1

 

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                       FOOD AND DRUG ADMINISTRATION

 

               CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

 

 

 

 

 

 

 

 

 

 

                     FOOD ADVISORY COMMITTEE MEETING

 

                     Advice on CFSAN'S Draft Report:

 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Wednesday, July 13, 2005

 

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

 

 

 

 

                            Greenbelt Marriott

                              6400 Ivy Lane

                              Grand Ballroom

                        Greenbelt, Maryland 20770

                                                                  2

 

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

 

       FOOD ADVISORY COMMITTEE STANDING MEMBERS:

 

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

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

       Patrick S. Callery, Ph.D.

       Dennis Gonsalves, Ph.D., M.S.

       Jean M. Halloran (Consumer Representative)

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

       Margaret C. McBride, M.D.

       Mark Nelson, Ph.D. (Industry Representative)

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

 

       TEMPORARY VOTING MEMBERS:

 

       Petr Bocek, M.D., Ph.D.

       Margaret Briley, Ph.D., R.D.

       Erica Brittain, Ph.D.

       Ciaran P. Kelly, M.D.

       Soheila June Maleki, Ph.D.

       David O. Oryang

       Marc D. Silverstein, M.D.

       Suzanne Teuber, M.D.

 

       FOOD AND DRUG ADMINISTRATION:

       Catherine Copp, J.D. - Senior Policy Advisor

       Food and Drug Administration, CFSAN

 

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

       Food and Drug Administration

       National Center for Food Safety and Technology

 

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

       Food and Drug Administration, CFSAN

 

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

 Food and Drug Administration, CFSAN

 

       Stefano Luccioli, M.D. - Senior Medical Advisor

       Food and Drug Administration, CFSAN

 

 Marcia Moore, Food Advisory Committee, Executive Secretary

 

       Jenny Slaughter - Director

       Food and Drug Administration Integrity and Ethics Staff

                                                                  3

 

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

 

       GUEST SPEAKERS:

 

       Rene Crevel, Ph.D. - Senior Scientist

 Unilever, Safety and Environmental Assurance Centre, United Kingdom

 

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

 Food Allergy Research and Resource Program, University of Nebraska

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

 CFSAN, FDA Assistant Professor, Georgetown University

 

       Anne Munoz-Furlong

 Director, Food Allergy & Anaphylaxis Network

 

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

 Food Allergy Research and Resource Program, University of Nebraska

 

       Robert Wood, M.D. - Professor

 Johns Hopkins University School of Medicine

                                                                  4

 

                             C O N T E N T S

 

                                                               PAGE

 

       Call to Order, Welcome and Introductions

       Charge to the Food Advisory Committee

                 Richard Durst, Ph.D., Acting Chairman            6

 

       Conflict of Interest Statement & Other

       Instructions

                 Jenny Slaughter, FDA                            10

 

       Welcome and Opening Statement

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

 

       Use of Food allergen Thresholds

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

 

       Introduction to Food Allergens

                 Robert Wood, M.D.                               23

 

       Patient Perspectives on Food Allergies

                 Anne Munoz-Furlong                              72

 

       Allergenicity:  Analytical Methods

                 Susan Hefle, Ph.D.                              99

 

       Question and Answer Session                              126

 

       Oral Challenge Studies:  Purpose, Design,

       and Evaluation

                 Stefano Luccioli, M.D.

                 Senior Medical Advisor, CFSAN, FDA             133

 

       Question and Answer Session                              161

 

       Threshold Modeling Approach

                 Rene Crevel, Ph.D.                             170

 

       Food Allergen Thresholds

                 Steve Taylor, Ph.D.                            189

 

       Overview of Approaches to Establishing

       Thresholds:  Allergens

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

                                                                  5

 

                       C O N T E N T S (Continued)

 

                                                               PAGE

 

       Public Comments:

 

                 Tracy Atagi                                    228

 

                 John Carroll                                   232

 

                 Diane Castiglione                              242

 

 

                 Will Duensing                                  247

 

                 Martin J. Hahn, Esq.                           250

 

                 Peggy Mockett                                  254

 

                 Kim Mudd                                       257

 

                 Kim Mulherin                                   260

 

                 Linda Webb                                     264

 

                 Jupiter Yeung                                  268

 

       Committee Discussion:

 

                 Panel Discussion with Guest Speakers

                 Thresholds for Food Allergens - Questions      272

 

       Adjournment

 

                 Richard Durst, Ph.D., Acting Chairman          414

                                                                  6

 

                          P R O C E E D I N G S

 

                CALL TO ORDER, WELCOME, AND INTRODUCTIONS

 

                  CHARGE TO THE FOOD ADVISORY COMMITTEE

 

                 CHAIRMAN DURST:  I would like to call the

 

       meeting to order.

 

                 Good morning.  I am Dick Durst, professor

 

       of chemistry in the Food Science and Technology

 

       Department at Cornell University.  I was asked to

 

       chair this meeting over the next two and a half

 

       days.  I would like to make a few announcements

 

       before we begin our meeting this morning.

 

                 I would appreciate it if everyone would

 

       turn off their cell phones, unless they are

 

       expecting a call of a super emergency nature.  I

 

       would also like to ask if the guest speakers could

 

       make themselves available for the discussion this

 

       afternoon, I would really appreciate it.  We may

 

       have some additional questions.

 

                 We have received a charge from the FDA to

 

       give our evaluation of the draft report prepared by

 

       the Threshold Working Group.  I assume all of the

 

       members have read that thoroughly.  In my opinion,

                                                                  7

 

       I it was fascinating.

 

                 It was an excellent article and I commend

 

       the Committee for coming up with it.  It was very

 

       educational.  Not being an expert on food allergens

 

       myself, it was extremely educational, and I was

 

       able to follow it quite clearly.

 

                 Our charge is to evaluate this report to

 

       determine whether the approaches that are presented

 

       in there are the only ones or the better ones,

 

       which of the ones that are in there might be the

 

       most appropriate.  This is the focus of our meeting

 

       today, both on the food allergens and on gluten.

 

 

                 Let me also begin by asking the committee

 

       members to introduce themselves.  We will start

 

       with Dr. Silverstein.

 

                 Marc, would you start it off?

 

                 DR. SILVERSTEIN:  Good morning.  My name

 

       is Marc Silverstein, and I'm a general internist

 

       and geriatrician at Baylor Health Care System in

 

       Dallas.

 

                 DR. TEUBER:  Good morning.  My name is

 

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

                                                                  8

 

                 MR. ORYANG:  Good morning.  I am

 

       David Oryang.  I am a risk analyst and agricultural

 

       engineer at the United States Department of

 

       Agriculture, Animal and Plant Health Inspection

 

       Service.

 

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

 

       gastroenterologist at the Harvard Medical School in

 

       Boston.

 

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

 

       scientist with the USDA.

 

                 DR. BRITTAIN:  Erica Brittain, I am a

 

       statistician at the National Institute of Allergy

 

       and Infectious Disease.

 

                 DR. BRILEY:  Margaret Briley, University

 

       of Texas at Austin, nutritionist.

 

                 DR. BOCEK:  Good morning.  I am

 

       Petr Bocek, medical officer in NIH's National

 

       Institute of Allergy and Infectious Diseases.

 

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

 

       the FDA as the executive secretary of the Food

 

       Advisory Committee.

 

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

                                                                  9

 

       nutritional epidemiologist at the University of

 

       Hawaii.

 

                 DR. McBRIDE:  I am Margaret McBride.  I am

 

       a child neurologist at Akron Children's Hospital.

 

                 DR. CALLERY:  I am Patrick Callery, a

 

       pharmaceutical scientist from West Virginia

 

       University.

 

                 DR. GONSALVES:  I am Dennis Gonsalves, a

 

       scientist with USDA in Hawaii.

 

                 DR. HEIMBURGER:  I am Doug Heimburger, a

 

       physician and nutrition specialist at the

 

       University of Alabama at Birmingham.

 

                 DR. BARACH:  Jeff Barach with Food

 

       Products Association, vice president for special

 

       projects and regulatory affairs.

 

                 DR. NELSON:  Mark Nelson with the Grocery

 

       Manufacturers Association responsible for

 

       regulatory and scientific policy.

 

                 MS. HALLORAN:  Jean Halloran from the

 

       Consumers Union where I am director of food policy

 

       initiatives.

 

                 CHAIRMAN DURST:  Thank you very much.

                                                                 10

 

                 One other item is that we may have some of

 

       our members leave early on Friday, depending on the

 

       amount of time we can spend.  What I propose is

 

       that today and tomorrow that we anticipate having

 

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

 

       that we have enough time for all of our

 

       discussions.

 

                 Okay.  Let me introduce our first speaker.

 

       This will be Jenny Slaughter, director of Ethics

 

       and Integrity Staff at the FDA, to describe the

 

       "Conflict of Interest Statement" and other

 

       instructions.

 

                      CONFLICT OF INTEREST STATEMENT

 

                          AND OTHER INSTRUCTIONS

 

                 MS. SLAUGHTER:  Well, good morning and

 

       welcome.  The Food and Drug Administration is

 

       convening today's meeting of the Food Advisory

 

       Committee under the authority of the Federal

 

       Advisory Committee Act of 1972.

 

                 With the exception of the industry

 

       representatives, all members of the Committee are

 

       special government employees or regular Federal

                                                                 11

 

       employees from other agencies subject to Federal

 

       conflict of interest laws and regulations.

 

                 FDA has determined that members of this

 

       Advisory Committee are in compliance with Federal

 

       ethics and conflict of interest laws including, but

 

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

 

       354.

 

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

 

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

 

       applicable to only FDA, Congress has authorized FDA

 

       to grant waivers to special government employees

 

       who have financial conflicts when it is determined

 

       that the Agency's need for particular

 

       interventional services outweighs the potential

 

       conflict of interest.

 

                 Members who are special government

 

       employees at today's meeting including special

 

       government employees appointed as temporary voting

 

       members, have been screened for potential financial

 

       conflicts of interest of their own as well as those

 

       of their spouse, minor child, and employer, which

 

       are related to the discussions of today's and

                                                                 12

 

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

 

       Draft Report: Approaches to Establish Thresholds

 

       for Major Food Allergens and for Gluten in Foods."

 

                 These interests may include investments,

 

       consulting, expert witness testimony, contracts,

 

       grants, research and development agreements, public

 

       speaking, writing, patents, royalties, and primary

 

       employment.

 

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

 

       full waivers have been granted to the following

 

       participants, Dr. Suzanne Teuber and Dr. Soheila

 

       Maleki, please note that all of the interests in

 

       the firms that could potentially be affected by the

 

       Committee's decisions.

 

                 A copy of the written waiver statements

 

       may be obtained by submitting a written request to

 

       the Agency's Freedom of Information Office, Room

 

       12A-30 of the Parklawn Building.

 

                 In addition, the following individuals are

 

       participating as FDA's invited guest speakers,

 

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

 

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

                                                                 13

 

       Dr. Robert Wood.

 

                 The following individuals will be

 

       participating as FDA invited guest speakers

 

       tomorrow, July 14th: Dr. Pekka Collin,

 

       Dr. Alessio Fasano, Dr. Donald Kasarda,

 

       Dr. Cynthia Kupper, and Dr. Joseph Murray.

 

                 Lastly, I would like to report that

 

       Dr. Jeffrey Barach and Dr. Mark Nelson are serving

 

       as the industry representatives on the Committee at

 

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

 

       regulated industry.

 

                 Dr. Jeffrey Barach is employed by the

 

       National Food Processors Association and

 

       Dr. Mark Nelson is employed by the Grocery

 

       Manufacturers of America.

 

                 A copy of this document will be placed on

 

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

 

       it.  I thank you.

 

                 CHAIRMAN DURST:  Thank you very much.

 

       We will now go on to the welcome and opening

 

       statement by Dr. Michael Landa, the deputy director

 

       for Regulatory Affairs at CFSAN, the FDA.

                                                                 14

 

                 Mike.

 

                      WELCOME AND OPENING STATEMENT

 

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

 

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

 

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

 

                 (General laughter.)

 

                 MR. LANDA:  Thanks again.  Good morning to

 

       everyone.  Welcome to the members of the committee,

 

       to the guest speakers, to members of the public who

 

       have joined us today, and to my fellow FDA

 

       employees.

 

                 I would like to give a special thanks to

 

       the Committee members for your willingness to take

 

       time from busy schedules to help us with your

 

       expertise for a meeting that will be several days

 

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

 

       chunk of Friday.

 

                 Let me just add that Dr. Brackett had

 

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

 

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

 

       some portion of the meeting.  He was called

 

       downtown for a meeting this morning.

                                                                 15

 

                 I am going to refer to a couple of points

 

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

 

       apply to celiac disease as well.  It is just less

 

       cumbersome to start with the food allergens.  The

 

       agenda has been making, I think, an opening

 

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

 

       that.

 

                 There are just a few points I want to make

 

       as you go into your inquiry today.  The first is

 

       virtually every FDA speaker makes at this kind of

 

       proceeding which is what we do really is based on

 

       science.

 

                 We talk about being a science-based

 

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

 

 

       In that context, I am going to paraphrase what may

 

       be a rather obscure 19th century Senator, Karl

 

       Shrews from Pennsylvania.

 

                 The paraphrase essentially is, Our science

 

       correct or incorrect, when it is correct, help us

 

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

 

       correct it.  That is as much as anything else what

 

       we want from you here in terms of your expertise in

                                                                 16

 

       the science.

 

                 If with respect to the threshold in the

 

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

 

       know from you that we have gotten it right.  We

 

       want your help in keeping it right.  If we have

 

       gotten it wrong, we want your help in getting it

 

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

 

       not considered an approach that we should have

 

       considered, we want to know that from  you.

 

                 The third point I will make is that

 

       Americans suffer from food allergies, particularly

 

       children.  There is some evidence that the number

 

       is increasing.  If you add to that family members,

 

       you really have tens of millions of folks who are

 

       involved.  At the moment their principle means of

 

       protection really is exquisite attention to the

 

       food label.  That is their pathway to safety I

 

       suppose.

 

                 We are hoping that eventually thresholds

 

       will provide another path to safety.  This is the

 

       beginning of the inquiry into thresholds, that is,

 

       the approaches that are outlined in the report.  It

                                                                 17

 

       is the first step in a very important process.

 

                 The last point I will make is just that

 

       this is as much as anything else for members of the

 

       public, the docket is going to remain open until

 

       about the middle of August.

 

                 If people have comments, based on what

 

       they have heard today, for example, they should

 

       feel free to submit those comments to the docket.

 

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

 

       precise date, but it is the middle of August.

 

                 In that connection, I should say we are

 

       especially interested, as I think is always the

 

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

 

       outlined in the report.

 

                 Thank you.

 

                 CHAIRMAN DURST:  Thank you, Mike.  Since

 

       Mr. Landa didn't want me conferring a doctorate

 

       degree on him, I will not do it with Catherine

 

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

 

       FDA, who will discuss the use of food allergens

 

       thresholds.

 

                     USE OF FOOD ALLERGENS THRESHOLDS

                                                                 18

 

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

 

                 (General laughter.)

 

                 MS. COPP:  Thank you, Dr. Durst.

 

                 Good morning.  As you know, the focus of

 

       this meeting today and tomorrow and the discussion

 

       on Friday is the Draft Report of CFSAN's Threshold

 

       Working Group:  Approaches to Establish Thresholds

 

       for Major Food Allergens and For Gluten in Food.

 

                 I have been asked to provide a context for

 

       the Draft Report in terms of CFSAN's programmatic

 

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

 

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

 

                 (Slide.)

 

                 MS. COPP:  Last August, Congress enacted

 

       the Food Allergen Labeling and Consumer Protection

 

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

 

       awkward acronym "FALCPA."

 

                 This new law amends the Federal Food, Drug

 

       and Cosmetic Act, the principle statute

 

       administered by FDA by requiring that the label of

 

       a food product that is or contains an ingredient

 

       that bears or contains a major food allergen

                                                                 19

 

       declare the presence of the allergen as specified

 

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

 

       in "consumer friendly" terms.

 

                 FALCPA defines a "major food allergen" as

 

       one of the eight foods or food groups or a food

 

       ingredient that contains protein derived from one

 

       of these foods.  Those are listed on the bottom of

 

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

 

       nuts and crustacean shellfish, which were

 

       identified by Congress in the law.

 

                 (Slide.)

 

                 MS. COPP:  The possible existence of

 

       threshold levels for food allergens is an important

 

       scientific issue, as Mr. Landa has pointed out,

 

       associated with our implementation of FALCPA.

 

                 Although the law does not require FDA to

 

       establish thresholds for any food allergen, there

 

       are three possible ways, which are listed on this

 

       slide, that such thresholds could be used to

 

       implement the new law, these are: administering the

 

       petition process provided for in FALCPA,

 

       administering its notification process, and

                                                                 20

 

       addressing the issue or the occurrence of

 

       cross-contact.

 

                 (Slide.)

 

                 MS. COPP:  FALCPA provides two processes

 

       by which an ingredient may be exempt from the

 

       FALCPA labeling requirements, a petition process

 

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

 

       own slides (laughter).  No, okay.

 

                 Under the petition process, an ingredient

 

       may be exempt, if the petitioner demonstrates that

 

       the ingredient does not cause an allergenic

 

       response that poses a risk to human health.

 

                 Given this language for the petition

 

       exemption standard, we believe it will be very

 

 

       important for us to both understand food allergen

 

       thresholds and to have a sound scientific framework

 

       for evaluating the existence of such thresholds.

 

                 Under the notification process, an

 

       ingredient may be exempt, if the notification

 

       contains scientific evidence that demonstrates that

 

       the ingredient does not contain allergenic protein,

 

       or, if FDA has previously determined under the food

                                                                 21

 

       additive approval process that the food ingredient

 

       does not cause an allergenic response that poses a

 

       risk to human health.

 

 

 

                 (Slide.)

 

                 MS. COPP:  Given this language for the

 

       notification exemption standard, we also believe

 

       that it will be very important for us to understand

 

       food allergen thresholds and to have a sound

 

       scientific framework for evaluating the existence

 

       of such thresholds.

 

                 (Slide.)

 

                 Finally, the FALCPA directs FDA to prepare

 

       and submit a report to Congress.  This report will

 

       focus principally on the issue of cross-contact of

 

       foods with food allergens and is to describe the

 

       types, current use of, and consumer preferences

 

       with respect to so-called "advisory labeling."

 

       Processed in a facility that also processes tree

 

       nuts is an example of such labeling.

 

                 Cross-contact may occur during food

 

       production when residues of an allergenic food are

                                                                 22

 

       present in the manufacturing environment and are

 

       unintentionally incorporated into a food.  Because

 

       the food is not intended to contain the allergen,

 

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

 

       label.  In some cases, however, the potential

 

       presence of the food allergen is declared by a

 

       voluntary advisory statement.

 

                 We also believe that understanding food

 

       allergen thresholds and developing a sound

 

       scientific framework for evaluating the existence

 

       of such thresholds may also be useful to us in

 

       evaluating and addressing food allergen

 

       cross-contact and the use of advisory labeling.

 

                 Thank you.

 

                 CHAIRMAN DURST:  Thank you very much.

 

                 Does the Committee have any questions or

 

       discussion of this presentation?

 

                 (No verbal response.)

 

                 CHAIRMAN DURST:  If not, I think we will

 

       proceed.

 

                 The next speaker is Dr. Robert Wood,

 

       professor at Johns Hopkins University School of

                                                                 23

 

       Medicine, who will give us an introduction to food

 

       allergens.

 

                      INTRODUCTION TO FOOD ALLERGENS

 

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

 

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

 

       provide an overview of food allergens and food

 

       allergy leading into the discussion that is going

 

       to go on over these next couple of days.

 

                 (Slide.)

 

                 DR. WOOD:  The beginning of this, any talk

 

       about food allergy really requires that we have

 

       some common definition that we can all agree on.

 

       This is something that is not as easy as it might

 

       sound and often generates a lot of confusion.  The

 

       reality is that a lot of what is called food

 

       allergy is really not food allergy and may fall

 

       under more of a food intolerance category.

 

                 When we are talking about food allergy,

 

       there are a couple of key ingredients.  One of them

 

       is that there is an immunologic component to the

 

       reaction.  The reaction is typically to the protein

 

       component of the food as opposed to a food

                                                                 24

 

       intolerance that is more often related to the

 

       carbohydrate component of the food.  Importantly to

 

       this meeting, exquisitely small amounts may cause a

 

       reaction and that these reactions can be severe and

 

       even life threatening.

 

                 (Slide.)

 

                 DR. WOOD:  The pathophysiology of the

 

       allergic response is sort of very schematically

 

       diagramed here.  What we are thinking about is a

 

       process that begins with exposure and with most

 

       allergy, probably all allergy, you have to have

 

       some prior exposure to develop your sensitivity.

 

                 (Slide.)

 

                 DR. WOOD:  There is a genetic

 

       predisposition that makes some people particularly

 

       more prone to develop allergy in general, whether

 

 

       it be food allergy or respiratory allergy, than

 

       others.   There are some people who no

 

       matter what, how, when and where they are exposed

 

       they will never develop an allergy, and others who

 

       with very trivial exposure may develop a severe

 

       allergy.

