peanut,

 

       with very allergic people so it is doable.  Now,

 

       what we can say about this is that these studies

 

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

 

       happen.

 

                 That automatically limits your population

 

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

 

       your group of milk-allergic adults to do these

 

       studies on, you are limited.

 

                 Now, they do tend to be more severe

 

       reactors.  From that standpoint, you have some

 

       patients out there, but there is no IRB that is

 

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

 

       be demonstrated benefit to do a study with risk.

 

                 The safety element is one that we are

 

       comfortable with, recognizing that you need to have

 

       emergency management available to you because there

 

       will be people that have bad reactions.

                                                                 63

 

                 The safety that is built into that is

 

       starting with exquisitely small doses and working

 

       up very gradually and aborting the challenge

 

       whenever you see your first symptom.

 

                 That may lead you to end some challenges

 

       prematurely.  You may end up with a false

 

       threshold, but you are obligated to stop when you

 

       have objective signs that patient is reacting.

 

                 The ethics beyond that to me is that if it

 

       is an adult patient who is willing to consent to

 

       that process, I have no problem with the ethics of

 

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

 

       patient to a food challenge.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. BRITTAIN:  This is Erica Brittain.

 

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

 

       know how this threshold might be different in

 

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

 

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

 

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

 

       large enough sample to have any validity

 

       whatsoever.  It is a superb question.  The argument

                                                                 64

 

       is going to be and will always be these children

 

       are much more reactive than the adults for most of

 

       these foods.

 

                 For peanut allergy it is going to be the

 

       simplest, because allergy tends to persist.  We

 

       think that people usually hit their peak level of

 

       severity as an adolescent or young adult, so that

 

       would be fairly easy to solve.

 

                 However, when you look at the others like

 

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

 

       large going to have the highest level of reactivity

 

       in your first couple of years of life.

 

                 When we think about those allergies, we

 

       usually think of growing into the allergy for one

 

       or two or three years where they are becoming more

 

       and more allergic, and then they are becoming less

 

 

       and less allergic over the next one or two or three

 

       or four or five years as they outgrow the allergy.

 

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

 

       severe reactivity is likely to be early on.

 

                 CHAIRMAN DURST:  Dr. Wood, I have a

 

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

                                                                 65

 

       clarification.  On your slides where you indicated

 

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

 

       as opposed to our discussion tomorrow on celiac

 

       disease?

 

                 DR. WOOD:  Yes, these results are entirely

 

       IgE.

 

                 CHAIRMAN DURST:  Okay.  Do other grains

 

       cause the IgE type reaction as the wheat?

 

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

 

       challenges, came out of about 3,000 food challenges

 

       that we have done.  There were five most common

 

       foods that I had enough data to make some

 

       conclusions that we were comfortable with.  All of

 

       the grains cause allergic reactions.

 

                 It turns out that wheat and rye are very

 

       cross reactive from an IgE-mediated allergy

 

       standpoint, and that most patients allergic to

 

       wheat are also allergic to rye; it turns out that

 

       about half are allergic to barley; and 10 to 20

 

       percent are allergic to oat.  Beyond those grains,

 

       all of the other grains and grain substitutes are

 

       clearly capable of causing allergy in select

                                                                 66

 

       patients.

 

                 CHAIRMAN DURST:  Thank you.  One other

 

       question as far as clarification at least for my

 

       mind.  One of your slides with the food challenge

 

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

 

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

 

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

 

       of IgE in a specific assay that Pharmacia has

 

       developed called an immunoCAP RAST.  It all goes

 

       back to this one technology that is thought to be

 

       the most accurate quantitative measure of specific

 

       IgE, and the results are represented in that kilo

 

       unit of IgE, the specific IgE antibody per liter of

 

       serum.

 

                 CHAIRMAN DURST:  Thank you.

 

                 There is another question?

 

                 DR. KELLY:  I have one other question.

 

       Dr. Wood, you made a very important comment about

 

       the potential for continued subclinical exposure to

 

       allergens perpetuating an allergic response.  How

 

       well accepted and how well documented is that, or

 

       is that largely a clinical impression?