                                                                 25

 

                 If you are in this group who is

 

       genetically predisposed, your immune system then

 

       goes through a process we will refer to as

 

       sensitization.  Sensitization is most often

 

       involving the production of IgE antibodies.  We

 

       will talk about this in a little bit more detail

 

       about some different food allergy syndromes.

 

                 However, it is also important to note that

 

       not every food allergy involves IgE and that there

 

       may be differences in the types of reactions and

 

       the doses of food required to induce a reaction in

 

       those patients that have IgE versus

 

       non-IgE-mediated food allergy.

 

                 Once you have become sensitized, then

 

       reexposure to this food will lead to symptoms.

 

       These symptoms may be abrupt, they may occur within

 

       seconds of eating the food, or they may be very

 

       low-grade and chronic.  This is another concept

 

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

 

                 With some patients it will be very easy to

 

       determine a threshold, and in some patients it will

 

       be virtually impossible to determine a threshold

                                                                 26

 

       because their symptoms will not appear in a

 

       challenge test.  They may take days or weeks of

 

       chronic exposure and then develop very significant

 

       disease based on that chronic exposure.

 

                 (Slide.)

 

                 DR. WOODS:  The prevalence of food allergy

 

       is substantial.  The numbers that we would be most

 

       comfortable with would be 5 to 7 percent of young

 

       children; 2 to 3 percent of adolescents and adults;

 

       at least 10 or 11 million Americans affected.

 

                 We do believe that the prevalence is

 

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

 

       food allergy.  There has been a substantial rise in

 

       asthma and other allergic diseases as well as food

 

       allergy.

 

                 Now, the reason that these numbers change

 

       between childhood and adolescence and adulthood is

 

       because a large proportion of food allergy is

 

       outgrown over the first five to seven years of

 

       life.

 

                 (Slide.)

 

                 DR. WOOD:  There is a long list of

                                                                 27

 

       potential food allergens out there.  At least 200

 

       foods have been identified and characterized as

 

       truly food allergens, but there is a relatively

 

       shorter list that are focused upon because they are

 

       responsible for the vast majority of food allergy

 

       that occurs.

 

                 The list on the left-hand side

 

       representing what is most common in young children:

 

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

 

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

 

       older children, adolescents and adults and is

 

       dominated by peanuts, tree nuts, fish, and

 

 

       shellfish.

 

                 The reason that this list changes from

 

       childhood to adulthood is because four of these

 

       most common food allergens in your children --

 

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

 

       outgrown.

 

                 Eighty to 90 percent of children will

 

       outgrow those food allergens and not carry them

 

       into adolescence or adulthood, whereas the peanuts,

 

       tree nuts, fish and shellfish are significantly

                                                                 28

 

       more difficult to outgrow, less commonly outgrown,

 

       and tend to persist into adulthood and actually

 

       through the patient's entire lifespan.

 

                 (Slide.)

 

                 DR. WOOD:  Now, the signs and symptoms of

 

       food allergy are highly varied.  They may be

 

       chronic and low grade as I mentioned, they may be

 

       acute and life threatening.  What I want to run

 

       through in the next couple of minutes are just some

 

       examples of allergic reactions that will point out

 

       a number of things about not only the kinds of

 

       reactions, but the exquisitely small amounts of

 

       food that induce these reactions we are going to

 

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

 

       patients with food allergy are facing.

 

                 (Slide.)

 

                 DR. WOOD:  The first couple of patients I

 

       am going to show you have urticaria or hives.  This

 

       is a total body hive reaction that this boy is

 

       experiencing, a patient I have known since he was

 

       an infant.

 

                 He is school age at this point.  This

                                                                 29

 

       reaction occurred when he was in the grade school

 

       cafeteria, was being teased about this food

 

       allergy, another child blew a straw full of milk

 

       across the table into his face, and he had this

 

       really significant reaction.

 

                 (Slide.)

 

                 DR. WOOD:  This baby here was identified

 

       with milk allergy in the first few weeks of life.

 

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

 

       allergy until they are two or three or four years

 

       old, while there are others who are really

 

       demonstrating food allergy in the first days of

 

       life.

 

                 This was a baby who was so allergic that

 

       he would react very acutely if his mother, who was

 

       breast feeding him, ingested any milk protein.  She

 

       was on a very strict avoidance diet after we

 

       identified his milk allergy, but on the occasion of

 

       her birthday ate a piece of cheesecake, breastfed

 

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

 

       hive reaction.

 

                 (Slide.)

                                                                 30

 

                 DR. WOOD:  Now, when we are thinking about

 

       urticaria or hives, there are patients that may

 

       have chronic urticaria.  Food allergy is rarely a

 

       cause of chronic urticaria.

 

                 However, when someone shows up with an

 

       acute episode of hives, the chance that it is food

 

       allergy becomes higher.  Again, we are looking a

 

       relatively short list of foods that are most

 

       commonly implicated: peanut, nuts, eggs, milk,

 

       fish, and shellfish.

 

                 Importantly, these reactions are usually

 

       very quick in their onset.  Ninety percent of them

 

       or thereabouts will have an onset within 30

 

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

 

       and virtually all of them, within 2 hours.

 

                 When a patient has this type of reaction,

 

       it is often very easy to identify the culprit food

 

       because of the abrupt association of the ingestion

 

       of that food with the onset of these hives.

 

                 Then, in more severe episodes, there may

 

       be swelling or angioedema or associated

 

       gastrointestinal or respiratory symptoms.  That is

                                                                 31

 

       moving into more of a systemic reaction that we

 

       would refer to as "anaphylaxis."

 

                 (Slide.)

 

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

 

       is having an anaphylactic reaction.  When you look

 

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

 

       you see her front, though, she is having swelling

 

       and breathing difficulty.

 

 

 

                 (Slide.)

 

                 DR. WOOD:  This is a patient who was

 

       having a reaction in the midst of a food challenge

 

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

 

       dose of egg protein, she went into this very

 

       severe, anaphylactic reaction.

 

                 (Slide.)

 

                 DR. WOOD:  This boy here is someone who is

 

       having a dramatic episode of swelling.  His

 

       reaction occurred.  Most patients, we should say,

 

       who are having severe reactions know about their

 

       food allergy and are making efforts to avoid it.

 

                 He was shellfish allergic -- he is

                                                                 32

 

       shellfish allergic.  He was making efforts to avoid

 

       shellfish, and he had been reaction-free for

 

       several years.

 

                 Then, on another birthday occasion, he ate

 

       chicken in a restaurant and the chicken had been

 

       fried in the same oil as shrimp had been fried.

 

       With that cross-contact, this severe reaction.

 

                 (Slide.)

 

                 DR. WOOD:  Anaphylactic reactions are

 

       defined as a systemic allergic reaction,

 

       involvement of multiple organ systems.  These have

 

       an abrupt onset typically.  They are related to IgE

 

       antibodies.

 

                 You can identify these by doing a skin

 

       test or a blood test looking for IgE.  The

 

       manifestations are not always severe.  There is an

 

       impression that all anaphylaxis is

 

       life-threatening.  Some episodes are relatively

 

       mild, but others progress rapidly to

 

       life-threatening or fatal reactions.

 

                 We think that there are at least 150

 

       deaths in the United States each year due to fatal

                                                                 33

 

       food-induced anaphylaxis.  That number is probably

 

       a substantial underestimation, but we would be very

 

       comfortable saying that it is well identified of

 

       100 to 150 deaths per year.

 

                 There are different types of reactions:

 

       some are single phase and some have two phases,

 

       where a patient may look better and then two or

 

       three or four hours later have an even more severe

 

       reaction than they had initially, some of those

 

       lead to the worst outcomes.

 

                 (Slide.)

 

                 DR. WOOD:  This is a patient with one of

 

       the more chronic forms of food allergies, the

 

       patient with severe itching due to his eczema.  In

 

       Eczema, a food allergy is often underappreciated

 

       because there is not an obvious cause and effect.

 

                 This is one where it is more of a

 

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

 

       harder for a patient or a family member to identify

 

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

 

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

 

       reaction where you don't see these direct

                                                                 34

 

       relationships between ingestion of the food and the

 

       outcome being their eczema or atopic dermatitis.

 

                 It is also a condition where food allergy

 

       is underappreciated by physicians and where

 

       patients may be treated with a variety of different

 

       creams and lotions and only later on find out that

 

       it was really a food allergy that was driving the

 

       eczema.

 

                 Overall, 40 to 50 percent of patients with

 

       severe atopic dermatitis and 20 or 25 percent with

 

       less severe cases have an underlying food allergy.

 

                 The same list of foods: egg allergy being

 

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

 

       and fish.  These six foods account for the vast

 

       majority of food sensitivities seen in atopic

 

       dermatitis.

 

                 From our standpoint, it makes it

 

       relatively easy to screen patients and find which

 

       of them are allergic by testing for a relatively

 

       short list of foods.

 

                 (Slide.)

 

                 DR. WOOD:  Now, the last category that I

                                                                 35

 

       want to mention is something that we will lump

 

       together as gastrointestinal food hypersensitivity.

 

       There are a variety of conditions that fall under

 

       this umbrella.

 

                 There are some that are in the immediate

 

       hypersensitivity category.  This would be part,

 

       say, of an anaphylactic reaction where someone ate

 

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

 

       abdominal pain, or other gastrointestinal symptoms.

 

                 There is another condition called "oral

 

       allergy syndrome" where patients have reactions

 

       that are confined to their mouth or throat or lips,

 

       particularly related to fresh fruits and

 

       vegetables.

 

                 There is another group of conditions that

 

       are lumped under a category of eosinophilic

 

       disorders of the GI tract.  There is a specific

 

       condition, eosinophilic esophagitis, where only the

 

       esophagus is involved.  As most people in the

 

       audience know, the eosinophil is a type of white

 

       blood cell that is most affiliated with allergic

 

       reactions.

                                                                 36

 

                 If you take someone who is having a bad

 

       hay fever day outside today and look at their nasal

 

       secretions, their nasal secretions will be loaded

 

       with eosinophils.  If you take someone that is

 

       having difficult asthma, their bronchial mucosa

 

       will be loaded with eosinophils.

 

                 By the same token, if you have allergic

 

       eosinophilic esophagitis, the lining of your

 

       esophagus is loaded with eosinophils.  It may be

 

       isolated to the stomach, it may be more diffuse

 

       where we would call it "allergic eosinophilic

 

       gastroenteritis."  This is somebody who may have

 

       disease anywhere in their GI tract, and oftentimes

 

       very diffusely.

 

                 There are some other conditions,

 

       enterocolitis syndrome and dietary protein

 

       proctitis, that are much more common in very young

 

       babies.

 

                 The importance of presenting these

 

       different syndromes here is that some of these

 

       syndromes are IgE mediated and some of them are not

 

       IgE mediated, some of them are very acute and some

                                                                 37

 

       of them are very chronic.

 

                 It turns out that those syndromes that are

 

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

 

       any acute symptoms, don't present with any clear

 

       cause and effect of eating the food and having

 

       increased gastrointestinal symptoms are going to

 

       be, potentially, the most difficult for this

 

       Committee to grasp.  That is because these patients

 

       are often reacting to remarkably small exposures.

 

                 I will come back at the end to sort of

 

       give a couple of examples of the dilemma that kind

 

       of patient is going to present to us as we really

 

       try to figure out what is safe and what is not

 

       safe.

 

                 It also turns out in the same vein that

 

       the non-IgE conditions in general are probably

 

       going to be most difficult to deal with, both

 

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

 

       symptoms, and because they are predominantly

 

       mediated by a different part of your immune system

 

       that can recognize even smaller degrees of these

 

       food proteins that identifying thresholds are going

                                                                 38

 

       to be much more difficult.

 

                 (Slide.)

 

                 DR. WOOD:  Now, when we are trying to

 

       approach a patient with a food allergy, one of the

 

       real difficulties is making an accurate diagnosis.

 

       The diagnosis, as in most everything we do, begins

 

       with a history, talking about the foods they

 

       suspect are causing problems, whether we think the

 

       symptoms are consistent with food allergy, whether

 

       this is something that may not be food allergy at

 

       all, or whether it may be a food intolerance rather

 

       than an allergy.  We are going to be interested in

 

       the timing of the symptoms and the reproducibility

 

       of reactions.

 

                 It turns out that when you do a very

 

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

 

       will be correct in the acute reactions, where you

 

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

 

       scrambled eggs for the first time last week, and he

 

       had hives all over."

 

                 "She took her first bite of peanut butter,

 

       and developed hives within 2 minutes."

                                                                 39

 

                 It is very likely that the history will be

 

       born out when you do further testing.  However,

 

       when you look at the bulk of patients with food

 

       allergies, many of them will have these more

 

       chronic conditions like eczema or the

 

       gastrointestinal disorders.  When you are looking

 

       at those patients, you will only verify the history

 

       when you do further testing about a third of the

 

       time.

 

                 (Slide.)

 

                 DR. WOOD:  The next set of tests we do

 

       after taking a history would typically either be

 

       skin testing or serologic testing.  A RAST test,

 

       "radioallergosorbent test," is the most common

 

       serologic test that is used.

 

                 These tests have some value and they also

 

       have some problems.  The problems they have is that

 

       there is a relatively high rate of false-positive

 

       tests.  They do not have a terribly good positive

 

       predictive accuracy.

 

                 They are generally accurate when they are

 

       negative.  Although, they will only be active when

                                                                 40

 

       they are negative when you are convinced this

 

       patient has an IgE-mediated condition, because both

 

       of these tests rely on the presence of IgE

 

       antibodies to identify the specific food allergy.

 

                 An example would be if a patient develops

 

       hives or anaphylaxis, which typically are

 

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

 

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

 

       likely that they have that allergy.  If you get a

 

       negative test back, then you need to keep looking.

 

       It was not likely that food that caused that

 

       reaction.

 

                 However, if you have a patient with

 

       something like the allergic eosinophilic

 

       gastroenteritis where there may not always be IgE

 

       antibodies, you cannot stop with a negative test

 

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

 

       allergy."  That is something that happens all the

 

       time, but it is often going to lead to a

 

       misdiagnosis and mismanagement of that patient.

 

                 The bottom line is that we need to

 

       carefully interpret our tests in the context of the

                                                                 41

 

       overall clinical picture, and that we need to rely

 

       on oral challenge tests as the more accurate tests,

 

       so that we will say that they are not completely

 

       definitive.  They are more definitive but not

 

       completely definitive.

 

                 Again, they are going to be less

 

       definitive in the patients that have more delayed

 

       type reactions or more chronic conditions where

 

       they won't react in that four-hour observation

 

       period of your food challenge.

 

                 (Slide.)

 

                 DR. WOOD:  You are going to hear more

 

       about food challenges this afternoon, but I will

 

       just mention a couple of issues here in terms of

 

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

 

       down as open challenges where both the patient and

 

       the person administering the challenge knows what

 

       is being given.

 

                 A single-blind challenge is where the

 

       patient is blinded but the person administering the

 

       challenge knows the food that is being

 

       administered, whereas a double-blind,

                                                                 42

 

       placebo-controlled challenge is regarded as the

 

       most accurate test because it eliminates the bias

 

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

 

       may be feeling a great deal of anxiety about this

 

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

 

       may have their own biases about this patient's

 

       allergy and might overinterpret or underinterpret

 

       symptoms.

 

                 We would say that these are going to be

 

       the most accurate tests for the diagnosis of food

 

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

 

       results don't provide a clear diagnosis.  That is

 

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

 

       that may not be accurate and laboratory tests that

 

       may not be completely accurate.

 

                 Then, we also do them very commonly to

 

       determine when an allergy has been outgrown.  This

 

       would be a patient who has been known to be

 

       allergic to a food, and we would be monitoring them

 

       with some regularity in determining at some point

 

       that it is worth trying to retry that food.

 

                 We would typically do it in a controlled

                                                                 43

 

       setting, just because even in some patients you

 

       don't expect to react at all there may be

 

       significant reaction.  Consequently, we have to do

 

       these with considerable caution.

 

                 (Slide.)

 

                 DR. WOOD:  I think I pretty much mentioned

 

       this.

 

                 (Slide.)

 

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

 

       briefly, a study that we published last year

 

       looking at the risk of oral food challenges.  What

 

       we have presented in this paper were results on

 

       almost 600 challenges, 253 of which were failed

 

       challenges.  The patients reacted in the challenge,

 

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

 

       other 57 percent, the patients had no symptoms, so

 

       it was a risk-free challenge once they might have

 

       gotten over the anxiety of being there.

 

                 We collected a lot of information on

 

       demographics, other atopic disease, symptoms during

 

       challenges, treatment needed, doses at which

 

       reactions occurred.  Even though there is a lot

                                                                 44

 

       said about safety of food challenges, there has

 

       been very little published before this paper on

 

       what really occurs.

 

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

 

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

 

       front here, that these results are not

 

       representative of the general population of food

 

       allergy.

 

                 These patients that are being challenged

 

       in this either had an unclear diagnosis, so it

 

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

 

       thought to have potentially outgrown their allergy

 

       and were being challenged to potentially prove that

 

       their allergy was gone.

 

                 We are really looking at very low-risk

 

       population, and it is not representative of the

 

       whole population of food allergy patients that are

 

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

 

       times looking at the specific data.

 

                 (Slide.)

 

                 DR. WOOD:  Now, whenever we are doing this

 

       sort of analysis, we try to break things into

                                                                 45

 

       categories.  One of the tough categories to decide

 

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

 

       literature some different definitions that have

 

       been used.

 

                 We chose to create our own for a series of

 

       studies that we were doing, and talked about mild

 

       reactions that were skin and/or oral symptoms only.

 

       Oral symptoms is just at itching or they will often

 

       have an obvious hive-like reaction in their mouth

 

       or pharynx when they are having one of these

 

       localized reactions.

 

                 A "moderate reaction" was described as

 

       upper respiratory and or GI symptoms only or any

 

       three systems.  When we are talking about systems,

 

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

 

       lower respiratory and cardiovascular.

 

                 Then, severe reactions were those that

 

       were that were potentially life threatening, where

 

       they have lower respiratory and/or cardiovascular

 

       symptoms or any four systems were involved.

 

                 (Slide.)

 

                 DR. WOOD:  When we broke things down into

                                                                 46

 

       these different systems which were involved in

 

       which challenges, you will see here that when we

 

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

 

       total in this paper we reported on milk, egg,

 

       peanut, soy and wheat.

 

                 The greatest number of failed challenges

 

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

 

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

 

       that skin manifestations were most common, 78

 

       percent.

 

                 This is actually similar to what we have

 

       seen and what is in the literature in terms of

 

       reactions that happen out in the real world.

 

       Eighty percent of food reactions, 80 percent of

 

       anaphylactic reactions involve the skin, but about

 

       20 percent do not.

 

                 Oral symptoms occurred in about a quarter,

 

       upper respiratory in a quarter, lower respiratory

 

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

 

       thankfully, had no cardiovascular reactions in this

 

       population.

 

                 Now, why would that be the case?  It would

                                                                 47

 

       be for two reasons.  The biggest reason is that

 

       cardiovascular reactions are not that common in

 

       children.

 

                 The cardiovascular system of a child is

 

       really sturdy enough to put up with the insult of

 

       an allergic reaction without necessarily becoming

 

       involved.  Cardiovascular reactions are much more

 

       common in adults, and this population was entirely

 

       childhood.

 

                 The other reason that we might have seen

 

       the absence of cardiovascular reactions would be

 

       that we were dealing with a relatively low-risk

 

       population.

 

                 When we break it down into those three

 

       severity classifications -- mild, moderate and

 

       severe -- you will see that the numbers are

 

       relatively similar for each food.  When we look at

 

       the total category, they broke pretty close to a

 

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

 

       severe.

 

                 When you look across the specific foods,

 

       the most important point that came out of this is

                                                                 48

 

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

 

       this kind of setting is more dangerous than

 

       another.

 

                 It turned out that the greatest number of

 

       severe reactions occurred with egg challenges.

 

       This was important information we thought to get

 

       out to get out to people doing challenges.

 

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

 

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

 

       I'm not touching a peanut challenge because they

 

       are really dangerous.  However, I will do egg and

 

       milk challenges out in my office any time."

 

                 The message there is that really all of

 

       these foods have a potential to have severe

 

       reactions and need to be done in a setting where

 

       you are really equipped to deal with that potential

 

       for a severe reaction.

 

                 (Slide.)

 

                 DR. WOOD:  When we looked at the RAST test

 

       score or the median IgE level for these different

 

       challenge results, we found that there was really

 

       no strong association between their IgE level and

                                                                 49

 

       the reaction severity.

 

                 Now, this is an example of where this

 

       population is not a good one to look at for this

 

       data.  The reason is that we were essentially only

 

       challenging people that had relatively or very low

 

       levels.

 

                 We were not challenging people with very

 

       high levels where they were extremely likely to

 

       fail the challenge.  There is no reason in most

 

       instances to prove that they are allergic.  When

 

       you know with, say, 99 percent certainty that they

 

       are allergic, we would not put that patient through

 

       a challenge.

 

                 Consequently, if you went out in the real

 

       world where the RAST test levels range anywhere

 

       from zero to 100, you would typically see

 

       escalating reaction severity with levels that are

 

       higher.  We have that data for peanut allergy where

 

       the group of patients that had levels at 100 did

 

       have more severe reactions when they had accidental

 

       exposures.

 

                 (Slide.)

                                                                 50

 

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

 

       present from this study is whether reaction

 

       severity was correlated or related to the percent

 

       of food ingested in these challenges.  It turns

 

       out, if anything, it is inversely correlated.  The

 

       more severe reactions, and none of these were

 

       statistically significantly, but if you look at the

 

       general trends, you will see here that the more

 

       severe reactions occurred with milk and eggs.

 

                 As you can see, the severe reaction for

 

       milk is 15 percent and 30 percent for eggs.  When

 

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

 

       percent and 30 percent.

 

                 (Slide.)

 

                 DR. WOOD:  What is the reason this

 

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

 

       have your more severe reactions with smaller

 

       exposures?  The reason we think it happens is

 

       because it is just identifying the more reactive

 

       patients.

 

                 It is picking out those that even though

 

       our test scores said that they are not so allergic

                                                                 51

 

       that they should do this, it is picking out those

 

       that react more abruptly and have more severe

 

       symptoms early in the challenge just because they

 

       were higher risk patients.

 

                 Now, we have come up in our studies about

 

       some decision making about when we would do food

 

       challenges.  This is purely for clinical purposes.

 

       These are for those reasons of when we are trying

 

       to decide if they are truly allergic or when we

 

       think that the food allergy might have been

 

       outgrown.

 

                 What we would say is that we would do food

 

       challenges based on their history of reactions.  If

 

       they have reacted recently, we wouldn't feel the

 

       need to do a food challenge.

 

                 We would base it on their laboratory

 

       testing, the skin testing and the RAST testing.

 

       Then he would base it on the importance of the food

 

       to the diet.  There are some foods that are

 

       obviously much more important to the diet.

 

                 A family may never care whether that child

 

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

                                                                 52

 

       may elect to never have a pea challenge done, but

 

       they may be jumping to do a milk or what challenge

 

       at the first opportunity, because milk or wheat

 

       back in the diet would make such a dramatic

 

       difference in their day-to-day life.

 

                 Then, we have come up with some

 

       recommendations based on RAST testing of when we

 

       would recommend doing challenges.  These cutoffs

 

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

 

       greater than 50 percent chance of passing the

 

       challenge, if you have levels below that range.

 

       For other foods, it has been harder to determine

 

       cutoffs, and we would challenge at higher levels

 

       for things like wheat and soy.

 

                 (Slide.)

 

                 DR. WOOD:  Just to go through an algorithm

 

       of how we approach diagnosis, then, because it does

 

       impact on the discussions that are going to happen

 

       here, we would first take our history.

 

                 Based on the history, we would make some

 

       distinction whether we think this is consistent

 

       with an IgE type reaction or whether we think that

                                                                 53

 

       it is consistent with a non-IgE type reaction.

 

                 If it is IgE-mediated in all likelihood,

 

       then a skin test or a RAST test will help identify

 

       whether that food that was suspected to cause a

 

       reaction probably did or probably didn't.

 

                 If the test is negative, because the

 

       negative predictive accuracy is so high, we would

 

       feel that you could stop worrying about that food

 

       at that time.  If the skin test is positive,

 

       because there are false-positive tests that occur,

 

       we need to do something more.

 

                 We might do a trial on an elimination

 

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

 

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

 

       would arrive on the specific elimination diet

 

       recommended for that patient.

 

                 If it falls into a non-IgE category, the

 

       situation is much more difficult because we can't

 

       rely on a simple screening test to weed out those

 

       patients.

 

                 They are going to need some combination of

 

       challenges -- endoscopy, if it is a

                                                                 54

 

       gastrointestinal symptom; elimination diets,

 

       rechallenges, maybe a reendoscopy -- so there is a

 

       much more difficult plan on this side of the screen

 

       to sort out those patients.

 

                 (Slide.)

 

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

 

       with a couple of conclusions and present a couple

 

       of dilemmas.  The conclusions are that food allergy

 

       is very common.  This is a remarkably worthwhile

 

       initiative that is going on here, and that right

 

       now avoidance is the only treatment plan.

 

                 We really hope in the next 5 or 10 years

 

       that there are going to be other treatments for

 

       food allergy.  It may be enough so that even if

 

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

 

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

 

       have these meetings, that small exposures won't

 

       even be relevant.  We are not even close to their

 

       yet, so avoidance is the only option.

 

                 Strict avoidance is essential to prevent

 

       reactions obviously, but we also think that in many

 

       patients it also helps to promote the outgrowing

                                                                 55

 

       process.

 

                 Here is where we may have very different

 

       thresholds.  We may have a threshold that this

 

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

 

       fact that they can eat this bread that has whey as

 

       the tenth ingredient and never have a symptom.

 

       They are perfectly fine with it.

 

                 What we have found that getting that bread

 

       on a regular basis may keep their immune system

 

       more revved up to maintain the allergy so this

 

       thing that is way below their threshold for

 

       reacting acutely may still drive the immune system

 

       to maintain the allergy and prevent them from

 

       outgrowing the allergy.

 

                 The next conclusion is that food

 

       challenges are a useful means to diagnose food

 

       allergy and a useful means to determine threshold

 

       doses.  There are going to be some limitations of

 

       challenges, and one of them is that as opposed to

 

       the study that I presented that Dr. Perry did with

 

       me, you have to include in a threshold type study

 

       the most allergic patients.

                                                                 56

 

                 Doing the kind of patients that we are

 

       studying on the lower end of the spectrum has

 

       nothing to do with thresholds.  It is irrelevant

 

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

 

       looks like a threshold because we are not including

 

       in those kinds of studies those highly allergic

 

       patients."

 

                 The greater dilemma, and this one is

 

       solvable, there are plenty of real allergic

 

       patients out there.  They won't necessarily want to

 

       undergo these studies, because it is not a pleasant

 

       thing to have allergic reactions, but that part is

 

       potentially solvable.

 

                 The more difficult thing is a

 

       determination of the threshold doses that I

 

       mentioned for the chronic allergic conditions,

 

       especially those that are not IgE mediated probably

 

       isn't possible.

 

                 To give a couple of examples, if we take,

 

       say, milk allergy, the most common food allergy of

 

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

 

       formula, there are a bunch of different options we

                                                                 57

 

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

 

       them are also allergic to soy.

 

                 Some would go on to a formula like

 

       Alimentum or Nutramigen, which is a formula where

 

       the milk protein has hydrolyzed to a small enough

 

       fragment that in 98 or 99 percent of kids with milk

 

       allergy.  It completely solves the problem.  They

 

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

 

       protein that remains in that formula.

 

                 That other 2 percent, though, may react

 

       severely to that.  They are typically the patients

 

       with the gastrointestinal disease.  They are

 

       typically very sick; they are typically not

 

       growing; they are typically malnourished.

 

                 They are a group of patients who aren't at

 

       risk for the acute dangerous reactions, but they

 

       may be at very high risk for chronic disease from

 

       their food allergy.

 

                 Those patients will typically respond

 

       dramatically to a formula that is based in a single

 

       amino acids as a protein source, and that is a

 

       formula like Neocate and Elecare.

                                                                 58

 

                 Now, when you take that population, and

 

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

 

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

 

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

 

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

 

       react severely to it.

 

                 We know that because of their

 

       gastrointestinal biopsies, their biopsies that are

 

       taken from their esophagus or stomach or intestinal

 

       tract still show evidence of severe allergy.

 

                 What we think those patients are reacting

 

       to would be either the absolutely trivial amounts

 

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

 

       that is the eighteenth ingredient in Neocate, or

 

       the trivial, trivial amounts of protein that may be

 

       left in the safflower oil that is used as a fat

 

       component of Neocate.

 

                 When we switched those patients off of

 

       Neocate we can prove, and we have 15 patients now

 

       who we have proven, that taking them off Neocate

 

       resolved their food allergy.  In this supposedly

 

       non-allergenic formula, they were still reacting.

                                                                 59

 

                 Now, whether the direction this Committee

 

       needs to focus on is this very unusual patient or

 

       not is sort of a separate debate all together, but

 

       it is safe to say that there are going to be

 

       patients out there who break all rules.  No matter

 

       what rules are established, there will be patients

 

       who completely break them and make all of our lives

 

       difficult from that standpoint.

 

                 I would be delighted to take any questions

 

       from the Committee or otherwise.  Thank you for

 

       your attention.

 

                 CHAIRMAN DURST:  Thank you, Dr. Wood.

 

                 Are there questions for discussion?

 

                 Suzanne.

 

       QUESTION-AND-ANSWER SESSION

 

                 DR. TEUBER:  This is Suzanne Teuber.  I

 

       had a question about your patients with the Neocate

 

       sensitivity in terms of what the company reported

 

       for the soy lecithin, did they have any values that

 

       you could report back as to a chronic ingestion

 

       threshold?

 

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

                                                                 60

 

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

 

       have that data on the protein content of their soy

 

       lecithin.  They say it is zero.  These kids when

 

       they were switched to Neocate One Plus, which has

 

       no soy lecithin, their disease went away.  We have

 

       to assume that there was enough there to drive that

 

       process.

 

                 CHAIRMAN DURST:  Yes.

 

                 MS. HALLORAN:  Jean Halloran.  Could you

 

       say something about the process about growing

 

       allergies?  How does that work?  What actually

 

       happens?

 

                 DR. WOOD:  Well, that is a very good

 

       question.  There are a number of things that we

 

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

 

       is that in the majority of patients we think that

 

       outgrowing is most related to the immune system

 

       gradually forgetting about that concern that it

 

       earlier had.

 

                 That is where we think that strict

 

       avoidance is likely to promote the outgrowing

 

       process, and with a prolonged period of strict

                                                                 61

 

       avoidance for many of these foods, the immune

 

       system has a memory that isn't long enough to

 

       maintain the allergy and that it will gradually

 

       wane and then full tolerance will be accomplished.

 

       There are probably lots of other mechanisms going

 

       on immunologically that are not well understood.

 

                 The other question with this that we have

 

       no great explanations for, lots of theories but no

 

       great explanations, is why you can take a food

 

       allergy like milk, which in early infancy can be

 

       every bit as severe as a peanut allergy, and have

 

       most kids outgrow that allergy, while very few kids

 

       outgrow the peanut allergies.  There is something

 

       very different about the immunologic memory of one

 

       food allergen versus another.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. KELLY:  Ciaran Kelly.  I wanted to

 

       come back to the issue of challenging individuals

 

       with severe allergies as a method for determining a

 

       threshold.  I would like to hear your comments as

 

       regards the feasibility and safety and whether that

 

       would be ethical to perform?  I guess my concern is

                                                                 62

 

       that once the threshold is crossed, whatever that

 

       threshold might be, isn't there a potential for

 

       severe allergic reaction?

 

                 DR. KELLY:  Yes.  Absolutely.  There have

 

       been threshold studies done for the biggie, peanut,

 

       with very allergic people so it is doable.  Now,

 

       what we can say about this is that these studies

 

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

 

       happen.

 

                 That automatically limits your population

 

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

 

       your group of milk-allergic adults to do these

 

       studies on, you are limited.

 

                 Now, they do tend to be more severe

 

       reactors.  From that standpoint, you have some

 

       patients out there, but there is no IRB that is

 

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

 

       be demonstrated benefit to do a study with risk.

 

                 The safety element is one that we are

 

       comfortable with, recognizing that you need to have

 

       emergency management available to you because there

 

       will be people that have bad reactions.

                                                                 63

 

                 The safety that is built into that is

 

       starting with exquisitely small doses and working

 

       up very gradually and aborting the challenge

 

       whenever you see your first symptom.

 

                 That may lead you to end some challenges

 

       prematurely.  You may end up with a false

 

       threshold, but you are obligated to stop when you

 

       have objective signs that patient is reacting.

 

                 The ethics beyond that to me is that if it

 

       is an adult patient who is willing to consent to

 

       that process, I have no problem with the ethics of

 

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

 

       patient to a food challenge.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. BRITTAIN:  This is Erica Brittain.

 

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

 

       know how this threshold might be different in

 

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

 

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

 

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

 

       large enough sample to have any validity

 

       whatsoever.  It is a superb question.  The argument

                                                                 64

 

       is going to be and will always be these children

 

       are much more reactive than the adults for most of

 

       these foods.

 

                 For peanut allergy it is going to be the

 

       simplest, because allergy tends to persist.  We

 

       think that people usually hit their peak level of

 

       severity as an adolescent or young adult, so that

 

       would be fairly easy to solve.

 

                 However, when you look at the others like

 

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

 

       large going to have the highest level of reactivity

 

       in your first couple of years of life.

 

                 When we think about those allergies, we

 

       usually think of growing into the allergy for one

 

       or two or three years where they are becoming more

 

       and more allergic, and then they are becoming less

 

 

       and less allergic over the next one or two or three

 

       or four or five years as they outgrow the allergy.

 

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

 

       severe reactivity is likely to be early on.

 

                 CHAIRMAN DURST:  Dr. Wood, I have a

 

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

                                                                 65

 

       clarification.  On your slides where you indicated

 

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

 

       as opposed to our discussion tomorrow on celiac

 

       disease?

 

                 DR. WOOD:  Yes, these results are entirely

 

       IgE.

 

                 CHAIRMAN DURST:  Okay.  Do other grains

 

       cause the IgE type reaction as the wheat?

 

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

 

       challenges, came out of about 3,000 food challenges

 

       that we have done.  There were five most common

 

       foods that I had enough data to make some

 

       conclusions that we were comfortable with.  All of

 

       the grains cause allergic reactions.

 

                 It turns out that wheat and rye are very

 

       cross reactive from an IgE-mediated allergy

 

       standpoint, and that most patients allergic to

 

       wheat are also allergic to rye; it turns out that

 

       about half are allergic to barley; and 10 to 20

 

       percent are allergic to oat.  Beyond those grains,

 

       all of the other grains and grain substitutes are

 

       clearly capable of causing allergy in select

                                                                 66

 

       patients.

 

                 CHAIRMAN DURST:  Thank you.  One other

 

       question as far as clarification at least for my

 

       mind.  One of your slides with the food challenge

 

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

 

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

 

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

 

       of IgE in a specific assay that Pharmacia has

 

       developed called an immunoCAP RAST.  It all goes

 

       back to this one technology that is thought to be

 

       the most accurate quantitative measure of specific

 

       IgE, and the results are represented in that kilo

 

       unit of IgE, the specific IgE antibody per liter of

 

       serum.

 

                 CHAIRMAN DURST:  Thank you.

 

                 There is another question?

 

                 DR. KELLY:  I have one other question.

 

       Dr. Wood, you made a very important comment about

 

       the potential for continued subclinical exposure to

 

       allergens perpetuating an allergic response.  How

 

       well accepted and how well documented is that, or

 

       is that largely a clinical impression?

                                                                 67

 

                 DR. WOOD:  Very well accepted, very poorly

 

       documented.  It is widely accepted.  There is very

 

       poor information to support it.  There are only a

 

       couple of studies.  The problem we have is we tried

 

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

 

       is so widely accepted that to go to the IRB and

 

       propose to them that we are going to take this

 

       group of kids with milk allergy and keep them on

 

       low-dose milk and take this group and have them

 

       strictly avoid it was turned down.

 

                 Now, there is some work being done that

 

       has identified instead of looking at the IgE

 

       against milk globally, it has turned out that if

 

       you have IgE against certain portions of the milk

 

       molecule it may be more predictive of a longer-term

 

       allergy, and if you have it toward others, other

 

       epitopes, it may be more predictive of an allergy

 

       that is easier to lose.

 

                 We think that it may be feasible to focus

 

       on that population that has a very good chance of

 

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

 

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

                                                                 68

 

       outcome is about 10 years down.

 

                 CHAIRMAN DURST:  Marc.

 

                 DR. SILVERSTEIN:  I have had some

 

       experience --

 

                 CHAIRMAN DURST:  Identify yourself.

 

                 DR. SILVERSTEIN:  Marc Silverstein, Baylor

 

       Health Care System in Dallas.  I have had some

 

       experience in studying the epidemiology of asthma

 

       and anaphylaxis.  In both of those conditions, your

 

       findings are very much dependent upon your

 

       diagnostic criteria.

 

                 In clinical medicine, we have diagnostic

 

       criteria.  You have described the criteria for food

 

       allergy, which would involve components of:

 

       history, physical exam, laboratory tests, food

 

       challenge, and response to clinical management with

 

       elimination diets.

 

                 Are there standardized criteria that you

 

       would see moving the diagnostic criteria that you

 

       would use from clinical practice to investigation

 

       and publication in peer review literature and/or

 

       perhaps the policy in making regulatory decisions?

                                                                 69

 

                 I am interested in, Is there a set of

 

       standardized criteria that professional

 

       organizations or clinicians would use for

 

       investigation or for recommending policy?  I

 

       understand there is some recent work on definitions

 

       and standards for anaphylaxis?

 

                 DR. WOOD:  The definitions for

 

       IgE-mediated food allergy are pretty clear and it

 

       is pretty well accepted that it is if you have a

 

       history that is consistent, you have a positive

 

       allergy test, and you either fail a challenge test

 

       or pass a challenge with a dose that is generally

 

       accepted to indicate full tolerance.  It is fairly

 

       straightforward and well accepted in the peer

 

       review literature.

 

                 It is much more difficult on the group of

 

       patients with, say, eosinophilic gastroenteritis

 

       where they don't necessarily have IgE.  You require

 

       a histologic diagnosis to identify the condition,

 

       and then figuring out whether they have food

 

       allergy driving the process exclusively, partially

 

       or not at all is a much more difficult process.

                                                                 70

 

                 It is doable, but you have to eliminate

 

 

       foods, rebiopsy, reintroduce foods, and rebiopsy.

 

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

 

       much more difficult to do that there is much less

 

       of an acceptance of an absolute diagnostic

 

       criteria, much, much less.

 

                 It is being looked at.  This is a form of

 

       allergy that is clearly either happening much more

 

       often or being identified much more often or both,

 

       so that the potential is there, but it is much

 

       further away from a definition that is well agreed

 

       upon.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. BRITTAIN:  This is Erica Brittain.  I

 

       have a clarification question on the food

 

       challenge.  How is the placebo control implemented?

 

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

 

       lot more about food challenges this afternoon, but

 

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

 

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

 

       idea that it needs to be well disguised and

 

       obviously safe from the perspective of that

                                                                 71

 

       patient's allergen --

 

                 (Simultaneous discussion.)

 

                 DR. BRITTAIN:  But --

 

                 DR. WOOD:  Go ahead.

 

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

 

       dose?  Is a particular dose placebo, or does a

 

       patient get all placebo?

 

                 DR. WOOD:  Yes.  I'm sorry I

 

       misunderstood.  The normal way the challenge is

 

       done is to have a separate challenge for the

 

       placebo and for the actual food being studied.  The

 

       usual way it is done is that the patient would come

 

       in and have a day doing a placebo challenge and

 

       come in and have a day doing the food challenge.

 

                 Challenges can be done in a matter of a

 

       couple of hours in some situations, but to do

 

       highly allergic people in a placebo-controlled

 

       manner would usually take 8 or 10 hours for each

 

       day.

 

                 CHAIRMAN DURST:  All right.  Seeing no

 

       further hands in the air, I think we will thank

 

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

                                                                 72

 

                 Our next speaker will be

 

       Anne Munoz-Furlong, who is director of the

 

       Food Allergy and Anaphylaxis Network, who will

 

       discuss patient perspectives on food allergies.

 

                  PATIENT PERSPECTIVES ON FOOD ALLERGIES

 

                 MS. MUNOZ-FURLONG:  Thank you.  I would

 

       like to thank the organizers of the meeting for the

 

       opportunity to be here.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  What I would like to

 

       do is in that time that I have been allotted is

 

       give you a sense of who this food allergic consumer

 

       is; the food allergen labeling from their

 

       perspective; and then, most importantly, their way

 

       of looking at threshold levels for food allergens.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  By way of background,

 

       the Food Allergy & Anaphylaxis Network or "FAAN" is

 

       a non-profit organization.  We were established in

 

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

 

       members.  Eighty percent of these people come to us

 

       from physician referrals, so we know we are talking

                                                                 73

 

       about IgE-mediated responses when we are looking at

 

       our membership.

 

                 Our mission has four points: to increase

 

       public awareness, provide advocacy and education,

 

       and advance research on behalf of those with food

 

       allergy.

 

                 (Slide.)

 

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

 

       food allergy is believed to affect about 11 million

 

       Americans or 4 percent of the population; fish and

 

       shellfish allergy, 2.3 percent or 6.5 million;

 

       individuals in peanut and tree nut, 3 million.

 

                 Consequently, between these four foods we

 

       are talking about almost 10 million Americans.

 

       These are the four foods, as was presented earlier,

 

       that are lifetime allergies and also are believed

 

       to cause the majority of the severe or fatal

 

       reactions in this country.

 

                 The other point I want to make here is

 

       that although we are talking about 11 million

 

       patients, our data shows us over and over again

 

       that most of these patients have families who

                                                                 74

 

       follow their restricted diet.  The impact is

 

       actually many times greater than the number of

 

       patients.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  When we look at

 

       shellfish allergy, this is looking at data that we

 

       published about a year ago now.  Te prevalence of

 

       shellfish, we found about 2 percent of the

 

       population or 6 million Americans.