                                                                 67

 

                 DR. WOOD:  Very well accepted, very poorly

 

       documented.  It is widely accepted.  There is very

 

       poor information to support it.  There are only a

 

       couple of studies.  The problem we have is we tried

 

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

 

       is so widely accepted that to go to the IRB and

 

       propose to them that we are going to take this

 

       group of kids with milk allergy and keep them on

 

       low-dose milk and take this group and have them

 

       strictly avoid it was turned down.

 

                 Now, there is some work being done that

 

       has identified instead of looking at the IgE

 

       against milk globally, it has turned out that if

 

       you have IgE against certain portions of the milk

 

       molecule it may be more predictive of a longer-term

 

       allergy, and if you have it toward others, other

 

       epitopes, it may be more predictive of an allergy

 

       that is easier to lose.

 

                 We think that it may be feasible to focus

 

       on that population that has a very good chance of

 

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

 

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

                                                                 68

 

       outcome is about 10 years down.

 

                 CHAIRMAN DURST:  Marc.

 

                 DR. SILVERSTEIN:  I have had some

 

       experience --

 

                 CHAIRMAN DURST:  Identify yourself.

 

                 DR. SILVERSTEIN:  Marc Silverstein, Baylor

 

       Health Care System in Dallas.  I have had some

 

       experience in studying the epidemiology of asthma

 

       and anaphylaxis.  In both of those conditions, your

 

       findings are very much dependent upon your

 

       diagnostic criteria.

 

                 In clinical medicine, we have diagnostic

 

       criteria.  You have described the criteria for food

 

       allergy, which would involve components of:

 

       history, physical exam, laboratory tests, food

 

       challenge, and response to clinical management with

 

       elimination diets.

 

                 Are there standardized criteria that you

 

       would see moving the diagnostic criteria that you

 

       would use from clinical practice to investigation

 

       and publication in peer review literature and/or

 

       perhaps the policy in making regulatory decisions?

                                                                 69

 

                 I am interested in, Is there a set of

 

       standardized criteria that professional

 

       organizations or clinicians would use for

 

       investigation or for recommending policy?  I

 

       understand there is some recent work on definitions

 

       and standards for anaphylaxis?

 

                 DR. WOOD:  The definitions for

 

       IgE-mediated food allergy are pretty clear and it

 

       is pretty well accepted that it is if you have a

 

       history that is consistent, you have a positive

 

       allergy test, and you either fail a challenge test

 

       or pass a challenge with a dose that is generally

 

       accepted to indicate full tolerance.  It is fairly

 

       straightforward and well accepted in the peer

 

       review literature.

 

                 It is much more difficult on the group of

 

       patients with, say, eosinophilic gastroenteritis

 

       where they don't necessarily have IgE.  You require

 

       a histologic diagnosis to identify the condition,

 

       and then figuring out whether they have food

 

       allergy driving the process exclusively, partially

 

       or not at all is a much more difficult process.

                                                                 70

 

                 It is doable, but you have to eliminate

 

 

       foods, rebiopsy, reintroduce foods, and rebiopsy.

 

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

 

       much more difficult to do that there is much less

 

       of an acceptance of an absolute diagnostic

 

       criteria, much, much less.

 

                 It is being looked at.  This is a form of

 

       allergy that is clearly either happening much more

 

       often or being identified much more often or both,

 

       so that the potential is there, but it is much

 

       further away from a definition that is well agreed

 

       upon.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. BRITTAIN:  This is Erica Brittain.  I

 

       have a clarification question on the food

 

       challenge.  How is the placebo control implemented?

 

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

 

       lot more about food challenges this afternoon, but

 

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

 

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

 

       idea that it needs to be well disguised and

 

       obviously safe from the perspective of that

                                                                 71

 

       patient's allergen --

 

                 (Simultaneous discussion.)

 

                 DR. BRITTAIN:  But --

 

                 DR. WOOD:  Go ahead.

 

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

 

       dose?  Is a particular dose placebo, or does a

 

       patient get all placebo?

 

                 DR. WOOD:  Yes.  I'm sorry I

 

       misunderstood.  The normal way the challenge is

 

       done is to have a separate challenge for the

 

       placebo and for the actual food being studied.  The

 

       usual way it is done is that the patient would come

 

       in and have a day doing a placebo challenge and

 

       come in and have a day doing the food challenge.

 

                 Challenges can be done in a matter of a

 

       couple of hours in some situations, but to do

 

       highly allergic people in a placebo-controlled

 

       manner would usually take 8 or 10 hours for each

 

       day.

 

                 CHAIRMAN DURST:  All right.  Seeing no

 

       further hands in the air, I think we will thank

 

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

                                                                 72

 

                 Our next speaker will be

 

       Anne Munoz-Furlong, who is director of the

 

       Food Allergy and Anaphylaxis Network, who will

 

       discuss patient perspectives on food allergies.

 

                  PATIENT PERSPECTIVES ON FOOD ALLERGIES

 

                 MS. MUNOZ-FURLONG:  Thank you.  I would

 

       like to thank the organizers of the meeting for the

 

       opportunity to be here.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  What I would like to

 

       do is in that time that I have been allotted is

 

       give you a sense of who this food allergic consumer

 

       is; the food allergen labeling from their

 

       perspective; and then, most importantly, their way

 

       of looking at threshold levels for food allergens.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  By way of background,

 

       the Food Allergy & Anaphylaxis Network or "FAAN" is

 

       a non-profit organization.  We were established in

 

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

 

       members.  Eighty percent of these people come to us

 

       from physician referrals, so we know we are talking

                                                                 73

 

       about IgE-mediated responses when we are looking at

 

       our membership.

 

                 Our mission has four points: to increase

 

       public awareness, provide advocacy and education,

 

       and advance research on behalf of those with food

 

       allergy.

 

                 (Slide.)

 

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

 

       food allergy is believed to affect about 11 million

 

       Americans or 4 percent of the population; fish and

 

       shellfish allergy, 2.3 percent or 6.5 million;

 

       individuals in peanut and tree nut, 3 million.

 

                 Consequently, between these four foods we

 

       are talking about almost 10 million Americans.

 

       These are the four foods, as was presented earlier,

 

       that are lifetime allergies and also are believed

 

       to cause the majority of the severe or fatal

 

       reactions in this country.

 

                 The other point I want to make here is

 

       that although we are talking about 11 million

 

       patients, our data shows us over and over again

 

       that most of these patients have families who

                                                                 74

 

       follow their restricted diet.  The impact is

 

       actually many times greater than the number of

 

       patients.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  When we look at

 

       shellfish allergy, this is looking at data that we

 

       published about a year ago now.  Te prevalence of

 

       shellfish, we found about 2 percent of the

 

       population or 6 million Americans.

 

                 The key foods responsible for the majority

 

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

 

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

 

       the population: salmon, tuna, catfish, and cod

 

       being the primary fish that cause reactions.

 

                 However, if you look at these a different

 

       way, these foods, especially shrimp or salmon, are

 

       available on almost every menu that you are going

 

       to look at in a restaurant or food service

 

       establishment.  Therefore, the risk for these

 

       individuals is constant.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Talking about tree

                                                                 75

 

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

 

       peanuts; they are different.  Most people with a

 

       peanut allergy avoid tree nuts as a precaution but

 

       not because they are allergic to them.  About

 

       20 percent of the 20 peanut allergic population is

 

       allergic to tree nuts as well.

 

                 When we are talking about tree nuts, it

 

       affects about 1.5 million Americans.  Again,

 

       looking at data from our patient registry of 5,000

 

       patients, we find that walnut, cashew, almond and

 

       pecan are the leading cause of tree-nut-allergic

 

       reactions in this country.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  What does it mean to

 

       have food allergies?  It is vigilant label reading.

 

       You have got to read labels not just for food

 

       ingredients but anything coming into the home.

 

       Bath products can have tree nuts, milk or eggs in

 

       them, for example.

 

                 Pet food, if you have ever looked at the

 

       ingredient statement on a pet food, it can have

 

       almost every single one of the major eight

                                                                 76

 

       allergens.

 

                 That is something you have to worry about,

 

       especially if you have a toddler who will pick up

 

       food from the floor or anyplace else they can get

 

       it.  Also, medications have been known to have

 

       allergens in them, particularly milk.

 

                 It is not just a question of label reading

 

       for food; it is for anything.  Trace amounts can

 

       cause an allergic reaction, and that has been

 

 

       proven over and over again.

 

                 Just one bite can cause a reaction.