 

                 The key foods responsible for the majority

 

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

 

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

 

       the population: salmon, tuna, catfish, and cod

 

       being the primary fish that cause reactions.

 

                 However, if you look at these a different

 

       way, these foods, especially shrimp or salmon, are

 

       available on almost every menu that you are going

 

       to look at in a restaurant or food service

 

       establishment.  Therefore, the risk for these

 

       individuals is constant.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Talking about tree

                                                                 75

 

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

 

       peanuts; they are different.  Most people with a

 

       peanut allergy avoid tree nuts as a precaution but

 

       not because they are allergic to them.  About

 

       20 percent of the 20 peanut allergic population is

 

       allergic to tree nuts as well.

 

                 When we are talking about tree nuts, it

 

       affects about 1.5 million Americans.  Again,

 

       looking at data from our patient registry of 5,000

 

       patients, we find that walnut, cashew, almond and

 

       pecan are the leading cause of tree-nut-allergic

 

       reactions in this country.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  What does it mean to

 

       have food allergies?  It is vigilant label reading.

 

       You have got to read labels not just for food

 

       ingredients but anything coming into the home.

 

       Bath products can have tree nuts, milk or eggs in

 

       them, for example.

 

                 Pet food, if you have ever looked at the

 

       ingredient statement on a pet food, it can have

 

       almost every single one of the major eight

                                                                 76

 

       allergens.

 

                 That is something you have to worry about,

 

       especially if you have a toddler who will pick up

 

       food from the floor or anyplace else they can get

 

       it.  Also, medications have been known to have

 

       allergens in them, particularly milk.

 

                 It is not just a question of label reading

 

       for food; it is for anything.  Trace amounts can

 

       cause an allergic reaction, and that has been

 

 

       proven over and over again.

 

                 Just one bite can cause a reaction.

 

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

 

       allergic they are going to be or what their

 

       tolerance will be to that food.

 

                 Currently, as Dr. Woods said, the only

 

       cure now is a dose of epinephrine, if the patient

 

       has a history of severe reaction.  The onus is on

 

       the patient or the family to read the label and

 

       avoid the allergen and then be quickly prepared to

 

       handle an allergic reaction, if they have made a

 

       mistake or accidentally ingested the food to which

 

       they are allergic.

                                                                 77

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Because there is no

 

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

 

       are centered around food allergy.  This is what

 

       makes food allergy so stressful on the family and

 

       on the patients.

 

                 Whereas with other allergies you have

 

       seasonal components and you might have an easy

 

       spring but fall is the bad season or if you are

 

       allergic to cats or dogs you can avoid those, with

 

       a food allergy every decision every single day is

 

       affected by your food allergy.

 

                 Food shopping can take two to three to

 

       hours just from reading labels.  Cooking, if the

 

       family is bringing the allergen into the home, they

 

       then have to prepare two meals, the

 

       non-allergen-containing meal and then the

 

       allergen-containing meal, and take precautions to

 

       avoid cross-contact.

 

                 Decisions about dining out and socializing

 

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

 

       food safe.

                                                                 78

 

                 "Can the manager be trusted to give us

 

       accurate information?"

 

                 "Can the person we are visiting be trusted

 

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

 

                 Then, the decision is made to move forward

 

       based on the answers to those questions.

 

                 Even what school or childcare the

 

       individual will be sending their food allergic

 

       child to are going to first be centered on food

 

       safety from a food allergy perspective.

 

                 Vacation and travel where you and I might

 

       decide whether we want to go someplace warm or go

 

       skiing in the winter, these families have to think

 

       first about food.

 

                 "Can we ship food there?"

 

                 "Is there a safe place?"

 

                 "Can we rent a room with a kitchenette and

 

       make some of the meals so that we can maintain some

 

       level of safety?"

 

                 Even family relationships, there is always

 

       somebody in the family that does not believe the

 

       food allergy is real, and so decisions are made

                                                                 79

 

       about whether they can visit that individual or

 

       not.

 

                 (Slide.)

 

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

 

       this, it has a tremendous impact on quality of

 

       life.  We published a study several years ago

 

       looking at the impact of food allergy on quality of

 

       life.

 

                 What we found is that families who have a

 

       food-allergic child score lower on their perception

 

       of whether their child has good health or not, the

 

       emotional health and family activities than the

 

       general population.

 

                 Certainly, they scored lower or worse than

 

       families who are looking at or dealing with other

 

       chronic diseases such as diabetes, juvenile,

 

       rheumatoid arthritis and attention deficit

 

 

       disorder, for example.

 

                 We also looked at some of the other

 

       influences.  If the individual has a food allergy

 

       and asthma or atopic dermatitis, that further

 

       lowers their score for the quality of life.

                                                                 80

 

                 If a family has a child with two or more

 

       food allergies, that group scored much lower in 9

 

       out of 12 scales compared to those who only have

 

       one or two food allergies that they are dealing

 

       with.

 

                 When we look at our patient population at

 

       FAAN, we see that it is not uncommon for our

 

       members to report a child with a milk, egg and

 

       peanut allergy simultaneously.  You can imagine

 

       eliminating those three foods and how it compares

 

       to the impact on the quality of life for the entire

 

       family.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  This is how, again

 

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

 

       is "General health" perception.  Food allergy lower

 

       than the normal for asthma, attention deficit

 

       disorder and some of these other symptom scores.

 

                 Now, in talking about label reading, which

 

       is really the cornerstone of managing a food

 

       allergy.  Here is what goes on.

 

                 (Slide.)

                                                                 81

 

                 MS. MUNOZ-FURLONG:  The person with a food

 

       allergy is told by the physician, as you heard

 

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

 

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

 

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

 

       don't eat that product.

 

                 If the allergen is listed on the label or

 

       the label says "Contains allergen," they are not

 

       going to eat that product because they are trying

 

       to avoid a reaction.  As a result, they expect

 

       ingredient labels to be consistent and, most of

 

       all, reliable because this is what they are basing

 

       the decision about food on.  It will affect their

 

       health and safety.

 

                 When they see the same product with

 

       different ingredient statements, it makes them very

 

       confused and frustrated and sometimes very nervous

 

       because they, again, are looking for consistency in

 

 

       labeling.

 

                 What we are already seeing with some of

 

       the companies complying with FALCPA regulations is

 

       that there are products on the market that are

                                                                 82

 

       pre-FALCPA and FALCPA compliant with different

 

       ingredient information regarding allergens.

 

       Already we are getting calls from our members.

 

                 "Which one of these labels is correct?"

 

                 "What if I hadn't picked up that second

 

       label?  How would I have known?"

 

                 This is what we are heading into as we

 

       start to change these labels.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The challenge for

 

       food-allergic individuals is that the patients are

 

       told to strictly avoid the allergen, there is zero

 

       tolerance or be prepared to handle an allergic

 

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

 

       how severe that is going to be.

 

                 They are not aware that there are

 

       scientific names to foods when they are newly

 

       diagnosed.  This is something FAAN spends a lot of

 

       time doing.  It will get better as FALCPA is

 

       implemented because labels will have simple

 

       ingredient terms on them.

 

                 We have to remember it is not just the

                                                                 83

 

       patient or the patient's family reading the label,

 

       but it is the teacher, the scout leader, the

 

       friends and family members.  The impact for any

 

       labeling decisions are going to be quite broad.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Allergens can appear

 

       in unexpected places.  This is just one slide of a

 

       number of examples that we have for "Common Foods

 

       in Unexpected Places."  Every one of these examples

 

       have caused an allergic reaction to one of our

 

       members, because they were not expecting to find

 

       the allergen.

 

                 Just to give you an example, if you have a

 

       milk allergy, you would not have expected that

 

       barbecue-flavored potato crisps might have milk in

 

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

 

       that canned tuna might have soy in it.  Therefore,

 

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

 

       be looking for unexpected sources.

 

                 (Slide.)

 

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

 

       reflected in a study that was published in 2002 by

                                                                 84

 

       Joshi, et al.  They took some food-allergic

 

       individuals, gave them products that were on the

 

       market, and asked them to read the label for the

 

       food they were trying to avoid.

 

                 You can see here that families avoiding

 

       milk, only 7 percent were able to accurately

 

       identify milk on the labels that were presented to

 

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

 

       percent; but peanut, only 54 percent got the label

 

       reading correct, and most of this was because of

 

       confusion about allergen labeling information.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The problem with

 

       allergen labeling information, there are no

 

       guidelines or standards for use.  This is

 

       completely voluntary.  As a result, every company

 

       has their own decision tree and algorithm and

 

       wording for what terms they will use and under what

 

       conditions.

 

                 This makes it very difficult for us to

 

       educate consumers and the others who are reading

 

       labels on their behalf and telling them what to do

                                                                 85

 

       and what these mean.

 

                 The proliferation of "may contain"

 

       labeling has really caused us some problems.  Just

 

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

 

       volunteer go out in the Northern Virginia area to

 

       one grocery store and look at products from

 

       cookies, crackers, candy and bakery.  We were

 

       trying to follow the model of a previous FDA study.

 

                 She came back with 28 different versions

 

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

 

       perspective, what does that mean?  Can they be

 

       trusted, or should we ignore them?

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The current

 

       environment because of this, there are some

 

       physicians that advise their patients to ignore

 

       precautionary labeling, because it is everywhere

 

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

 

                 There are others who tell them, "Heed the

 

       warning and avoid those foods."

 

                 Then, there are some companies who tell

 

       the consumers, "It is on the package only because

                                                                 86

 

       our legal counsel has advised us to put this on

 

       there."

 

                 Then, there are others that say, "You have

 

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

 

                 How does a consumer determine which is

 

       which?

 

                 We are also seeing advisory statements for

 

       peanut allergy only.  The way the consumer

 

       interprets these statements is that they are

 

       shortcuts to label reading.

 

                 If they see "contains peanuts" or "may

 

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

 

       ingredient declaration if they are looking for milk

 

       or soy, because they think that the company

 

       understands food allergy and would have listed all

 

       of the allergens on there.

 

                 As a result of all of this, consumers are

 

       confused and frustrated.  Particularly what is

 

       going on as their food choices are further

 

       minimized is that there is risk taking behavior by

 

       parents of kids with food allergies who decide,

 

       seemingly randomly to us, that some companies can

                                                                 87

 

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

 

       contain" on the companies they trust.

 

                 Then, the teenagers, our highest-risk

 

       population for a severe reaction, want to be like

 

       everyone else are reporting that they are ignoring

 

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

 

       foods they have eaten the food and not had a

 

       reaction, so they don't really believe that these

 

       are true.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  This is one of the

 

       labeling studies that we conducted with our FAAN

 

       members during a spring meeting a year or two ago.

 

       We asked a question.  They were supposed to answer,

 

       "I would never purchase a product that says it

 

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

 

 

       that almost 100 percent of them would avoid a

 

       contain statement.

 

                 However, as you go from very specific to

 

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

 

       that also produces," say, peanuts or nuts or

 

       whatever the allergen might be, only 74 percent

                                                                 88

 

       would avoid purchasing that product.

 

                 Consequently, 25 percent of the allergic

 

       consumers are going to purchase products where they

 

       don't really understand the precautionary labeling.

 

       If the company is putting this on here because of

 

       some risk, we've got a miscommunication or a

 

       communication gap going on.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG: Let's talk about

 

       thresholds, then.  Again, from the consumer's

 

       perspective, their physicians advise, as you heard

 

       from Dr. Wood, is strict avoidance or a reaction

 

       may occur and you will not outgrow this allergen.

 

       They are very motivated to try to strictly avoid

 

       that food.

 

                 When we talk about thresholds to our

 

       members, and these tend to be the most motivated

 

       and well-educated of the food allergy population,

 

       this is what we consistently get back.  They

 

       believe that threshold levels may put their

 

       children at risk because their child is so

 

       allergic.

                                                                 89

 

                 They also wonder whether the threshold

 

       levels, the whole discussion is based on the

 

       industry or the government trying to figure out a

 

       way not to have to clean or label for allergens.

 

       Again, they are wary that this might be a loophole

 

       that is trying to be directed at them.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The catch 22 here,

 

       from where we are at FAAN, is that we understand

 

       that if we label for all allergens at all levels it

 

       will further restrict diets.  If we further

 

       restrict the diet, we are going to increase

 

       frustration which will yield risk taking.

 

                 It is going to undermine the integrity of

 

       the ingredient label.  As I showed already with

 

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

 

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

 

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

 

       reaction, we are going to diminish the validity of

 

       that statement.

 

                 If we undermine the integrity of the

 

       ingredient label this will potentially lead to more

                                                                 90

 

       allergic reactions as they take more risk, which is

 

       going to increase the number of doctor visits;

 

       hospital visits; and, potentially, fatalities.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  Here is an example of

 

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

 

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

 

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

 

       had safely eaten soy lecithin in the past.  Most of

 

       our members, although we tell them to read the

 

       ingredient declaration on products every time they

 

       purchase them, become brand dependent and stop

 

       reading the ingredient label.  That is exactly what

 

       happened here.

 

                 This was a product that the child had

 

       safely eaten in the past.  The mother did not read

 

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

 

 

       it.  She then started reading the label and saw

 

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

 

       nervous and screamed that it contained soy and

 

       asked the child to spit the food out.

 

                 Immediately, he started having itching,

                                                                 91

 

       leading to hives, and a feeling of impending doom.

 

       The mother gave him medication and thought she was

 

       having a full-blown reaction.

 

                 The question we have to ask ourselves, Was

 

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

 

       called the manufacturer and was told that the

 

       "contains soy" is because it contains soy lecithin.

 

       Therefore, the ingredients hadn't really changed

 

       from the product that they had safely eaten before.

 

                 From our perspective, we do not want to

 

       see consumers or their families subjected to this

 

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

 

       that once this reaction is taken care of, it takes

 

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

 

       have reports of children developing eating

 

       disorders and just being very cautious about being

 

       around other people once they have had a reaction.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  From the consumer's

 

       perspective, if we are looking at developing a

 

       threshold level, and as I said there are pros and

 

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

                                                                 92

 

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

 

       got to educate physicians and registered dieticians

 

       so that they can counsel patients accurately.

 

                 As you saw, we have done no training for

 

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

 

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

 

       threshold levels.

 

                 We also have to educate patients and their

 

       families and assure them that the food is still

 

       safe and that they can trust the information on the

 

       label.  We also have to do outreach to the food

 

       industry so that they can answer the queries from

 

       food-allergic consumers in a way that will give

 

       them confidence instead of make them nervous or

 

       suspicious about whether they can trust the

 

       information on the label.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  In summary,

 

       food-allergic consumers want as many food choices

 

       as safely possible.  This is really why we are here

 

       and why we are seeing some of this behavior with

 

       advisory statements.

                                                                 93

 

                 They want to open the diet.  The children

 

       want to be like everyone else, and they want the

 

       least amount of restrictions, but they need to be

 

       safe.

 

                 The consumer needs to understand the

 

       information on the ingredient statement.  They need

 

       most of all to trust that that information is

 

       reliable and it is going to be consistent from one

 

       product to the other.  They also need a minimal

 

       number of precautionary allergen statements and a

 

       guideline so that they understand what these

 

       statements mean and what they should do as a result

 

       when they see these on products.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  In conclusion, the

 

       current labeling and manufacturing practices

 

       present enormous challenges to food-allergic

 

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

 

       patients is increasing.

 

                 To give you an example, we conducted a

 

       prevalence study of peanut and tree nut allergy in

 

       1997, repeated that same study in 2002, and found

                                                                 94

 

       that in that five-year period the number of

 

       children with peanut allergy had doubled.  We don't

 

       know how it is continuing to trend, but reports are

 

       that it is still increasing.

 

                 (Slide.)

 

                 MS. MUNOZ-FURLONG:  The bottom line is

 

       above all we must protect the integrity of the

 

       ingredient information.  Because from the

 

       food-allergic consumer's perspective, they depend

 

       on this information to avoid an allergic reaction

 

       and, most of all, to maintain their health and

 

       safety.  We already have data showing that food

 

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

 

       to further diminish their quality of life.

 

                 With that, I will end here and open for

 

       questions.

 

                 CHAIRMAN DURST:  Thank you.

 

                 Does the Committee have any questions?

 

                 Yes.

 

                 MS. HALLORAN:   I mean, obviously a person

 

       can survive without ever having to buy any packaged

 

       food.  I am wondering in terms of the kinds of

                                                                 95

 

       things you were talking about -- teenager's

 

       preferences, the needs of a busy mother, et cetera

 

       -- are there particular categories of food that are

 

       prepared and packaged that are most sort of

 

       important and essential in our modern life?  I

 

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

 

                 MS. MUNOZ-FURLONG:  If they ate

 

       vegetables, they would be fine.  How many kids want

 

 

       to eat vegetables?

 

                 (General laughter.)

 

                 MS. MUNOZ-FURLONG:  I think it really goes

 

       back to quality of life.  Children want to be like

 

       everyone else, and they will do everything they can

 

       to fit that mold.

 

                 I have a daughter that was diagnosed with

 

       milk allergy and egg allergy when she was an

 

       infant.  I will tell you that I did everything I

 

       could to make sure that she felt like her friends.

 

                 It is not just the patient or the child,

 

       it is also the family wanting to not have their

 

       child isolated or feel stigmatized because of the

 

       allergy.

                                                                 96

 

                 If everyone else is having breakfast in a

 

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

 

       to make sure that those labels are accurate, if the

 

       family makes that decision.

 

                 Granted, there are some families that are

 

       very cautious and will only make food from home,

 

       make it from scratch.  However, as the child gets

 

       older and is out with friends, that is just not

 

       doable.

 

                 MS. HALLORAN:  Are there any particular

 

       categories of foods?

 

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

 

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

 

       are seeing allergens everywhere.  We have just got

 

       to make sure that all of the labels are correct and

 

       can be trusted.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. KELLY:  Ciaran Kelly.  A question for

 

       you from your perspective and the perspective of

 

 

       the people you represent, the patients with food

 

       allergies.

 

                 I understand that you are frustrated and

                                                                 97

 

       find it very difficult to work with the current

 

       system of many different types of wording.  Would

 

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

 

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

 

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

 

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

 

       acceptable?

 

                 MS. MUNOZ-FURLONG:  Well, I will start

 

       from the back end of your question.  If you poll

 

       our members or just the general consumers, they all

 

       want "does not contain" labeling.

 

                 I would caution to you because of the

 

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

 

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

 

       recalls to products that say "does not contain

 

       peanuts" when they do contain peanuts undeclared.

 

                 From the way the consumer is going to

 

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

 

       read that ingredient declaration because that is

 

       the guarantee they have been waiting for.

 

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

 

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

                                                                 98

 

       ingredient declaration and know that they can trust

 

       if it doesn't have peanuts in that ingredient

 

       statement, the product should be safe for them.

 

                 When we start to see different allergen

 

       statements, we want to make sure that those can be

 

       trusted.  When we are talking about "does not

 

       contain," that is an implied endorsement or

 

       guarantee, which makes me very worried.  If the

 

       company makes a mistake and that is on the label in

 

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

 

       reaction.

 

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

 

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

 

       and that all companies are following this

 

       guideline, that makes it much easier.  Right now,

 

       you can go poll 12 companies and they each do

 

       different things.

 

                 CHAIRMAN DURST:  I think we need to move

 

       on.

 

                 Thank you.

 

                 Our next speaker will be Susan Hefle,

 

       associate professor and co-director of the Food

                                                                 99

 

       Allergy Research and Resource Program at the

 

       University of Nebraska, who will be speaking on

 

       "Allergenicity:  Analytical Methods."

 

                 Dr. Hefle?

 

                    ALLERGENICITY:  ANALYTICAL METHODS

 

                 DR. HEFLE:  Thank you, Chairman Durst.

 

                 Good morning.  I am going to discuss the

 

       basic analytical methods for allergens.  The model

 

       used is the ELISA-based model which has lateral

 

       flow.  This model has been used for several years

 

       now.  We will discuss this more later.

 

                 Our second bullet, the most successful

 

       kids do use polyclonal antibodies but occasionally

 

       a kit uses monoclonal antibodies directed against a

 

       single protein.  Usually, the antibodies are

 

       directed against a crude extract of an allergenic

 

       food not the specific proteins themselves.  It is

 

       not necessary to really measure the allergen.

 

                 The industry just cares if any peanut is

 

       there, not if one particular protein from a peanut

 

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

 

       allergen.  The industry just wants to know if any

                                                                100

 

       peanut or whichever peanut is there.

 

                 A lot of times a lot of the successful

 

       kids use a much more kind of crude approach to

 

       detecting peanut rather than specifically horning

 

       on the allergens themselves.

 

                 There is a challenge, though, in that

 

       different standards are used in the different kids,

 

       depending on the manufacturer, and also different

 

       antibodies are used in the different kids depending

 

       on the manufacturer.  It is not like a standardized

 

       approach across the board, necessarily.

 

                 (Slide.)

 

                 DR. HEFLE:  The detection limits range

 

       from around 0.1 to 2.5 parts per million for the

 

       quantitative methods.  There are also quality

 

       methods; however, if we are talking about threshold

 

       levels, we need to talk about quantitation here.