 

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

 

       allergic they are going to be or what their

 

       tolerance will be to that food.

 

                 Currently, as Dr. Woods said, the only

 

       cure now is a dose of epinephrine, if the patient

 

       has a history of severe reaction.  The onus is on

 

       the patient or the family to read the label and

 

       avoid the allergen and then be quickly prepared to

 

       handle an allergic reaction, if they have made a

 

       mistake or accidentally ingested the food to which

 

       they are allergic.

                                                                 77

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Because there is no

 

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

 

       are centered around food allergy.  This is what

 

       makes food allergy so stressful on the family and

 

       on the patients.

 

                 Whereas with other allergies you have

 

       seasonal components and you might have an easy

 

       spring but fall is the bad season or if you are

 

       allergic to cats or dogs you can avoid those, with

 

       a food allergy every decision every single day is

 

       affected by your food allergy.

 

                 Food shopping can take two to three to

 

       hours just from reading labels.  Cooking, if the

 

       family is bringing the allergen into the home, they

 

       then have to prepare two meals, the

 

       non-allergen-containing meal and then the

 

       allergen-containing meal, and take precautions to

 

       avoid cross-contact.

 

                 Decisions about dining out and socializing

 

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

 

       food safe.

                                                                 78

 

                 "Can the manager be trusted to give us

 

       accurate information?"

 

                 "Can the person we are visiting be trusted

 

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

 

                 Then, the decision is made to move forward

 

       based on the answers to those questions.

 

                 Even what school or childcare the

 

       individual will be sending their food allergic

 

       child to are going to first be centered on food

 

       safety from a food allergy perspective.

 

                 Vacation and travel where you and I might

 

       decide whether we want to go someplace warm or go

 

       skiing in the winter, these families have to think

 

       first about food.

 

                 "Can we ship food there?"

 

                 "Is there a safe place?"

 

                 "Can we rent a room with a kitchenette and

 

       make some of the meals so that we can maintain some

 

       level of safety?"

 

                 Even family relationships, there is always

 

       somebody in the family that does not believe the

 

       food allergy is real, and so decisions are made

                                                                 79

 

       about whether they can visit that individual or

 

       not.

 

                 (Slide.)

 

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

 

       this, it has a tremendous impact on quality of

 

       life.  We published a study several years ago

 

       looking at the impact of food allergy on quality of

 

       life.

 

                 What we found is that families who have a

 

       food-allergic child score lower on their perception

 

       of whether their child has good health or not, the

 

       emotional health and family activities than the

 

       general population.

 

                 Certainly, they scored lower or worse than

 

       families who are looking at or dealing with other

 

       chronic diseases such as diabetes, juvenile,

 

       rheumatoid arthritis and attention deficit

 

 

       disorder, for example.

 

                 We also looked at some of the other

 

       influences.  If the individual has a food allergy

 

       and asthma or atopic dermatitis, that further

 

       lowers their score for the quality of life.

                                                                 80

 

                 If a family has a child with two or more

 

       food allergies, that group scored much lower in 9

 

       out of 12 scales compared to those who only have

 

       one or two food allergies that they are dealing

 

       with.

 

                 When we look at our patient population at

 

       FAAN, we see that it is not uncommon for our

 

       members to report a child with a milk, egg and

 

       peanut allergy simultaneously.  You can imagine

 

       eliminating those three foods and how it compares

 

       to the impact on the quality of life for the entire

 

       family.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  This is how, again

 

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

 

       is "General health" perception.  Food allergy lower

 

       than the normal for asthma, attention deficit

 

       disorder and some of these other symptom scores.

 

                 Now, in talking about label reading, which

 

       is really the cornerstone of managing a food

 

       allergy.  Here is what goes on.

 

                 (Slide.)

                                                                 81

 

                 MS. MUNOZ-FURLONG:  The person with a food

 

       allergy is told by the physician, as you heard

 

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

 

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

 

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

 

       don't eat that product.

 

                 If the allergen is listed on the label or

 

       the label says "Contains allergen," they are not

 

       going to eat that product because they are trying

 

       to avoid a reaction.  As a result, they expect

 

       ingredient labels to be consistent and, most of

 

       all, reliable because this is what they are basing

 

       the decision about food on.  It will affect their

 

       health and safety.

 

                 When they see the same product with

 

       different ingredient statements, it makes them very

 

       confused and frustrated and sometimes very nervous

 

       because they, again, are looking for consistency in

 

 

       labeling.

 

                 What we are already seeing with some of

 

       the companies complying with FALCPA regulations is

 

       that there are products on the market that are

                                                                 82

 

       pre-FALCPA and FALCPA compliant with different

 

       ingredient information regarding allergens.

 

       Already we are getting calls from our members.

 

                 "Which one of these labels is correct?"

 

                 "What if I hadn't picked up that second

 

       label?  How would I have known?"

 

                 This is what we are heading into as we

 

       start to change these labels.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The challenge for

 

       food-allergic individuals is that the patients are

 

       told to strictly avoid the allergen, there is zero

 

       tolerance or be prepared to handle an allergic

 

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

 

       how severe that is going to be.

 

                 They are not aware that there are

 

       scientific names to foods when they are newly

 

       diagnosed.  This is something FAAN spends a lot of

 

       time doing.  It will get better as FALCPA is

 

       implemented because labels will have simple

 

       ingredient terms on them.

 

                 We have to remember it is not just the

                                                                 83

 

       patient or the patient's family reading the label,

 

       but it is the teacher, the scout leader, the

 

       friends and family members.  The impact for any

 

       labeling decisions are going to be quite broad.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Allergens can appear

 

       in unexpected places.  This is just one slide of a

 

       number of examples that we have for "Common Foods

 

       in Unexpected Places."  Every one of these examples

 

       have caused an allergic reaction to one of our

 

       members, because they were not expecting to find

 

       the allergen.

 

                 Just to give you an example, if you have a

 

       milk allergy, you would not have expected that

 

       barbecue-flavored potato crisps might have milk in

 

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

 

       that canned tuna might have soy in it.  Therefore,

 

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

 

       be looking for unexpected sources.

 

                 (Slide.)

 

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

 

       reflected in a study that was published in 2002 by

                                                                 84

 

       Joshi, et al.  They took some food-allergic

 

       individuals, gave them products that were on the

 

       market, and asked them to read the label for the

 

       food they were trying to avoid.

 

                 You can see here that families avoiding

 

       milk, only 7 percent were able to accurately

 

       identify milk on the labels that were presented to

 

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

 

       percent; but peanut, only 54 percent got the label

 

       reading correct, and most of this was because of

 

       confusion about allergen labeling information.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The problem with

 

       allergen labeling information, there are no

 

       guidelines or standards for use.  This is

 

       completely voluntary.  As a result, every company

 

       has their own decision tree and algorithm and

 

       wording for what terms they will use and under what

 

       conditions.

 

                 This makes it very difficult for us to

 

       educate consumers and the others who are reading

 

       labels on their behalf and telling them what to do

                                                                 85

 

       and what these mean.

 

                 The proliferation of "may contain"

 

       labeling has really caused us some problems.  Just

 

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

 

       volunteer go out in the Northern Virginia area to

 

       one grocery store and look at products from

 

       cookies, crackers, candy and bakery.  We were

 

       trying to follow the model of a previous FDA study.

 

                 She came back with 28 different versions

 

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

 

       perspective, what does that mean?  Can they be

 

       trusted, or should we ignore them?

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The current

 

       environment because of this, there are some

 

       physicians that advise their patients to ignore

 

       precautionary labeling, because it is everywhere

 

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

 

                 There are others who tell them, "Heed the

 

       warning and avoid those foods."

 

                 Then, there are some companies who tell

 

       the consumers, "It is on the package only because

                                                                 86

 

       our legal counsel has advised us to put this on

 

       there."

 

                 Then, there are others that say, "You have

 

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

 

                 How does a consumer determine which is

 

       which?

 

                 We are also seeing advisory statements for

 

       peanut allergy only.  The way the consumer

 

       interprets these statements is that they are

 

       shortcuts to label reading.

 

                 If they see "contains peanuts" or "may

 

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

 

       ingredient declaration if they are looking for milk

 

       or soy, because they think that the company

 

       understands food allergy and would have listed all

 

       of the allergens on there.