 

                 Using a method that has a very low

 

       detection limit has certain challenges.  Every kit

 

 

       has the ability to have a low detection limit.  Ten

 

       years ago, when I started developing kits,

 

       Steve Taylor and I sat around and thought about

                                                                101

 

       what the detection limit should be based on our

 

       years of experience in dealing with consumer

 

       reactions and things like that.

 

                 We set a certain level with the kits we

 

       developed; we picked 2.5.  It seems to have gone

 

       very well over the last seven or eight years since

 

       these kits have been on the market.  Some of the

 

       other companies have a little bit lower range of

 

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

 

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

 

       they can all push these kits really, really, really

 

       low.  The problem is, Is there clinical relevance

 

       at that point?

 

                 If there is no clinical relevance,

 

       companies may be chasing molecules around their

 

       processing plant.  They will have all of this

 

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

 

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

 

       analysis."

 

                 We want the data to be relevant.  We want

 

       the data to be useful.  If the industry goes back

 

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

                                                                102

 

       all of these positive results at a low level?"

 

       Detection limits have to be kept in mind.  They

 

       should be tied to threshold levels, whatever we

 

       decide the threshold levels should be.

 

                 It adversely affects the quality of life

 

       for food-allergic consumers, if you use detection

 

       limits that are really low or push those detection

 

       limits without a good clinical basis.  Because of

 

       the industry reaction in the form of increased use

 

       of "may contain" label.

 

                 When they did paralysis by analysis and

 

       they get positive results, maybe they throw a lot

 

       of "may contain" labeling on that product that they

 

       are worried about and so they are going to put that

 

       on there.  That decreases the number of foods that

 

       allergic individuals can eat.

 

                 The current detection limits that are set

 

       that the industry uses right now have worked very

 

       well for seven years in protecting the

 

       food-allergic consumer.

 

                 I don't think at this point there is any

 

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

                                                                103

 

       science comes in and we know more about threshold

 

       levels, there might be an adjustment here or there.

 

                 We just finished an egg threshold study.

 

       Contrary to what Robert Wood said, you can do

 

       threshold studies in kids, because we did this in

 

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

 

       people we could find to have egg allergy are kids.

 

                 When we crunch those numbers and look at

 

       that data, if the threshold is low enough that we

 

       need to adjust the kids for egg out there, the

 

       manufacturers have all said they would be willing

 

       to do that based on the science.

 

                 (Slide.)

 

                 DR. HEFLE:  Many companies are testing for

 

       allergen residues.  What they are primarily testing

 

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

 

       verify sanitation procedures.  They have been using

 

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

 

                 Certainly with the new law coming up,

 

       there are a lot more using them than used to use

 

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

 

       incorporating testing using these test kits.  As

                                                                104

 

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

 

       easier for them to use them.

 

                 Again, the ELISA or lateral flow, which is

 

       kind of like a dipstick method are the preferred

 

       methods.  Some do the test in house.  They really

 

       like it if they can do that because they can fix

 

       things right away.

 

                 However, if you don't have in-house

 

       capabilities, they will send it out to a contractor

 

       lab or if they want third-party verification, they

 

       will do that.

 

                 Most companies, as I said, are not testing

 

       finished product.  They are testing to validate

 

 

       sanitation methods or doing environmental swabbing

 

       to try to find where the problem is before they get

 

       to the final product.  They want to fix the problem

 

       before they get there and figure out if their

 

       sanitation is accurate before they get to the final

 

       product.

 

                 Some testing of finished product on

 

       certain occasions though is done, especially when

 

       you can have the product under full control.  They

                                                                105

 

       don't usually want to release something that they

 

       have tested and they find out there is a problem

 

       and they have to call it back from the marketplace

 

       later and perhaps put consumers at risk.

 

                 There are tests that are based on DNA

 

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

 

       advocate these for allergenic residue detection

 

       because it doesn't prove the presence of the

 

       protein.  You need the protein to have the allergic

 

       reaction.  It just says that there is DNA from that

 

       particular allergenic food there.

 

                 It is not practical at all for in-plant

 

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

 

       processing line.  It is very expensive and requires

 

       a lot of segregation and things.  It is meant more

 

       for a regulatory agency or a big corporate lab who

 

       has this ability.  It does not prove the absence or

 

       presence of the protein or the allergen.  It is

 

       just an indirect kind of a marker.

 

                 There are ATP tests out there.  This is a

 

       test that is commonly used in the industry for

 

       sanitation assessment.  Some companies would like

                                                                106

 

       to use this to detect allergens, specifically the

 

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

 

       not knowing that these correlate well with the more

 

       specific protein-based tests.

 

                 (Slide.)

 

                 DR. HEFLE:  Three peanut, like ELISA test

 

       kits, have been performance tested by FDA through

 

       AOAC-RI.  Those companies with those tests are

 

       Neogen, R-Biopharm, Tepnel.

 

                 Five peanut ELISA kits have been studied

 

       in one JRC interlab trial.  This is the European

 

       Union's group in Belgium that does these sorts of

 

       things, and they put these three tests plus two

 

       more through a validation trial.  They are

 

       currently doing another validation trial on the two

 

       peanut lateral flow devices.  They are not finished

 

       with that yet, but they are only doing one matrix

 

       not several matrices.  They are just testing it in

 

       cookies right now.

 

                 (Slide.)

 

                 DR. HEFLE:  FDA works with AOAC and has

 

       said they plan more validation studies with other

                                                                107

 

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

 

       a couple of years now with no apparent progress on

 

       this front, though.

 

                 The U.S. food industry and other

 

       regulatory agencies -- for example, the Canadian

 

       regulatory agency, the JRC -- has moved way ahead

 

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

 

       running validation trials themselves, but they run

 

       in-house validation things like that.

 

                 However, there are regulatory agencies who

 

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

 

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

 

       things done in validated interlab trials."  There

 

       are several trials that are planned right now

 

       internationally to, hopefully, get some of these

 

       things "validated" in the next few years.

 

                 The U.S. industry has been testing for

 

       about seven years now, since the first peanut tests

 

       came out.  They have increased the amount of

 

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

 

       millions of dollars once they've gotten test

 

       results to change equipment, to make modifications,

                                                                108

 

       for allergens specifically.

 

                 Before about 10 years ago, we didn't have

 

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

 

       become implemented, they have used them to make

 

       changes in how they manufacture food.

 

                 Health Canada/CFIA has a Compendium of

 

       Food Allergen Methodologies.  They crunch through a

 

       lot more of these kind of in-house validations that

 

       they do so that they can use them for their

 

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

 

       both commercial and their own in-house methods.

 

                 (Slide.)

 

                 DR. HEFLE:  Validation of kits, there are

 

       more JRC trials coming out of the EU more likely.

 

       We know of several that are planned, and other

 

       groups have them planned, too.  Other groups are

 

       planning more interlab trials, some with kind of

 

       "modeled" foods.

 

                 A lot of these tests are done where you

 

       spike peanut into something else.  It is not really

 

       like a manufactured product, so it doesn't really

 

       mimic the manufacturing process.

                                                                109

 

                 A "model food" is actually where the

 

       allergen is manufactured into the matrix, so that

 

       it more appropriately represents what would happen

 

       in the food industry.

 

                 Therefore, those are king of challenging

 

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

 

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

 

       on an industrial level, so it can be quite an

 

       undertaking.

 

                 (Slide.)

 

                 DR. HEFLE:  Kit companies do much more

 

       extensive validation than ever will be done by any

 

       regulatory agency or academic center.  It is

 

       usually that the are in the process of selling

 

       kits, and they don't necessarily share the data

 

       like they should.  I have been encouraging all of

 

       them to go ahead and publish all of this great data

 

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

 

       us to evaluate how good their kits really are.  So

 

       far, they still want to sell kits and not spend

 

       time writing papers.

 

                 However, they do have liability issues. 

                                                                110

 

       Their kits have to work.  They have liability

 

       issues.  They have reputation issues if the kits

 

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

 

       validations before they put a product on the

 

       market.

 

                 (Slide.)

 

                 DR. HEFLE:  Reference materials are solely

 

       lacking for allergens.  It would be really nice if

 

       we had a bunch of reference materials we could do

 

       all of these interlab validations with.

 

                 However, we are having a problem finding

 

       the appropriate reference materials.  There are not

 

       many available, and they are really needed.  NIST

 

       is one source of reference materials.

 

                 Unfortunately, the NIST standards that are

 

       available were not made for allergen testing, were

 

       not designed for that and often do not represent

 

       the type of allergenic materials used in the food

 

       industry.

 

                 A case in point was the standard that was

 

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

 

       butter made by a major manufacturer.  It is fine

                                                                111

 

       for things like aphlatoxin determination and other

 

       things.  Unfortunately, the varieties are not known

 

       with certainty, because the manufacturer wouldn't

 

       tell FDA about every little peanut that might be in

 

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

 

       NIST not FDA, I'm sorry.

 

                 Different peanut varieties have different

 

       responses in the kits.  It is imperative to know

 

       exactly what is one of these standards.

 

       Unfortunately, there aren't a whole lot of other

 

       standards around the world around to do that.

 

                 There are other sources of materials that

 

       could be used as reference materials, but we have

 

       to come to a worldwide decision on what is the

 

       appropriate criteria for considering something in

 

       the reference material.  Is something the JRC makes

 

       in Europe representative of something we use in the

 

       United States?

 

                 There are several of these materials

 

       available, and we could begin to talk about going

 

       through some interlab trials with some of these, if

 

       they met certain criteria.

                                                                112

 

                 (Slide.)

 

                 DR. HEFLE:  Processing can have a huge

 

       effect on extraction and kit performance.  Most

 

       kits are not validated using these model foods, so

 

       we have to do some more of this stuff;

 

       international call for more use of modeled foods.

 

                 The old method of spiking, which is where

 

       you put a peanut extract into some of the matrix

 

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

 

       again, does not truly represent what happens in the

 

       food industry.

 

                 However, the spiking does provide some

 

       useful information, but the manufacturing of these

 

       model foods gives the best information about how a

 

       kit will work.

 

                 Model foods have to be made on a pilot,

 

       plant or industrial size scale.  If you make this

 

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

 

       really appropriate what a model food is in the

 

       industry, either.

 

                 If you make many cookies in a home-size

 

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

                                                                113

 

       not going to be the same thing as what Keebler or

 

       what Pepperidge do on a huge scale.

 

                 The results of these are not practical or

 

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

 

       model foods.  They are involving for assessing how

 

       a kit is going to work with a specific commodity,

 

       how efficient the extraction method is under

 

       industrial conditions.

 

                 It is becoming more and more important to

 

       use these types of standards in assessing the kit's

 

       performance for certain commodities and processing.

 

       I think spiking is pass.

 

                 I get yelled at in my professional

 

       society, AOAC, because spiking is the way of the

 

       food chemists.  However, we have to do some spiking

 

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

 

       foods and do that sort of assessment also.

 

                 (Slide.)

 

                 DR. HEFLE:  The extraction method, is it

 

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

 

       sufficient?  Is the recovery good?  Can we trust

 

       the results?

                                                                114

 

                 Some foods are challenging.  There are

 

       tannins and polyphenols in dark chocolate that bind

 

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

 

       difficult matrices to do with allergen

 

       determination.

 

                 High fat levels can hide the allergen in

 

       other types of ingredients.  If the product is

 

       hydrolyzed, you cannot analyze hydrolyzed or

 

       fermented ingredients in these test kits.  They

 

       were never designed for this.  When you start

 

       chopping up the proteins, the ELISA signals go

 

       away.  The methods are meant to detect intact

 

       proteins and not peptides.

 

                 Processing, if you burn stuff, it is going

 

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

 

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

 

       food, but sometimes they want to detect burned

 

       foods on band ovens or something they can't readily

 

       clean.  These are challenges to kit performance,

 

       too.

 

                 (Slide.)

 

                 DR. HEFLE:  Most kits for most allergens

                                                                115

 

       have good reactivity with processed forms of the

 

       allergenic food in my experiences over the last 15

 

       years, and that is just my experience.

 

                 The use of polyclonal antibodies and crude

 

       extracts and making antibodies against processed

 

       forms are recipes for successful kits.  There are

 

       several on the market today that do very well.

 

                 Monoclonals are okay if they use a

 

       heat-resistant epitope in making the monoclonals.

 

       They can accommodate the processing changes that

 

       occur.

 

                 Some of the egg residue kits have some

 

       issues in this regard.  The industry has been able

 

       to adjust and adapt.  Many survey the raw material

 

       instead.  Instead of worrying about the processed

 

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

 

       that way, or use a kit that has antibodies against

 

       raw and processed egg, to get around that

 

       particular issue.

 

                 Matrix effects, my lab has used all of the

 

       ELISA-based test kits available on the market in

 

       our own validations and tests.  It is kind of my

                                                                116

 

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

 

       usually not a problem for most of the test kits out

 

       there, for the vast majority.

 

                 Kit companies have added extraction

 

       additives to their extraction buffers to assist.

 

       When it was recognized dark chocolate was a

 

       problem, they added some secret extraction

 

       additives to help you pull the protein out of dark

 

       chocolate easier.

 

                 Model foods, though, again are going to be

 

       of great use in assessing the true extraction

 

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

 

       we need to make more of these.

 

                 In cross-reactivity issues, even though

 

       most methods do use polyclonal antibodies, which

 

       those of you who know something about polyclonal

 

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

 

       cross-reactivity problems with them."

 

                 We really don't see this happening.  The

 

       kit companies really couldn't sell any kits if

 

       their peanut kit cross reacted with everything

 

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

                                                                117

 

       problems in that they have looked at that before

 

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

 

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

 

       one that is going to crop up sometime.

 

                 (Slide.)

 

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

 

       with hydrolyzed proteins, hydrolyzed vegetable

 

       proteins, hydrolyzed soy proteins.  You can't

 

       really detect them.

 

                 The industry would love to do this, to

 

       chase them through the facility and see if they

 

       have cleaned up afterwards because we know there

 

       can be some residual allergenicity in hydrolyzed

 

       protein preparations.

 

                 However, the ELISAs are pretty much

 

       rendered useless when trying to analyze for

 

       hydrolyzed protein.  It is not what they are

 

       designed to do.  The company has had to make a

 

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

 

       chasing hydrolyzed proteins, but it is chasing the

 

       intact proteins.  We have to balance the kits to go

 

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

                                                                118

 

                 Unfortunately, a negative result in an

 

       ELISA in this case does not mean that there is no

 

       allergenic residue left.  You have to ascertain

 

       residual allergenicity via a different method using

 

       human allergic IgE in something like a Western blot

 

       or a RAST analysis.

 

                 Another related area is the analysis of

 

       fermented ingredients: gums, Lactobacillus

 

       cultures, starter cultures.  Once they start eating

 

       at the substrate, the proteins are partially

 

       hydrolyzed and the ELISAs won't detect them

 

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

 

       just ascertain the true allergenicity.

 

                 Companies don't tell contract labs the

 

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

 

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

 

       hydrolyzed, so we have some challenges.

 

                 I try to communicate with the contract

 

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

 

       don't give them a negative result, because it

 

       couldn't be truly negative maybe from an allergenic

 

       standpoint."  I think this is the minority of the

                                                                119

 

       samples out there.

 

                 (Slide.)

 

                 DR. HEFLE:  My lab performs testing for

 

       food-allergic consumers, their physicians, their

 

       lawyers when they call for free when they report a

 

       reaction to a food.  We work with some members of

 

       the Food Allergy & Anaphylaxis Network when they

 

       have a problem.

 

                 If there is an analysis I can do, I will

 

       try to help a food-allergic consumer identify what

 

       happened with that particular food, if they have

 

       managed to keep it in the height of the moment.

 

                 In 10 years of doing this, we have only

 

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

 

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

 

       judgments on that right now -- amounts of

 

       undeclared allergenic food causing reactions.

 

 

                 (Slide.)

 

                 DR. HEFLE:  We cannot currently do

 

       immediate monitoring in the food industry, though.

 

       The technology doesn't exist.  It is getting

                                                                120

 

       better.  These lateral flow devices can sometimes

 

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

 

       they will be able to make a more immediate

 

       response.

 

                 Right now, a lot of them are 30 minutes

 

       long.  If you are swabbing things and waiting

 

       around for 30 minutes to see if the result is

 

       positive and then having to go back and clean

 

       again, it is pretty impractical for the food

 

       industry to do.

 

                 Sanitation and verification is the most

 

       practical, not the test and release kind of thing.

 

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

 

       release and test and release kind of analogy.

 

                 We do not have tests for some of the

 

       allergens, and fish is a notable example.  You

 

       cannot test for the hydrolyzed or the fermented

 

       allergen sources using these types of methods.

 

                 Some types of cross-contact are not

 

       homogenous or 100 percent cleaning is not possible

 

       due to the nature of the product.  Food equipment

 

       was never historically designed for allergen clean.

                                                                121

 

                 Sometimes these facilities are quite old,

 

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

 

       different equipment.  They have to try to redesign

 

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

 

       hangup areas.

 

                 You cannot take enough samples to

 

       practically test, to be a hundred percent sure all

 

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

 

       statistician in to tell me how many samples I would

 

       need, the industry would just spend the whole day

 

       testing rather than trying to make food product.

 

                 In some of these cases, precautionary

 

       labeling is justified due to the nature of the

 

       product and the process in FARRP's opinion.  For

 

       example, dark chocolate and milk chocolate on the

 

       same line is one example where we think

 

       precautionary labeling is justified.  That doesn't

 

       mean we think precautionary labeling is justified

 

       in every case.

 

                 (Slide.)

 

                 DR. HEFLE:  This is a study that we

 

       recently completed and published in 2004 of some

                                                                122

 

       incidents from milk allergic consumer complaints.

 

       These were the casein levels we found in those

 

       particular products.  They range from 5,000 on up

 

       to 44,000 parts per million in things that were

 

       supposed to be free of milk or labeled even

 

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

 

       parts per million.

 

                 They also asked me to talk a little bit

 

       about highly refined oils.  What does HRO mean?  In

 

       FARRP's opinion, "highly refined oil" means

 

       neutralized, bleached and deodorized or refined

 

       bleached and deodorized.

 

                 The definition of what "refined oil" is,

 

       is kind of debated a lot right now in terms of

 

       FALCPA, opinions based on scientific review of oil

 

       challenges with oils in the literature and what we

 

       feel refined oil should be.

 

                 The available quantitative methods, there

 

       are methods used in the literature including ELISA

 

       and other methods that reports the levels of

 

       protein in highly refined oils.  None of these,

 

       though, have been validated in interlab trials or

                                                                123

 

       other types of validation for protein and oil

 

       determination to date.

 

                 Somebody will run something and they will

 

       report it, and they will do a certain number of

 

       samples, but no one has looked at whether that is

 

       an appropriate method across the board for

 

       detecting this.

 

                 There is a question as to whether a small

 

       amount of protein in the HRO is completely

 

       extracted in aqueous buffer.  "Aqueous buffer" is

 

       something that people often use to do these sorts

 

       of biochemical tests.  It means trying to partition

 

       the proteins from the oil into an aqueous buffer.

 

                 If they really like oil, they might not

 

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

 

       The question is, Does this capture the true protein

 

       content of the oil or whether some of the more

 

       hydrophobic proteins stay in the oil fraction, and,

 

       therefore, do not get extracted and therefore

 

       determined?

 

                 My lab uses an amino acid determination

 

       based on Edman degradation, but we also use aqueous

                                                                124

 

       extraction.  We try to maximize that aqueous

 

       extraction.

 

                 We use heat; we use a large amount of

 

       buffer; and we concentrate the sample.  However, I

 

       cannot guarantee that I'm pulling all of the

 

       protein out of that highly refined oil when I

 

       measure that.

 

                 We report the results as relative and not

 

       a complete picture of the possible protein count

 

       out of HR oil.  I still think you are capturing

 

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

 

       sit up here and say we are covering a hundred

 

       percent of it.

 

                 (Slide.)

 

                 DR. HEFLE:  The protein levels of HRO are

 

       reported in the literature, and there are lots of

 

       different reports and levels.  The caveats again:

 

       The use of aqueous buffers in the determination,

 

       how good if they use an immuno-chemical-based

 

       method is the epitope recognition of the antibody?

 

       Does it really recognize those soy proteins at that

 

       level of processing?

                                                                125

 

                 Relating "total" nitrogen, sometimes they

 

       use the total nitrogen amount to what the protein

 

       is.  Well, total nitrogen can be free and running

 

       around in the protein and not associated with --

 

       free and running around in the oil and not

 

       associated with the protein.  Consequently, it may

 

       be an overestimate actually of the protein amount.

 

                 Limitations of certain types of methods

 

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

 

       will bind to certain proteins preferentially and

 

       not bind to others as well.  When you use a

 

       dye-binding method, is it really representative of

 

       everything that is in there?  You can't absolutely

 

       tell.

 

                 The protein levels reported in the

 

       literature are usually a few milligrams per

 

       kilogram, which are a few parts per million.  You

 

       will see some widely ranging estimates, though,

 

       from different investigators.  A lot of times I

 

       question their methods sometimes or their ability

 

       to reproduce that particular result.