 

                 As a result of all of this, consumers are

 

       confused and frustrated.  Particularly what is

 

       going on as their food choices are further

 

       minimized is that there is risk taking behavior by

 

       parents of kids with food allergies who decide,

 

       seemingly randomly to us, that some companies can

                                                                 87

 

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

 

       contain" on the companies they trust.

 

                 Then, the teenagers, our highest-risk

 

       population for a severe reaction, want to be like

 

       everyone else are reporting that they are ignoring

 

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

 

       foods they have eaten the food and not had a

 

       reaction, so they don't really believe that these

 

       are true.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  This is one of the

 

       labeling studies that we conducted with our FAAN

 

       members during a spring meeting a year or two ago.

 

       We asked a question.  They were supposed to answer,

 

       "I would never purchase a product that says it

 

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

 

 

       that almost 100 percent of them would avoid a

 

       contain statement.

 

                 However, as you go from very specific to

 

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

 

       that also produces," say, peanuts or nuts or

 

       whatever the allergen might be, only 74 percent

                                                                 88

 

       would avoid purchasing that product.

 

                 Consequently, 25 percent of the allergic

 

       consumers are going to purchase products where they

 

       don't really understand the precautionary labeling.

 

       If the company is putting this on here because of

 

       some risk, we've got a miscommunication or a

 

       communication gap going on.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG: Let's talk about

 

       thresholds, then.  Again, from the consumer's

 

       perspective, their physicians advise, as you heard

 

       from Dr. Wood, is strict avoidance or a reaction

 

       may occur and you will not outgrow this allergen.

 

       They are very motivated to try to strictly avoid

 

       that food.

 

                 When we talk about thresholds to our

 

       members, and these tend to be the most motivated

 

       and well-educated of the food allergy population,

 

       this is what we consistently get back.  They

 

       believe that threshold levels may put their

 

       children at risk because their child is so

 

       allergic.

                                                                 89

 

                 They also wonder whether the threshold

 

       levels, the whole discussion is based on the

 

       industry or the government trying to figure out a

 

       way not to have to clean or label for allergens.

 

       Again, they are wary that this might be a loophole

 

       that is trying to be directed at them.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The catch 22 here,

 

       from where we are at FAAN, is that we understand

 

       that if we label for all allergens at all levels it

 

       will further restrict diets.  If we further

 

       restrict the diet, we are going to increase

 

       frustration which will yield risk taking.

 

                 It is going to undermine the integrity of

 

       the ingredient label.  As I showed already with

 

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

 

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

 

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

 

       reaction, we are going to diminish the validity of

 

       that statement.

 

                 If we undermine the integrity of the

 

       ingredient label this will potentially lead to more

                                                                 90

 

       allergic reactions as they take more risk, which is

 

       going to increase the number of doctor visits;

 

       hospital visits; and, potentially, fatalities.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Here is an example of

 

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

 

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

 

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

 

       had safely eaten soy lecithin in the past.  Most of

 

       our members, although we tell them to read the

 

       ingredient declaration on products every time they

 

       purchase them, become brand dependent and stop

 

       reading the ingredient label.  That is exactly what

 

       happened here.

 

                 This was a product that the child had

 

       safely eaten in the past.  The mother did not read

 

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

 

 

       it.  She then started reading the label and saw

 

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

 

       nervous and screamed that it contained soy and

 

       asked the child to spit the food out.

 

                 Immediately, he started having itching,

                                                                 91

 

       leading to hives, and a feeling of impending doom.

 

       The mother gave him medication and thought she was

 

       having a full-blown reaction.

 

                 The question we have to ask ourselves, Was

 

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

 

       called the manufacturer and was told that the

 

       "contains soy" is because it contains soy lecithin.

 

       Therefore, the ingredients hadn't really changed

 

       from the product that they had safely eaten before.

 

                 From our perspective, we do not want to

 

       see consumers or their families subjected to this

 

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

 

       that once this reaction is taken care of, it takes

 

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

 

       have reports of children developing eating

 

       disorders and just being very cautious about being

 

       around other people once they have had a reaction.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  From the consumer's

 

       perspective, if we are looking at developing a

 

       threshold level, and as I said there are pros and

 

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

                                                                 92

 

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

 

       got to educate physicians and registered dieticians

 

       so that they can counsel patients accurately.