 

                 I think that is the end of my

                                                                126

 

       presentation, and I thank you very much for your

 

       attention.

 

                 CHAIRMAN DURST:  Thank you.

 

                 Committee, do you have any questions or

 

       comments?

 

                       QUESTION-AND-ANSWER SESSION

 

                 DR. MALEKI:  Soheila.

 

                 DR. HEFLE:  Soheila.

 

                 DR. MALEKI:  Yes, Soheila Maleki.  I was

 

       wondering, just based on your experience and you

 

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

 

       kind of correlation or if there are any standards

 

       between what the companies use to label "may

 

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

 

       2.5 parts per million that the kits provide as a

 

       may contain or a not contain and so forth?

 

                 DR. HEFLE:  They don't really use the

 

       analytical results to make a definite decision

 

       about that.  Usually, the companies make a decision

 

       to put precautionary labeling on through a certain

 

       stringent set of criteria.  It is something they

 

       have tried to clean up, and they are still having

                                                                127

 

       issues.

 

                 They have intermittent contamination.

 

       They would never allow something that consistently

 

       had a significant amount of allergen in it to be

 

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

 

       more, if it is not supposed to be there.

 

                 They don't set a level like that.  They

 

       use the analytical results to help them determine

 

       whether that is justified or not.  It has to be

 

       potentially hazardous, intermittent, hard to clean.

 

       Those sorts of things are taken into consideration

 

       much more than just the simple analytical result.

 

                 DR. MALEKI:  Thank you.

 

                 CHAIRMAN DURST:  Yes.

 

                 DR. NELSON:  Mark Nelson.  I just wanted

 

       to follow up to that in response to Soheila.  In

 

       2001, the food industry, a group of associations

 

 

       representing their members did put together

 

       guidelines on labeling.

 

                 The preference is obviously and clearly

 

       the requirement is to label the ingredient in the

 

       presence of an allergen when it is directly added

                                                                128

 

       to the food.  In the situation where there is a

 

       potential for cross contact, we did establish some

 

       guidelines before companies should use "may

 

 

       contain" labeling because of the concerns we have

 

       heard about before.

 

                 One of those key guidelines was to make

 

       sure that we could not avoid it even after applying

 

       good manufacturing practices: appropriate cleaning,

 

       appropriate separation, and so on and so forth.

 

                 DR. MALEKI:  I see.  Depending on how much

 

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

 

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

 

       well, if it contains it was directly added to the

 

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

 

       correctly.

 

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

 

       Sue's point that we aren't necessarily measuring

 

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

 

       release situation.

 

                 DR. MALEKI:  I see.

 

                 DR. NELSON:  It is understanding your

 

       system; what ingredients are going into the food;

                                                                129

 

       what other products might be made on that line;

 

       validating your cleaning processes between

 

       products; scheduling products, depending on the

 

       ingredients that they contain; the sequence in

 

       which you might make the product and so on.  There

 

       are a lot of things that go into it.

 

                 CHAIRMAN DURST:  Anything else?

 

                 Yes.

 

                 DR. CALLERY:  Pat Callery.  It appears

 

       that the allergens themselves are not that well

 

       defined, especially when you can find in actuality

 

       generated new allergens by treating food in a

 

       certain way.  I am wondering how you address the

 

       analytical problem of false negatives and false

 

       positives?

 

                 DR. HEFLE:  For a lot of foods the

 

       allergens are indeed known, and there are very rare

 

       cases where you make new allergens through

 

       processing.  That is an extreme case in the

 

       literature, I think.

 

                 However, false positives and false

 

       negatives are evaluated at the company level first

                                                                130

 

       by testing tens of thousands of food commodities

 

       and looking for potential issues.  Also, I kind of

 

       poke around myself and see if there is anything

 

       that I can challenge the kits with.

 

                 In my experience, the false positive/false

 

       negative rate for most of these methods is very

 

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

 

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

 

       systematic study.

 

                 However, I think that the use of these

 

       interlab trials with model foods will help us look

 

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

 

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

 

       and negative is out there.

 

                 I just know in our experience, and we use

 

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

 

       When the occasional issue crops up, and we call the

 

       manufacturer.  We usually work through it pretty

 

       easily.

 

                 They do tell the manufacturers to validate

 

       or run their own in-house validations before they

 

       truly test the results.  The manufacturers do tell

                                                                131

 

       the manufacturers to do that, so, theoretically,

 

       they should hopefully find some of these things.

 

       However, every method has a chance of a false

 

       positive or a false negative.

 

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

 

       without standard materials.

 

                 DR. HEFLE:  I'm sorry?

 

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

 

       of that without standard materials to validate

 

       them.

 

                 DR. HEFLE:  Some of the manufacturers will

 

       give you a standard to work with, either the

 

       standards from the kit or a recognized standard or

 

       perhaps one of the NIST standards, which is what we

 

       are all defaulting to because we have nothing else.

 

                 DR. CALLERY:  I think you mentioned that

 

       one kit, they have some secret materials that they

 

       put into the kit to help extract protein.  This

 

       seems inconsistent with being able to validate a

 

       method if you don't even know what the test

 

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

 

       antibodies are that are made.

                                                                132

 

 

                 DR. HEFLE:  Well, the extraction additive

 

       is not a reference material.  The extraction

 

       additive is just an aid in extraction.  Usually,

 

       the companies will tell you what it is.  It is

 

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

 

       secret, but it is not that secret.

 

                 It is just an additional protein in the

 

       mix that helps pull the proteins out of oily

 

       matrices or hard to extract matrices.  The

 

       companies know this, and they share that with

 

       customers.  However, these sorts of extraction

 

       additives aren't really the reference materials or

 

       the standards used in the kit.

 

                 CHAIRMAN DURST:  Sue, will you be around

 

       for discussion this afternoon?

 

                 DR. HEFLE:  Yes, I will.

 

                 CHAIRMAN DURST:  I think we will hold

 

       further questions until that time because we are

 

       running a little bit late.

 

                 DR. HEFLE:  Okay.

 

                 CHAIRMAN DURST:  I would like to take the

 

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

                                                                133

 

       reconvene at 10:45.

 

                 Thank you.

 

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

 

       there was a pause in the proceedings.)

 

                 CHAIRMAN DURST:  We will start with our

 

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

 

       senior medical advisor to CFSAN, FDA.  He is also

 

       assistant professor at Georgetown University.  He

 

       will be speaking on "Oral Challenge Studies:

 

       Purpose, Design and Evaluation."

 

                         ORAL CHALLENGE STUDIES:

 

                      PURPOSE, DESIGN AND EVALUATION

 

                 DR. LUCCIOLI:  Thank you, Dr. Durst.

 

                 Good morning.  Today, I really want to not

 

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

 

       allergist who has experience in performing and

 

       evaluating oral challenge studies.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  The goals of my talk today

 

       are basically just to give you a basic overview of

 

       oral challenge studies, the purpose, why they are

 

       done, the design and conduct, and also spend a

                                                                134

 

       little time on evaluation and interpretation of

 

       data, especially with regard to sensitivity of

 

       subjects as well as clinical response and severity

 

       and maybe present some data gaps that may be of

 

       interest while you deliberate on thresholds

 

                 (Slide.)

 

                 DR. LUCCIOLI:  The purpose of challenge

 

       studies are manifold, but the primary reason is to

 

       diagnose allergy, food allergy.  The gold standard,

 

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

 

       placebo-controlled, food challenge.

 

                 As we have heard, also people outgrow

 

       their allergies.  They are done also to evaluate

 

       tolerance where those individuals have outgrown

 

       their allergies.  They have also been done to

 

       evaluate specific ingredients that are allergens in

 

       specific populations.  For instance, there have

 

       been some studies on highly refined oils in

 

       peanut-allergic populations.

 

                 However, in recent years, there has been a

 

       lot of emphasis on using oral challenge studies to

 

       determine minimal eliciting doses.  This has

                                                                135

 

       important implications potentially to determine

 

       sensitivities of individuals within a population,

 

       but also potentially some therapeutic opportunities

 

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

 

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

 

       maybe we can raise people's sensitivity levels so

 

       that they may not react to very low trace amounts

 

       of food.

 

                 For reasons that you are all here today,

 

       also for establishing threshold challenges, they

 

       may be able to provide you data on low-effect

 

       levels and no-effect levels.

 

                 A problem in this field is that there are

 

       insufficient animal models which are commonly used

 

       to evaluate toxicologic ingredients and also

 

       scattered data about case reports where there is

 

       not a lot of information about exact doses that

 

       cause reactions.

 

                 Very few studies are done or have been

 

       done.  One study was reported by Dr. Wood on

 

       evaluating reaction severity, and we don't have any

 

       current biomarkers to predict severity.  This is an

                                                                136

 

       important, I think, factor when we are looking at

 

       evaluating minimal eliciting doses.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  I'm just presenting this

 

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

 

       just give you an overview that oral challenge

 

       studies are somewhat different to traditional tox

 

       models that are used to determine potential

 

       thresholds or acceptable doses.  I will, hopefully,

 

       be able to highlight some of these issues in my

 

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

 

                 (Slide.)

 

                 DR. LUCCIOLI:  When you are designing oral

 

       challenge studies, obviously the selection of

 

       subjects is an important factor.  Usually, you have

 

       populations of adults, children or infants just to

 

       keep the statistics in order.  Most studies involve

 

       both men and women as well as are from foreign

 

       countries and most high ethnicities.

 

                 The selection of subjects is basically

 

       geared to what the purpose of the study is for,

 

       whether you want to diagnose individuals with an

                                                                137

 

       equivocal IgE or clinical history; evaluate

 

       evidence of outgrowth of tolerance, as we have

 

       mentioned; and also potentially to evaluate

 

       co-existent allergies,  for instance, milk-allergic

 

       individuals who may have soy, especially in the

 

       infant population and also for evaluating specific

 

       ingredients, in this case how to evaluate infant

 

       formula.

 

                 Obviously, for specific ingredients, you

 

       may want to pick particular populations for that.

 

       In fact, most infant studies are done to evaluate

 

       infant formulas, and the majority of studies are in

 

       adults.

 

                 Another important factor is that there is

 

       a notable exclusion of individuals from these

 

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

 

       individuals who have a cutoff level of their IgE

 

       where above this level they have a 95 percent or

 

       more risk of already failing the challenge.  The

 

       challenge is basically useless.  You already have

 

       the information, and you tell those individuals to

 

       avoid the food.

                                                                138

 

                 However, these individuals may represent a

 

       fairly sensitive population.  Now with IRBs as they

 

       currently stand, it is very difficult to get these

 

       individuals tested in studies.

 

                 Also, classically individuals who have had

 

       anaphylaxis or very severe reactions which were

 

       fairly convincing for the actual food are excluded

 

       from the studies, because another rule of thumb is

 

       do no harm.

 

                 Consequently, you don't really want to

 

       test people who could have potentially severe

 

       reactions when you have already had a high clinical

 

       index that they are allergic.

 

                 Of course, there are a lot of people who

 

       self-exclude themselves from studies who may be

 

       part of a sensitive population.  I also mentioned

 

       here unstable asthma because in any study you don't

 

       want to test individuals who are unstable to begin

 

       with.

 

                 Individuals with asthma tend to have more

 

       severe reactions and are probably the group most

 

       representative of fatal reactions.  By not

                                                                139

 

       including these individuals, you may be missing not

 

       only sensitive individuals but individuals who are

 

       potentially very severe responders.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  With regards to test

 

       materials, there is a variety of test materials

 

       that can be used.  Various preparations, if you

 

       just look at peanut, you can have peanut flour,

 

       ground peanut, peanut butter.

 

                 There is evidence that the processing

 

       method of these various preparations may affect the

 

       allergenicity profile of proteins within these

 

       foods.

 

                 You may have some individuals who are more

 

       sensitive to peanut flour versus peanut butter.

 

       The importance, too, with choosing the material is

 

       that for logistic purposes you want to have it for

 

       an increased time, if you are going to be doing

 

       challenges over multiple months or time points.

 

                 A preferred method for these types of

 

       ingredients are dried ingredients.  You get into a

 

       problem where dried milk or spray-dried egg are not

                                                                140

 

       very commonly ingested ingredients in the

 

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

 

       cooked egg or milk, liquid milk.  Therefore, these

 

       are factors that need to be assessed.

 

                 Also, fresh versus processed foods, some

 

       individuals are more likely to react to the fresh

 

       food versus the processed as well as raw versus

 

       cooked.  These are issues that need to be

 

       considered when you choose a food for a particular

 

       challenge.

 

                 Then, the dose units are different within

 

 

       these challenges.  Some studies report milligram

 

       for food; others milligram for protein of food;

 

       and, very rarely, milligram per kilogram which

 

       would be fairly ideal if we wanted to evaluate

 

       potential differences between adults and smaller

 

       adults, infants.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Obviously, people who

 

       partake in these studies are people who think they

 

       have an allergy; may have had a fairly significant

 

       reaction; and are, understandably, under a lot of

                                                                141

 

       stress and are afraid.

 

                 Blinding is an important fact, since there

 

       is unfortunately a high incidence of the "nocebo

 

       effect," which is actually the opposite of placebo,

 

       people reacting to a substance that they think is

 

       going to harm them.

 

                 In blinding it is important to mask the

 

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

 

       what they are eating.  Factors that are used are

 

       called "vehicles" in one sense, and they are

 

       basically other types of foods that are thick that

 

       can hide the taste and smell and texture and that

 

       are also pleasant tasting, you hope.

 

                 However, when you are thinking about doing

 

       a challenge study over a few time limits, obviously

 

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

 

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

 

       make sure that the individual is not milk allergic

 

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

 

       things independent of what the actual food that you

 

       are studying would have.

 

                 In some cases, they don't always mask the

                                                                142

 

       taste.  Therefore, some researchers have preferred

 

       to use capsules, since this basically bypasses the

 

       taste issue.

 

                 However, using a capsule is difficult,

 

       especially if you are going in higher doses of

 

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

 

       a capsule.  I think people would know when they see

 

       a big capsule that there is more food in that.

 

                 Also, an important factor is that you may

 

       delay the absorption of that food putting it in a

 

       capsule, and also you bypass the oral cavity which

 

       may be a primary target organ for the initial

 

       allergic response.  You may have not only a delayed

 

       response but potentially a less severe response.

 

                 I won't talk about the protocol, I think

 

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

 

       also a question about placebos.  There are some

 

       studies that use placebos within the challenge.

 

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

 

                 You know, it is a very complicated process

 

       where you usually need some other people that blind

 

       those to both the researcher and the subject, but

                                                                143

 

       they are used as well.  However, I think the

 

       preferred method and the easier method is to do a

 

       separate placebo day.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Now this is just a

 

       schematic of an example of a dose protocol.  I

 

       think the important factor is this is an escalation

 

       study of divided doses.  One of the important

 

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

 

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

 

       all day.

 

                 To be able to determine a dose of food and

 

       get up to the final dose, which is usually a

 

       serving of the food, which is like 10 grams of

 

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

 

       achieve.

 

                 If there is no response at that dose,

 

       there is a good likelihood that the challenge is

 

       negative.  However, in many cases you still want to

 

       have the patient come back and do an open

 

       challenge.

 

                 Now, with choosing the starting dose, this

                                                                144

 

       varies among studies.  In many diagnostic studies,

 

       because of this issue about not wanting to be

 

       there, you choose a dose that is roughly half of

 

       the dose that caused the reaction.

 

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

 

       figure that out, but that is what has classically

 

       been used as the starting dose.  Even within a

 

       study, these doses shifts.  This dose usually comes

 

       out to be in the milligram range.

 

                 Now, more recent studies that have

 

       actually been targeted to study minimal eliciting

 

       doses, have started in doses in the even microgram

 

       range.  However, there are a variety of studies

 

       when you are looking at evaluating studies for

 

       eliciting doses.

 

                 Also, in this protocol, it is important to

 

       know the time interval differences.  Usually, also

 

       that is tailored to the patient when their symptoms

 

       first occurred.  Most allergic reactions occur

 

       within 15 to 30 minutes, so that is usually the

 

       time gap, but some other reactions may be a little

 

       bit more delayed.

                                                                145

 

                 As Dr. Wood discussed, there are

 

       individuals who have delayed reactions as well.

 

       Unfortunately, it is just not logistical to do a

 

       study and wait for these people's reactions to

 

       occur, because they might not occur that day; they

 

       may occur on a separate day.

 

                 In this model that I use, I just use a

 

       twofold dose incrementation, but also this could

 

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

 

       could affect also the starting dose and

 

       interpretation of doses in the dose response.

 

                 Now, you go and you do the challenge.  If

 

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

 

       after the first objective symptom occurs.  Some

 

       studies will also record the subjective symptoms,

 

       but that is not always the case, because the

 

       objective symptom is the symptom that denotes a

 

       positive allergic response.

 

                 When you record the dose, you can either

 

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

 

       recorded or the 7X, which would be the cumulative

 

       dose adding the X, 2X or 4X.

                                                                146

 

                 Just to put this also into some

 

       perspective in terms of safety assessment, when we

 

       are talking about LOAELs and NOAELs, the 4X would

 

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

 

       are doses before that, at least for this individual

 

       you can say that this dose did not cause a response

 

       and could be considered a no-effect level.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Some other issues are don't

 

       do this at home.  People can have a very severe

 

       reaction.  These studies are done in a clinic or an

 

       office where there is emergency equipment and

 

       personnel.  It is not a challenge that is done out

 

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

 

       that can also affect the interpretation or results.

 

                 Medications, too, most studies now have

 

       people stop the medicines, but with some earlier

 

       studies this was not a factor.  Antihistamines and

 

       other things, if people are on these drugs, may

 

       block the early responses so that can factor in.

 

                 Fasting, too, most people fast before the

 

       study, but in some studies this was not necessarily

                                                                147

 

       explained.  If you have a full meal right before

 

       the challenge, this could affect, potentially

 

       affect, absorption of the allergen and therefore

 

       affect the interpretation of the study.

 

                 The clinical history or reactivity, too,

 

       is important.  Dr. Wood talked about oral allergy

 

       syndrome, but he did not mention about exercise.

 

       There are some individuals who eat a food and have

 

       no problem.  However, if they eat the food and

 

       exercise, they have a problem.

 

                 Some studies actually test the individual

 

       and then put them on a treadmill and have them

 

       exercise to see if you can elicit the reaction.  I

 

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

 

       also can be done in terms of the oral challenge

 

       setting.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Statistical endpoints, I

 

       think these are fairly straightforward for most

 

       challenge studies.  You want to just know what

 

       percentage of individuals will react or not react

 

       to the challenge, or in cases where you are

                                                                148

 

       studying reaction severity which ones will have a

 

       mild versus a severe reaction.

 

                 If you assume that all of these

 

       individuals in the study are part of the sensitive

 

       population or general population, you can maybe

 

       make some assumptions about that and decide a

 

       percentage that will or will not react to a

 

       specific food concentration.

 

                 Also, there an importance in this is also

 

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

 

 

       to achieve a certain number of individuals to give

 

       you confidence levels for the incidence of allergic

 

       reactions.

 

                 In this example, this is a table that

 

       shows over here (pointing) the number of

 

       individuals that need to be tested to give you a

 

       confidence level that the incidence will be less

 

       than this.

 

                 For instance, if we were to design a study

 

       with 66 people, that would give us 99 percent

 

       confidence that 1 in 10 would potentially react, so

 

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

                                                                149

 

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

 

       percent confidence that 95 percent, 1 in 20, will

 

       not react.

 

                 Twenty-nine has been usually seen as a

 

       magic number for infant formulas.  If 29 patients

 

       do not react, if the infant with milk allergy does

 

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

 

       basis for hypoallergenicity.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  I will spend the rest of my

 

       talk on evaluation and interpretation of challenge

 

 

       study data.  Basically, a general interpretation as

 

       we just talked about the statistics, many of these

 

       studies are done in a very small population of

 

       patients, therefore you cannot make a very general

 

       assumption for the general population.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Because some of these

 

       studies do test the same food, there is a tendency

 

       to group these studies together to try to get the

 

       power higher and then potentially make some

 

       assumptions.

                                                                150

 

                 The problem with this is that I think it

 

       is important to note that all of the studies that

 

       are currently available are not standardized.  I

 

       think that was a question asked just a little

 

       earlier.

 

                 This is not standardized data.  They are

 

       not standardized to dose.  Starting dose or

 

       blinding or testing could also be a factor and also

 

       interpretation of clinical symptoms, which I will

 

       address a little later.

 

                 Another issue here is that all sensitive

 

       populations, are they included.  If you have

 

       information only on adults, is that going to

 

       predict what harm it will be to infants.

 

                 Again, in terms of statistical power, if

 

       you get individuals who are not reactive, if you

 

       are looking at total numbers to say "This is how

 

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

 

       about people who didn't react to the challenge at

 

       all?  Should they be included in the final analysis

 

       of individuals, or should only the ones who react

 

       to the challenge be part of that analysis?

                                                                151

 

                 What about foreign study data.  For

 

       instance, China has a very low prevalence of peanut

 

       allergy, presumably because peanuts there are

 

       boiled or fried versus in this country they are dry

 

       roasted.  If you have all of this data in the

 

       United States about peanut allergy, could that be

 

       transferred to data in China?

 

                 (Slide.)

 

                 DR. LUCCIOLI:  I just should mention, too,

 

       that with standardization it is important to note

 

       that there have been some very nice reviews on

 

       actually proposed protocols, standardized

 

       protocols, for food challenges which have been

 

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

 

       knowledge, there have been no studies that have

 

       used this protocol at least for a major food

 

       allergen for evaluation.

 

                 Another general interpretation is that

 

       this is an experimental exposure.  It is not real

 

       life.  There could be false negatives.  Individuals

 

       who have had a negative food challenge go out and

 

       have an open challenge and react.  It is not always

                                                                152

 

       a definitive assessment of allergy.  Also, I think

 

       it is difficult to predict reactions to future

 

       exposures.  I will try to talk about that as we

 

       come up.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Subject sensitivity, this

 

       is I think an important issue to consider when

 

       looking at evaluating food ingredients.  The

 

       genetic heterogeneity of individuals, there are

 

       multiple allergens in food.

 

                 People can be sensitized specifically to

 

       certain allergens within that food.  If you cook

 

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

 

       affect their allergenicity positively or

 

       negatively.  This may be what is apparent when they

 

       do studies and you see this enormous gap in

 

       responders.

 

                 You have almost a millionfold gap between

 

       the high responders or I should say the least

 

       sensitive who respond to low doses and the most

 

       sensitive to who respond to high doses.

 

                 There is also this potential link with

                                                                153

 

       severity, as Dr. Wood study has suggested and some

 

       others, that some studies suggest that the

 

       individuals most sensitive to low doses appear to

 

       have the most severe reactions.  Are we talking

 

       about a specific subpopulation of individuals here

 

       who are not only sensitive but severe?  Also, there

 

       is a sensitivity issue between foods and between

 

       food products.

 

                 Another important aspect is that the

 

       individual sensitivities may vary over time.

 

       Allergies can progress and individuals with food

 

       allergies develop asthma later in life.  This

 

       asthma, therefore, makes their reactions a little

 

       bit more severe.

 

                 Telling somebody right now that they

 

       reacted at a certain dose and that it is okay to

 

       ingest doses before that may not be relevant a year

 

       or five years from now.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  This just is a hypothetical

 

       dose curve adapted from Jonathan Hourihane, who has

 

       done some nice research in this area, basically

                                                                154

 

       just to show you how severity and sensitivity may

 

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

 

       that.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Evaluation of clinical

 

       responses, this is where interpretation of

 

       eliciting doses is important with regards to

 

       subjective versus objective symptoms as well as

 

       reaction severity in the dose response.

 

                 This table summarizes some of the

 

       reactions that you can see from an allergic

 

       response.  Basically, they are divided into

 

       subjective versus objective.  "Subjective" means

 

       that they are reported by the individual or the

 

       subject, and "objective" are responses that are

 

       actually visible or observed by the observer.

 

                 These reactions are reported in this

 

       manner.  As I said, it is when objective symptoms

 

       occur, that is when the study is felt to represent

 

       a positive reaction and stopped.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  To just show you some of

                                                                155

 

       these reactions, not only is there a wide range in

 

       reactions, but there are some fairly milder

 

       reactions, hives.  You down here to shock and this

 

       is anaphylaxis.  Wheezing and syncope are very

 

       close to systemic reaction and potential

 

       anaphylaxis.  Consequently, even within an

 

       objective response, you may have a severe

 

       anaphylactic response.

 

                 There are also some subjective reactions

 

       that may be somewhat severe: throat tightness,

 

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

 

       the pleasure, fortunately, to experience a patient

 

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

 

       have this sense of impending doom and go rapidly

 

       into anaphylaxis.  It is very, very serious.  It

 

       doesn't take much for a subjective reaction to go

 

       to something severe.

 

                 Also, there are some reactions that kind

 

       of are in between the line of what is subjective,

 

       what is objective: fussiness behavior, abdominal

 

       pain.  In adults, that could be suggestive of a

 

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

                                                                156

 

       mess around.  This is their symptom, so these could

 

       be positive responses for infants.

 

                 At the same time, you could have skin

 

       flushing or shortness of breath leading to

 

       increased respiratory rate, which could be an

 

       objective sign.  However, many times this could be

 

       due to also a nocebo effect.  Whether these are

 

       actual positive reactions is hard to determine.

 

       There is some clinical interpretation differences

 

       that can occur here.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Subjective versus objective

 

       symptoms -- as I told you, the measurable indicator

 

       of allergic response is the objective symptom.  It

 

       has got many different endpoints, and the

 

       interpretation may vary.  This could also be true

 

       for the subjective reactions.

 

                 Many times, subjective reactions do occur

 

       as part of a nocebo effect.  However, there are

 

       some that are potentially indicative of an allergic

 

       reaction.

 

                 How should these be factored into the

                                                                157

 

       assessment?  Many times they are not recorded in

 

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

 

       reactions to the objective dose, which may

 

       represent an earlier adverse event level.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  Some other eliciting dose

 

       considerations, the starting dose is important.  If

 

       the response occurs at this dose, you cannot

 

       determine the no-effect level.  Obviously, there is

 

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

 

       but is this starting dose the low-effect level?

 

       Could you have given a dose a little lower and they

 

       could have still reacted?

 

                 With dose increments, some are twofold and

 

       some are tenfold.  Using tenfold, you may miss some

 

       increment in between that there could have been a

 

       reaction, even maybe a fivefold difference.

 

                 Also, time intervals between doses, as

 

       Dr. Wood has explained, some doses are delayed.

 

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

 

       time, you might not know when a subjective response

 

       has become a subjective response or so forth.  This

                                                                158

 

       could also affect interpretation of these eliciting

 

       doses.

 

                 Of course, discrete versus cumulative

 

       dose, some studies report just a discrete dose;

 

       some the cumulative; some both, which is better.

 

       However, how do these factor into a true exposure

 

       assessment or prediction?

 

                 (Slide.)

 

                 DR. LUCCIOLI:  I just want to just show

 

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

 

       into perspective here, give you a mechanistic view

 

       that allergy is a unique toxicologic response.

 

                 When you get food that gets challenged, it

 

       causes a massive release of mediators and

 

       cytokines.  This is an amplification system that

 

       the immune system uses to protect itself.

 

                 Now, in many cases, this response occurs

 

       locally and may not amount to very much, but in

 

       some cases this amplification can involve other

 

       organs and spread systemically very rapidly.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  What has been observed is

                                                                159

 

       that the severity of an allergic response is on a

 

       continuum.  You can have subjective responses at

 

       some point, objective anaphylaxis, and potentially

 

       death in worse cases.

 

                 A few points to note is that this is not a

 

       fixed response.  The early objective system may

 

       rapidly progress to something worse.  Also, the

 

       degree of amplification, this is not always

 

       predictable or reproducible, so symptoms may not

 

       always be reproducible on subsequent rechallenge.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  To end, with the reaction

 

       severity, most studies only report the actual

 

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

 

       the continuum of severity many times.  Those few

 

       that do report the symptoms, they report them as

 

       mild, moderate, and severe.

 

                 You have to interpret the researchers, I

 

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

 

       there is some interpretation.  Also, when you have

 

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

 

       cases a third of individuals reacted and had mild

                                                                160

 

       reactions, a third had moderate, and a third had

 

       severe.  How do you factor in those severe

 

       responses when you determine uncertainty or other

 

       issues?

 

                 Also, potentiating mitigating factors are

 

       important: anxiety/stress, medications, and so

 

       forth.  These can either potentiate the reaction or

 

       stop it.

 

                 Then, the challenge stops after the first

 

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

 

       of knowing how far or how many more doses would

 

       have caused a more severe response.  Having that

 

       information is important when you are wanting to

 

       make some risk assessment decisions.  Again, it is

 

       a dose distribution, not a dose response.

 

                 (Slide.)

 

                 DR. LUCCIOLI:  In conclusion, the oral

 

       food challenge does provide data on clinical

 

       sensitivity to minimal eliciting doses and also

 

       reaction severity to the initial dose.  However,

 

       challenge data currently available for

 

       interpretation is not standardized among studies.

                                                                161

 

                 The current data pool may not include

 

       extremely sensitive populations with regards to

 

       severity.  Challenges have a proven value as a

 

       diagnostic tool but less value in predicting

 

       reaction severity to future exposures.

 

                 Thank you, and I will be glad to answer

 

       some questions.

 

                 CHAIRMAN DURST:  Thank you very much.

 

                 Are there any questions from the

 

       Committee?

 

                 We will start here.

 

                       QUESTION-AND-ANSWER SESSION

 

                 DR. BRITTAIN:  Yes.  I have a comment on

 

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

 

       sure that is incorporating the statistical power

 

       education we need to have more than these

 

       individuals.  Are you familiar with what I'm

 

       talking about like the 29 there?

 

                 DR. LUCCIOLI:  Yes.

 

                 DR. BRITTAIN:  I'm wondering if you get

 

       zero out of 29, then your confidence interval

 

       excludes --

                                                                162

 

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

 

       is usually a number that is targeted to challenge a

 

       number of study subjects.  If you show that 29

 

       individuals with the specific allergy do not

 

       respond to that ingredient, that gives you 95

 

       percent confidence that 90 percent will not react.

 

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

 

       that means if you observed 29, you get the desired

 

       confidence interval.  However, if you were planning

 

       a study and you wanted statistical power to be a

 

       certain amount, you would need to have a bigger

 

       study.

 

                 DR. LUCCIOLI:  Sure.

 

                 DR. BRITTAIN:  You couldn't assume that

 

       nobody would react.

 

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

 

       that to be totally assured you would have to test

 

       quite a few people.

 

                 DR. BRITTAIN:  I do have another question.

 

       You mentioned the placebos again, if someone does

 

       have a reaction with a placebo, how is that

 

       interpreted in terms of if they also have a

                                                                163

 

       reaction?

 

                 DR. LUCCIOLI:  Well, yes, many times you

 

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

 

       you find out that they reacted to the placebo.

 

       Now, technically, some studies will rechallenge

 

       that patient again.  They will have them come back

 

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

 

       react.

 

                 The difficulty is when they react to the

 

       active dose, to a real challenge, and to the

 

       placebo.  If the placebo is too close to the

 

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

 

       placebo, they are still having the active reaction.

 

                 Basically, if they are rechallenged and

 

       show again, they are excluded from the analysis.

 

       Now, that is what should happen.  Unfortunately,

 

       you never get that information a lot of times from

 

       these challenges.

 

                 CHAIRMAN DURST:  Suzanne.

 

                 DR. TEUBER:  One of the aspects that we

 

       are all very concerned about is which threshold to

 

       use and when it may cause a subjective reaction. 

                                                                164

 

       Actually, oral itching is a very important

 

       subjective reaction that you didn't have on your

 

       table up there in this presentation.

 

                 DR. LUCCIOLI:  Okay.

 

                 DR. TEUBER:  However, if that is

 

       reproducible with two active challenges and not

 

       seen with two placebos, which I think Dr. Taylor

 

       may address a little bit later, but some of the

 

       studies that Dr. Wensing and Bindslev-Jensen and

 

       Dr. Hefle have been doing, they have been looking

 

       at that.  All of these have been followed by

 

       objective reactions at higher doses.

 

                 DR. LUCCIOLI:  Yes.

 

                 DR. TEUBER:  I would really like people to

 

       comment on that because this may be a much safer

 

       way to approach obtaining thresholds to get these

 

       extremely sensitive populations, if we can use

 

       reproducible subjective data knowing, too, that

 

       there are those other factors that may affect it.

 

                 DR. LUCCIOLI:  Sure.

 

                 DR. TEUBER:  For instance, in these

 

       threshold studies that are being designed

                                                                165

 

       specifically for thresholds, people with unstable

 

       asthma would still be excluded.  I am curious if

 

       anybody knows anything about how unstable asthma

 

       would affect the threshold for a LOAEL that is

 

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

 

       any anecdotal experience with how that might

 

       change?  We want safety here.

 

                 DR. LUCCIOLI:  Obviously, a speaker that

 

       is coming after me would have some information on

 

       that, but some information from Jonathan Hourihane

 

       would suggest -- and I think some European studies

 

       actually do test some severe patients.  Now, I

 

       don't think that any of these patients are

 

       unstable.

 

                 I think that they are all excluding

 

       patients who have unstable asthma, but with asthma

 

       in general they haven't found that these

 

       individuals have a lower minimal eliciting dose

 

       than other individuals.  However, when they do get

 

       a reaction, they can have a much more severe

 

       reaction.

 

                 The assumption, though, is that because of

                                                                166

 

       the fatalities and other things that when their

 

       asthma becomes unstable their sensitivity could

 

       change and become more severe very quickly.

 

                 CHAIRMAN DURST:  Marc.

 

                 DR. SILVERSTEIN:  Marc Silverstein.  I

 

       have two comments that deal with sort of

 

       clarification of terminology and one comment that I

 

       think deals with a more difficult issue.  I thought

 

       this was a wonderfully helpful and concise summary

 

       of a variety of complex factors.

 

                 In terms of the two clarifications, in

 

       clinical medicine from the first days of medical

 

       school we are taught the difference between

 

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

 

       which are objective.

 

                 Some of us from the clinical side who will

 

       be reading the report will think that subjective

 

       symptom is redundant and objective symptom is an

 

       oxymoron.

 

                 To help the wide dissemination of the

 

       report and presentation, I would like to suggest

 

       that we in our thinking we may say "subjective

                                                                167

 

       finding such as symptoms of the disease" and

 

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

 

                 DR. LUCCIOLI:  Sure.

 

                 DR. SILVERSTEIN:  I think it is helpful

 

       because there will be a variety of readers of the

 

       report who may not appreciate that on the clinical

 

       side there is a clarification about that.

 

                 The second clarification had to do with

 

       the incidence versus prevalence in the sample size

 

       table.  What we are talking about is the proportion

 

       of subjects being tested to the proportion of

 

       individuals in a population, so that sample size

 

       table or the table we have is the expected number

 

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

 

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

 

       population.

 

                 DR. LUCCIOLI:  Okay.

 

                 DR. SILVERSTEIN:  I believe that what you

 

       are getting at is the sample size so that the lower

 

       confidence interval is that 10 percent or 1 percent

 

       rather than the sample size necessary to show that

 

       two populations differ in proportion or the sample

                                                                168

 

       size to show how tight you are around a rate of

 

       zero, which would be a different population.

 

                 DR. BRITTAIN:  Can I respond to that?

 

                 DR. SILVERSTEIN:  Sure.

 

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

 

       designing a study you want to think of it in terms

 

       of statistical power, which would be greater than

 

       the sample sizes.

 

                 DR. SILVERSTEIN:  The third comment I

 

       have, which is substantive and I think we may need

 

       to address this later in greater detail, has to do

 

       with sources of error.  There are two sort of

 

       classes of errors that we made in our inferences.

 

                 One types of error an epidemiologist or a

 

       clinical epidemiologist may say is biased, one of

 

       the most common sorts of types of errors we could

 

       make would be making inferences in the presence of

 

       certain biases.  The most common of which would be

 

       selection bias.

 

                 Of course, the selection of individuals

 

       who are referred to a physician, who are referred

 

       to an allergist, who are selected for an oral

                                                                169

 

       challenge, food challenge, study would potentially

 

       lead to erroneous inferences if there were

 

       non-representative selection.

 

                 That is something that in reading the

 

       literature and making decisions about inferences

 

       for studies or for policy I think we need to be

 

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

 

       errors that we need to be alerted to.

 

                 The second would be an epidemiologist

 

       would talk about confounding.  In your example of a

 

       study subject who has asthma, whether it is stable

 

       or unstable and how that is defined, asthma might

 

       be considered an extraneous factor that affects the

 

       relationship between the allergen and the response

 

       to the test.  We could use the framework of

 

       thinking of it as a confounding benefit.

 

                 Factors such as bias and factors such as

 

       confounding, I think, are useful as we make

 

       decisions about the report and the evidence for

 

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

 

       we think about the presentations.

 

                 DR. LUCCIOLI:  Thank you for the

                                                                170

 

       clarification.

 

                 CHAIRMAN DURST:  Are there any other

 

       Committee comments?

 

                 (No verbal response.)

 

                 CHAIRMAN DURST:  If not, thank you very

 

       much.

 

                 Our next speaker is Dr. Rene Crevel,

 

       senior scientist at Unilever, Safety and

 

       Environmental Assurance Centre in the United

 

       Kingdom.  He will be speaking on the "Threshold

 

       Modeling Approach."

 

                       THRESHOLD MODELING APPROACH

 

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

 

       for inviting me to share some thoughts on the work

 

       we have been doing on modeling thresholds.

 

                 (Slide.)

 

                 DR. CREVEL:  You have asked me to talk

 

       about the following, to look at different modeling

 

       approaches including what is named the

 

       "hyperallergen."  This is the model, and the

 

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

 

       the data requirements and underlying assumptions

                                                                171

 

       behind them; and then say something about

 

       interpreting the results of applying these models.

 

                 (Slide.)

 

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

 

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

 

       challenge in allergen risk management as far as

 

       industry certainly is concerned.

 

                 We want to protect allergic consumers of

 

       course, but we also are aware that protecting them

 

       by certain measures of risk management such as we

 

       have heard about this morning like precautionary

 

       advisory labeling does actually affect their

 

       quality of life.

 

                 We want to minimize the effects on their

 

       quality of life, the adverse effects on their

 

       quality of life.  We ultimately also want to

 

       maintain economic operation of food manufacturing,

 

       because if that doesn't happen, then that will

 

       affect the quality of life of a considerable number

 

       of individuals and people throughout society as

 

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

 

                 (Slide.)

                                                                172

 

                 DR. CREVEL:  How can we meet the

 

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

 

       label where the allergen is present, and that is

 

       fine.  You have legislation over here now in the

 

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

 

       many other regions and nations also have

 

       legislation.

 

                 (Slide.)

 

                 DR. CREVEL:  Or, we can ensure that the

 

       residual allergen content of product is low enough

 

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

 

       vast majority of allergic consumers), because we

 

       have heard here this morning some instances of

 

       people reacting to extremely low amounts.

 

                 I think it is questionable, and I think

 

       the Committee must address that particular

 

       question, whether those people can be protected by

 

       whatever we can do in the food industry.  We need

 

       to think about what alternative measures may need

 

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

 

       foods we can produce.

 

                 (Slide.)

                                                                173

 

                 DR. CREVEL:  How can we determine what is

 

       harmless to an allergic consumer?  Well, we have

 

       several sources of data, which I have listed on

 

       this particular table.

 

                 We can look at case reports from the

 

       literature, and those we have heard.  We have heard

 

       about people reacting to very low amounts.

 

       Unfortunately, the usefulness in risk assessment,

 

       actually an allergen risk assessment in my view is

 

       actually quite limited.

 

                 They do establish the hazard.  Yes, they

 

       tell you that a certain amount will affect some

 

       individuals, will provoke a reaction in some

 

       individuals.  They don't tell you in how many

 

       individuals that will happen.

 

                 We can use control challenge studies.  In

 

       fact, those of course provide the bedrock of what

 

       is needed, the information needed in allergen risk

 

       assessment because the population can actually be

 

       quite accurately describe.

 

                 You can describe them in terms of the

 

 

       symptoms they have experienced, the allergological

                                                                174

 

       history, or the medical history as appropriate --

 

       all of the demographics that you can think about.

 

                 Finally, dose distribution modeling, which

 

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

 

       very useful in allergen risk assessment.  But of

 

       course it relies on the experimental clinical data

 

       which is generated in control challenge studies.

 

       It cannot operate in a vacuum.  We do not have

 

       enough of those sorts of data at the moment.

 

                 (Slide.)

 

                 DR. CREVEL:  I have been asked to say

 

       something about the hypoallergenicity approach.  As

 

       I understand it, it is an unofficial standard for

 

       designating infant formula as hypoallergenic.

 

                 The original reference I found goes back

 

       to 1991, although I think the American Academy of

 

       Pediatrics has actually updated or at least issued

 

       the guidance more recently, I think, in 2000 or

 

       something of that sort.

 

                 The statistics of this approach are based

 

       on the binomial theorem, quite simply.  This shows

 

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

                                                                175

 

       participants, as we have already heard, and you

 

       observe no reactions, then you can be 95 percent

 

       confident that only 90 percent of the population

 

       from which these people have been taken will not

 

       react.

 

                 You can also extend that a bit, so if you

 

       observed one reaction and you added people to the

 

       study, then you would 46 for the same degree of

 

       confidence.

 

                 If you wanted 95 percent confidence then

 

       fewer than 99 percent would not react, then you

 

       have got those other numbers which already become

 

       very challenging, pardon the pun, for a challenge

 

       study both in terms of recruiting the people do it,

 

       to participate, and the economic cost of actually

 

       doing it.

 

                 (Slide.)

 

                 DR. CREVEL:  However, those are very

 

       useful data when they are generated, but protecting

 

       90 or 95 percent or even 99 percent of the allergic

 

       population is not sufficient as far as we are

 

 

       concerned as an objective for the food industry.

                                                                176

 

                 What we asked ourselves is, How can we

 

       improve this?  There are several ways.  We could

 

       try to look at the conventional toxicological

 

       approach and apply a safety factor to the lowest

 

       observed adverse effect level or the no observed

 

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

 

       got the no observed adverse effect level.