 

                 As you saw, we have done no training for

 

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

 

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

 

       threshold levels.

 

                 We also have to educate patients and their

 

       families and assure them that the food is still

 

       safe and that they can trust the information on the

 

       label.  We also have to do outreach to the food

 

       industry so that they can answer the queries from

 

       food-allergic consumers in a way that will give

 

       them confidence instead of make them nervous or

 

       suspicious about whether they can trust the

 

       information on the label.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  In summary,

 

       food-allergic consumers want as many food choices

 

       as safely possible.  This is really why we are here

 

       and why we are seeing some of this behavior with

 

       advisory statements.

                                                                 93

 

                 They want to open the diet.  The children

 

       want to be like everyone else, and they want the

 

       least amount of restrictions, but they need to be

 

       safe.

 

                 The consumer needs to understand the

 

       information on the ingredient statement.  They need

 

       most of all to trust that that information is

 

       reliable and it is going to be consistent from one

 

       product to the other.  They also need a minimal

 

       number of precautionary allergen statements and a

 

       guideline so that they understand what these

 

       statements mean and what they should do as a result

 

       when they see these on products.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  In conclusion, the

 

       current labeling and manufacturing practices

 

       present enormous challenges to food-allergic

 

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

 

       patients is increasing.

 

                 To give you an example, we conducted a

 

       prevalence study of peanut and tree nut allergy in

 

       1997, repeated that same study in 2002, and found

                                                                 94

 

       that in that five-year period the number of

 

       children with peanut allergy had doubled.  We don't

 

       know how it is continuing to trend, but reports are

 

       that it is still increasing.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The bottom line is

 

       above all we must protect the integrity of the

 

       ingredient information.  Because from the

 

       food-allergic consumer's perspective, they depend

 

       on this information to avoid an allergic reaction

 

       and, most of all, to maintain their health and

 

       safety.  We already have data showing that food

 

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

 

       to further diminish their quality of life.

 

                 With that, I will end here and open for

 

       questions.

 

                 CHAIRMAN DURST:  Thank you.

 

                 Does the Committee have any questions?

 

                 Yes.

 

                 MS. HALLORAN:   I mean, obviously a person

 

       can survive without ever having to buy any packaged

 

       food.  I am wondering in terms of the kinds of

                                                                 95

 

       things you were talking about -- teenager's

 

       preferences, the needs of a busy mother, et cetera

 

       -- are there particular categories of food that are

 

       prepared and packaged that are most sort of

 

       important and essential in our modern life?  I

 

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

 

                 MS. MUNOZ-FURLONG:  If they ate

 

       vegetables, they would be fine.  How many kids want

 

 

       to eat vegetables?

 

                 (General laughter.)

 

                 MS. MUNOZ-FURLONG:  I think it really goes

 

       back to quality of life.  Children want to be like

 

       everyone else, and they will do everything they can

 

       to fit that mold.

 

                 I have a daughter that was diagnosed with

 

       milk allergy and egg allergy when she was an

 

       infant.  I will tell you that I did everything I

 

       could to make sure that she felt like her friends.

 

                 It is not just the patient or the child,

 

       it is also the family wanting to not have their

 

       child isolated or feel stigmatized because of the

 

       allergy.

                                                                 96

 

                 If everyone else is having breakfast in a

 

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

 

       to make sure that those labels are accurate, if the

 

       family makes that decision.

 

                 Granted, there are some families that are

 

       very cautious and will only make food from home,

 

       make it from scratch.  However, as the child gets

 

       older and is out with friends, that is just not

 

       doable.

 

                 MS. HALLORAN:  Are there any particular

 

       categories of foods?

 

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

 

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

 

       are seeing allergens everywhere.  We have just got

 

       to make sure that all of the labels are correct and

 

       can be trusted.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. KELLY:  Ciaran Kelly.  A question for

 

       you from your perspective and the perspective of

 

 

       the people you represent, the patients with food

 

       allergies.

 

                 I understand that you are frustrated and

                                                                 97

 

       find it very difficult to work with the current

 

       system of many different types of wording.  Would

 

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

 

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

 

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

 

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

 

       acceptable?

 

                 MS. MUNOZ-FURLONG:  Well, I will start

 

       from the back end of your question.  If you poll

 

       our members or just the general consumers, they all

 

       want "does not contain" labeling.

 

                 I would caution to you because of the

 

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

 

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

 

       recalls to products that say "does not contain

 

       peanuts" when they do contain peanuts undeclared.

 

                 From the way the consumer is going to

 

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

 

       read that ingredient declaration because that is

 

       the guarantee they have been waiting for.

 

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

 

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

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       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

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       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

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       peanut or whichever peanut is there.

 

                 A lot of times a lot of the successful

 

       kids use a much more kind of crude approach to

 

       detecting peanut rather than specifically horning

 

       on the allergens themselves.

 

                 There is a challenge, though, in that

 

       different standards are used in the different kids,

 

       depending on the manufacturer, and also different

 

       antibodies are used in the different kids depending

 

       on the manufacturer.  It is not like a standardized

 

       approach across the board, necessarily.

 

                 (Slide.)

 

                 DR. HEFLE:  The detection limits range

 

       from around 0.1 to 2.5 parts per million for the

 

       quantitative methods.  There are also quality

 

       methods; however, if we are talking about threshold

 

       levels, we need to talk about quantitation here.

 

                 Using a method that has a very low

 

       detection limit has certain challenges.  Every kit

 

 

       has the ability to have a low detection limit.  Ten

 

       years ago, when I started developing kits,

 

       Steve Taylor and I sat around and thought about

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       what the detection limit should be based on our

 

       years of experience in dealing with consumer

 

       reactions and things like that.

 

                 We set a certain level with the kits we

 

       developed; we picked 2.5.  It seems to have gone

 

       very well over the last seven or eight years since

 

       these kits have been on the market.  Some of the

 

       other companies have a little bit lower range of

 

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

 

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

 

       they can all push these kits really, really, really

 

       low.  The problem is, Is there clinical relevance

 

       at that point?

 

                 If there is no clinical relevance,

 

       companies may be chasing molecules around their

 

       processing plant.  They will have all of this

 

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

 

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

 

       analysis."

 

                 We want the data to be relevant.  We want

 

       the data to be useful.  If the industry goes back

 

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

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       all of these positive results at a low level?"

 

       Detection limits have to be kept in mind.  They

 

       should be tied to threshold levels, whatever we

 

       decide the threshold levels should be.

 

                 It adversely affects the quality of life

 

       for food-allergic consumers, if you use detection

 

       limits that are really low or push those detection

 

       limits without a good clinical basis.  Because of

 

       the industry reaction in the form of increased use

 

       of "may contain" label.

 

                 When they did paralysis by analysis and

 

       they get positive results, maybe they throw a lot

 

       of "may contain" labeling on that product that they

 

       are worried about and so they are going to put that

 

       on there.  That decreases the number of foods that

 

       allergic individuals can eat.

 

                 The current detection limits that are set

 

       that the industry uses right now have worked very

 

       well for seven years in protecting the

 

       food-allergic consumer.

 

                 I don't think at this point there is any

 

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

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       science comes in and we know more about threshold

 

       levels, there might be an adjustment here or there.

 

                 We just finished an egg threshold study.

 

       Contrary to what Robert Wood said, you can do

 

       threshold studies in kids, because we did this in

 

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

 

       people we could find to have egg allergy are kids.

 

                 When we crunch those numbers and look at

 

       that data, if the threshold is low enough that we

 

       need to adjust the kids for egg out there, the

 

       manufacturers have all said they would be willing

 

       to do that based on the science.

 

                 (Slide.)

 

                 DR. HEFLE:  Many companies are testing for

 

       allergen residues.  What they are primarily testing

 

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

 

       verify sanitation procedures.  They have been using

 

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

 

                 Certainly with the new law coming up,

 

       there are a lot more using them than used to use

 

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

 

       incorporating testing using these test kits.  As

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

 

       easier for them to use them.

 

                 Again, the ELISA or lateral flow, which is

 

       kind of like a dipstick method are the preferred

 

       methods.  Some do the test in house.  They really

 

       like it if they can do that because they can fix

 

       things right away.

 

                 However, if you don't have in-house

 

       capabilities, they will send it out to a contractor

 

       lab or if they want third-party verification, they

 

       will do that.