 

                 However, that particular safety factor, I

 

       would say, would be arbitrary because we don't

 

       actually know enough about interindividual

 

       differences within the allergic population to apply

 

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

 

       protection still is undefined.  You do not know how

 

       many people you are protecting by applying that

 

       particular safety factor.

 

                 What about modeling of those distribution

 

       of minimum eliciting doses?  Well, that can

 

       actually define the level of protection for

 

       individual allergen level.  You can actually use a

 

       safety factor there.  You can use something which

 

       is like a lower 95 percent confidence interval

 

       instead of using the figure itself.

                                                                177

 

                 (Slide.)

 

                 DR. CREVEL:  Does modeling actually work?

 

       We asked ourselves could we fit a curve to the

 

       distribution of minimum eliciting doses that are

 

       generated by challenge studies, and could that

 

       curve be useful to predict the number of reactions

 

       likely to occur as a result of exposure to a

 

       specified amount of inadvertently present allergen

 

       in the food?

 

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

 

       not so much concerned about "declared allergen,"

 

       people who are allergic can avoid that, but what

 

       our concern is about is that which is present by

 

       cross-contact, mainly inadvertently.

 

                 (Slide.)

 

                 DR. CREVEL:  This just gives a very quick

 

       model curve.  It is just used to illustrate some of

 

       the points, right, okay.  From this particular

 

       curve, okay, we have got the data points

 

       schematically indicated like this.  The dose on

 

       this (indicating) particular axis an the proportion

 

       of the study population reacting here.  Obviously,

                                                                178

 

       it goes up to 100 percent.

 

                 Then, you have these particular points,

 

       which I have named "ED                                                  

                50" here.  This would be the

 

       dose expected to provoke a reaction in 50 percent

 

       of the study population or 10 percent. This

 

       particular one is an extrapolation, one way of

 

       extrapolating, which one could use.

 

                 (Slide.)

 

                 DR. CREVEL:  What is the impact of the

 

       choice of model on the predicted minimum eliciting

 

       doses?  I should go back a bit actually and say

 

       something else.

 

                 We collaborated actually with

 

       Dr. Bindslev-Jensen of Denmark in the initial

 

       development of the model.  At that particular point

 

       we used the lognormal distribution.  Having the

 

       papers published and so on, after that we decided

 

       to go back and look at a few more parameters and

 

       try to refine this particular approach.

 

                 Good clinical data were available for egg,

 

       milk and peanut.  We fitted the data using the

 

       following statistical distributions and calculated

                                                                179

 

       ED10s, the dose which would be predicted to cause

 

       responses in 10 percent of the population; and

 

       ED1s, in 1 percent of the population for each of

 

       those.  We used the following linear extrapolation

 

       from lowest observed adverse effect level to zero

 

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

 

       lognormal model, which was the original one in the

 

       2002 paper; the Weibull model; and the loglogistic

 

       model.

 

                 (Slide.)

 

                 DR. CREVEL:  What I want to do is to

 

       illustrate how these variously fit using the

 

       different distributions.  This is using real data

 

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

 

       on roasted peanuts.  You have got the data points

 

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

 

       original one we used.

 

                 You can fit loglogistic pretty well as

 

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

 

       linear -- you can even correlate these points

 

       linearly as well.

 

                 Although I haven't got the parameter fits

                                                                180

 

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

 

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

 

       doesn't actually tell you which is the most

 

       appropriate one for the particular distribution.

 

                 (Slide.)

 

                 DR. CREVEL:  This is illustrated in the

 

       differences between ED10s and ED1s between studies

 

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

 

       actually from -- in this particular case, we are

 

       just comparing the number of studies on peanuts

 

       including studies performed by Bock and May in the

 

       1970s and the later study by Wensing.

 

                 What is quite clear actually is for ED10s,

 

       which are still within the experimental zone, what

 

       I call the "experimental zone" in one of the

 

       previous slides.

 

                 The data actually drives what the

 

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

 

       difference between the ED10s, even though it is log

 

       scale, I know, even in this particular case.

 

                 (Slide.)

 

                 DR. CREVEL:  When you move away and go

                                                                181

 

       outside of the experimental zone to the ED1 and

 

       even further actually, the case is even stronger

 

       beyond that, the actual choice of model starts to

 

       drive the predictive responses.  That is an

 

       important point to bear in mind.

 

                 This is summarized on this slide for the

 

       ED10s in the experimental zone, that the

 

       differences between studies is greater than between

 

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

 

       doing that is to focus on standardizing protocols

 

       and having consistent patient selection criteria

 

       for the studies which you wish to undertake.

 

                 For the ED1 values, the differences

 

       between models are much larger as I showed and

 

       increase of course as we move further away from the

 

       experimental zone.

 

                 What this actually illustrates is that you

 

       need to validate the particular approach.  You need

 

       to validate whatever model you have chosen and

 

       adjust parameters in accordance with that.  What

 

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

 

       about doing that, what sort of data is needed.

                                                                182

 

                 (Slide.)

 

                 DR. CREVEL:  Now, there are a certain

 

       number of assumptions underlying the values

 

       generated by the model.  We are talking here about

 

       undeclared allergen, and that is quite important in

 

       relation to the one of these particular points.

 

                 First of all, we assume that the

 

       participants in a controlled challenge study are a

 

       representative sample of the whole allergic

 

       population.  That is a very important assumption,

 

       and one which actually is sometimes shall we say

 

       overlooked.

 

                 We have heard a lot about whether people

 

       are included or not included in particular studies.

 

       I would tend to argue actually that the population

 

       used in challenge studies, because of the way they

 

       are selected, is actually shall we say at the more

 

       severe, more sensitive end of the allergic

 

       population, basically because there are people who

 

       actually normally are referred to tertiary care

 

       centers.

 

                 There are people whose allergies are

                                                                183

 

       actually troubling them.  They are not people who

 

       might just get a small rash and just ignore it or

 

       ignore the particular food that caused it.  There

 

       are people who actually need to manage their

 

       allergy and they need some serious advice in doing

 

       so.

 

                 The second point is actually in terms of

 

       validating the model the allergic people actually

 

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

 

       particular case, it is quite important because if

 

       they are already avoiding them, the number of

 

       reactions that you will be able to enumerate in

 

       epidemiologic studies will not be the correct one.

 

                 The distribution of allergic reactivity

 

       study at the population level, now we've heard

 

       thresholds for individuals.  Minimal eliciting

 

       doses for individuals do vary.  However, what we

 

       are saying here actually is that overall it will be

 

       studied in these particular challenge studies.

 

                 Finally, the responses to a given dose of

 

       allergen are similar in the clinic to those

 

       experienced outside.  We are doing some work

                                                                184

 

       actually with Jonathan Hourihane, in fact, to try

 

       to quantitate the differences that may exist

 

       because, in fact, we are very aware that particular

 

       assumption probably does not hold entirely.

 

                 (Slide.)

 

                 DR. CREVEL:  Okay.  What data do we

 

       require for validation and application of a

 

       modeling approach?  We want to arrive at the risk

 

       assessment.  We have the hazard characterization.

 

       I would put it to you that actually what we are

 

       doing by the modeling approach is actually

 

       characterizing the hazard.  We are establishing how

 

       many people are likely to respond to a particular

 

       amount, and we use all of these.  These particular

 

       factors all influence it.

 

                 However, we also need to know the number

 

       of allergic consumers.  That is quite important in

 

       terms of prioritizing allergen management and so

 

       on.  Effectively, what the legislation does is also

 

       to acknowledge that particular fact.

 

                 The legislation either here, in Europe or

 

       anywhere else does not protect everybody because of

                                                                185

 

       course it only specifies a certain number of major

 

       common allergies rather than all of the 200 or so

 

       foods that may provoke allergic reactions.

 

                 We also need to know what the exposure is.

 

       We need to know what residual allergen levels are

 

       in the foods, residual allergen levels that are not

 

       declared.  Finally, we also need to know what the

 

       number of reactions is overall in the community.

 

                 Taking all of that together, we can

 

       actually validate the model.  Using those sorts of

 

       data, we can also apply it properly.

 

                 (Slide.)

 

                 DR. CREVEL:  To summarize, I think the

 

       modeling approach complements clinical studies and

 

       it certainly compliments clinical studies to

 

       establish minimal eliciting doses.  Of course, it

 

       relies on the data generated in those studies.

 

                 I think the advantage compared to just

 

       using the data as such is it actually permits more

 

       complete use of those data using the whole dose

 

       distribution rather than just one particular point,

 

       say, the lowest observed adverse effect level or

                                                                186

 

       the no observed adverse effect level.

 

                 It also, I think, makes the whole process

 

       of risk management more transparent, I guess you

 

       would say, allowing a more informed discussion of

 

       risk management objectives by all stakeholders.

 

       That is very important I think.

 

                 In order to agree on objectives, I think

 

       people need to know how or need to see the process

 

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

 

       big proviso, it does require validation before it

 

       can be fully operational.

 

                 We are doing work at the moment to see how

 

       we can address that.  Some of the data actually I

 

       should say will contribute to this particular

 

       assessment will be generated by some European

 

       projects which are currently running, but of course

 

       it will take a few years to get there.

 

                 That was my last slide.  Thank you.

 

                 CHAIRMAN DURST:  All right.  It is open

 

       for discussion.

 

                 Yes.

 

                 DR. BRITTAIN:  That was a really

                                                                187

 

       interesting talk.  There was one aspect of it that

 

       I'm a little --

 

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

 

                 DR. BRITTAIN:  There is one aspect of it

 

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

 

       of your last slides with all the graphics about the

 

       needing to know the number of allergic consumers.

 

                 If you are trying to find the dose at

 

       which the risk of a reaction, given you are

 

       allergic, which is what I thought we were trying to

 

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

 

       consumers?

 

                 DR. CREVEL:  Well, you need to know the

 

       prevalence of the condition within the population.

 

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

 

       because I mentioned validation as well as

 

       prediction in this particular context actually.

 

                 For validation, you certainly need to know

 

       how many reactions are occurring in order to see

 

       whether the model actually predicts the numbers of

 

       reaction which you are actually observing.

 

                 I mean, this is a big data gap at the

                                                                188

 

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

 

       and certainly not in Europe do we have data on

 

       actually the number of reactions that do occur.

 

       Certainly, we do not have any information on the

 

       total number of severe reactions or less severe

 

       reactions.

 

                 DR. BRITTAIN:  You mean the number of

 

       reactions that occur across a population as opposed

 

       to your study?

 

                 DR. CREVEL:  Yes.  No, across a

 

       population, sorry.  Sorry, that was in the

 

       population, sorry, yes.

 

                 CHAIRMAN DURST:  Any further discussion or

 

       questions?

 

                 (No verbal response.)

 

                 CHAIRMAN DURST:  If not, thank you very

 

       much, Dr. Crevel.

 

                 Our final speaker for this morning's

 

       session is Dr. Steve Taylor.  He is the Maxcy

 

       distinguished professor and director of the Food

 

       Allergy Research and Resource Program at the

 

       University of Nebraska, who will discuss Food

                                                                189

 

       Allergen Thresholds.

 

                         FOOD ALLERGEN THRESHOLDS

 

                 DR. TAYLOR:  Well, I would like to thank

 

       the Food and Drug Administration for giving me the

 

       opportunity to make a presentation to this panel.

 

       There are advantages and disadvantages to being the

 

       last speaker of the morning.  Much of what you are

 

       going to see on my slides may just be a reemphasis

 

       of some things that have already been said.

 

                 I think I got a rather difficult topic,

 

       also by being the last one on the agenda, because

 

       I'm supposed to talk about uncertainty factors,

 

       what are uncertainty factors and how are they

 

       derived and what is the underlying scientific

 

       rationale for such a factor.  I only wish I thought

 

       I knew the definitive answers to all of those

 

       questions.

 

                 (Slide.)

 

                 DR. TAYLOR:  I think the National Academy

 

       of Sciences outlined risk assessment approaches a

 

       number of years ago, and I always like to start

 

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

                                                                190

 

       discuss all of these different points, because I

 

       think that the same assessment can be used for food

 

       allergens as is used for pesticide residues and

 

       food additives and other things.  This is a very

 

       robust risk assessment approach.

 

 

                 (Slide.)

 

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

 

       few things on this slide today, and one is

 

       dose/response evaluation.  I have been thinking

 

       about this issue for probably 30 years.

 

                 This is one of the earliest slides that I

 

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

 

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

 

       more now than we knew when I wrote this slide a

 

       long time ago.

 

                 Trace amounts can elicit reactions.  I

 

       would argue that the severity of the response is

 

       directly related to the dose.  The higher the dose,

 

       the more severe the response.

 

                 I would agree that individuals can have

 

       different responses on different days to the same

                                                                191

 

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

 

       as dramatically different, or at least I would say

 

       that is an unproven point regarding some of the

 

       things that have been said this morning.

 

                 There are a lot of assumptions that are

 

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

 

       to identify all of the assumptions and question

 

       them.

 

                 Stefano Luccioli made a good point, that

 

       individuals vary widely in their degree of

 

       sensitivity in these controlled challenge studies a

 

       millionfold.  I completely agree with that.  That

 

       is kind of amazing in itself.

 

                 The big question is, How much is too much?

 

       The food industry has been focusing on trying to

 

       get an answer to this question for a long time for

 

       some of the reasons that Dr. Crevel just pointed

 

       out.

 

                 (Slide.)

 

                 DR. TAYLOR:  I think there is another part

 

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

 

       kind of pointed it out in his presentation.  It is

                                                                192

 

       the exposure assessment piece of the equation.

 

                 How frequently are food products

 

       contaminated with potentially hazardous levels of

 

       unlabeled allergens, and how frequently do

 

       food-allergic consumers suffer reactions?  We

 

       really don't know that part very well.  Only

 

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

 

       methodology necessary to determine with any degree

 

       of confidence how frequently food products might be

 

       contaminated and at what levels.

 

                 (Slide.)

 

                 DR. TAYLOR:  Gil Houben from TNO [The

 Netherlands Organization] prepared

 

       this slide, and I always like to steal good slides

 

       from speakers that I invite to be on programs.  I

 

       think this kind of pictorially describes the

 

       situation that exists.

 

                 We have food products in the marketplace

 

       that contained for one reason or another some level

 

       of undeclared allergen.  This may be from

 

       cross-contact, this may be from use of ingredients

 

       derived from commonly allergenic foods that are

 

       processing aids and historically haven't been

                                                                193

 

       labeled in most countries.

 

                 Then, we have individual thresholds for

 

       clinical response that varied by a millionfold as

 

       Dr. Luccioli pointed out.  There is an intersection

 

       here between products that have enough undeclared

 

       allergens that at least the most sensitive

 

       individuals have some probability of reacting to

 

       those.

 

                 If I was going to draw this slide myself,

 

       I would lengthen the tail of this curve because we

 

       know from analytical studies that there are

 

       products in the marketplace that are quite

 

       hazardous for these individuals containing

 

       comparatively higher levels of allergens that

 

       provoke severe reactions.  Dr. Hefle showed some of

 

       those data today.

 

                 (Slide.)

 

                 DR. TAYLOR:  I wanted to say just a little

 

       bit about the different kinds of clues that we can

 

       have for determining allergen thresholds.  Stefano

 

       already pointed this out, too.

 

                 Probably the best data we have comes from

                                                                194

 

       double-blind, placebo-controlled food challenges or

 

       clinical threshold experiments using double-blind,

 

       placebo-controlled food challenges and

 

       immunotherapy trials that also use challenge data.

 

                 (Slide.)

 

                 DR. TAYLOR:  I actually don't think that

 

       allergen cross-contact episodes turn out to be very

 

       useful in determining thresholds, and I wanted to

 

       emphasize that point, because there is a lot of

 

       anecdotal material in the clinical literature about

 

       these cross-contact episodes.

 

                 A lot of them are deficient, because the

 

       analytical methods used to detect the residues in

 

       those studies were probably not as accurate as the

 

       methods that Dr. Hefle described in her

 

       presentation, the methods that we have had for the

 

       last few years.  There is often a lot of lacking

 

       information in the investigation of these studies.

 

                 (Slide.)

 

                 DR. TAYLOR:  As I pointed out, this

 

       question of how much is too much has intrigued out

 

       group for a long time in the food allergy research

                                                                195

 

       and resource program.

 

                 I want to point out that we are funded by

 

       the food industry.  We have more than 40-member

 

       companies scattered around the world.  We began to

 

       focus on the threshold question in earnest in the

 

       mid-1990s and beyond.

 

                 (Slide.)

 

                 DR. TAYLOR:  We have held a series of

 

       threshold conferences.  The first one was held in

 

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

 

       and it is really hard to summarize it in 15 minutes

 

       or less.

 

                 I will point out the fact that the results

 

       of the First Threshold Conference have largely been

 

       published in the peer reviewed, scientific

 

       literature.

 

                 The question we asked at the First

 

       Threshold Conference is we invited a number of

 

       clinicians from around the world to come to South

 

       Carolina, because we thought that perhaps they had

 

       information on low-dose challenge trials.

 

                 When you hear studies of the kind that

                                                                196

 

       Dr. Wood reported this morning, recognize that most

 

       diagnostic challenges start at 400 to 500

 

       milligrams.

 

                 No wonder some people have severe

 

       reactions at those dose levels, because those are

 

       quite high in my opinion.  We were interested in

 

       clinicians who sometimes, because of the patient's

 

       history, started the challenge at a much lower

 

       level.

 

                 (Slide.)

 

                 DR. TAYLOR:  What did we find out?  We

 

       found out that there was considerable data on

 

       low-dose challenges for peanut, egg and milk in

 

       particular and more scattered data for some of the

 

       other foods.

 

                 The data were really hard to evaluate

 

       because of the lack of standardized protocols.  I

 

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

 

       provoking dose -- we had 306 patients for peanut,

 

       281 patients for egg, and 299 for milk.  These

 

       physicians brought this data to this conference.

 

                 (Slide.)

                                                                197

 

                 DR. TAYLOR:  The lowest provoking dose for

 

       peanut was about 1 milligram of peanut, which is

 

       .25 milligrams of peanut protein.  However, I have

 

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

 

       weekend in the conference room trying to figure out

 

       what the doses were in these challenge trials,

 

       because the physicians don't calculate that,

 

       particularly carefully in some cases.

 

                 Our personal favorite is the physician

 

       that used a drop of peanut butter as his lowest

 

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

 

       tried to figure out how much that actually was.

 

       These data look really finite when you show them

 

       this way, but there is a lot of glorified

 

       guesswork.  I just want you to understand that.

 

                 (Slide.)

 

                 DR. TAYLOR:  We determined that minimal

 

       eliciting doses or threshold doses do exist for

 

       commonly allergenic foods, that the threshold doses

 

       are finite, measurable and above zero.

 

                 However, it was really difficult to reach

 

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

                                                                198

 

       about 20 clinicians at this conference, and we did

 

       not reach consensus on what threshold doses should

 

       be.

 

                 In fact, for most of them this was their

 

       first introduction to this concept.  We had to

 

       teach them what NOAELs and LOAELs were.  They make

 

       risk assessments every day but not these kind.

 

                 (Slide.)

 

                 DR. TAYLOR:  We also found that reactions

 

       occur to hidden or undeclared allergens in foods.

 

       No big surprise there.  However, severe reactions

 

       to undeclared allergens tended to occur at higher

 

       dose levels.

 

                 We also determined that at least in these

 

       populations with these low-challenge doses that

 

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

 

       mild reversible symptoms.

 

                 (Slide.)

 

                 DR. TAYLOR:  The Second Threshold

 

       Conference was held in 2002 and was geared to

 

       address the biggest concern we had from the first

 

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

                                                                199

 

                 (Slide.)

 

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

 

       the consensus protocol other than to indicate that

 

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

 

       ongoing low-dose challenge trials underway around

 

       the world using this protocol or slight variations

 

       of it.

 

                 As Dr. Luccioli pointed out, most of those

 

       haven't been published yet because it takes a year

 

       to two years to do these studies to find the number

 

       of subjects to enroll in these studies.

 

                 (Slide.)

 

                 DR. TAYLOR:  We did have the Third

 

       Threshold Conference where we tried to determine

 

       what you do with the data once you collect it.

 

                 (Slide.)

 

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

 

       much, because much of it relates around the

 

       modeling stuff that Rene Crevel already described.

 

       Because the binomial approaches are just plain

 

       difficult, because it is very difficult to identify

 

       even 29 soybean-allergic individuals in the world

                                                                200

 

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

 

       there, and we know how hard it is.

 

                 It is easier to do peanut trials than

 

       perhaps others.  It is hard to do milk and egg

 

       because young children outgrow their allergies, so

 

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

 

       patient, still has the allergy that you are looking

 

       for.

 

                 (Slide.)

 

                 DR. TAYLOR:  There were a number of

 

       advantages to modeling.  I think Rene pointed those

 

       out.  I will just make the point that the consensus

 

       of the group was that you could do modeling.  Of

 

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

 

       are going to use.

 

                 Maybe we haven't validated them yet so we

 

       don't exactly know; however, using this lower

 

       confidence interval as the threshold might be a

 

       reasonable approach to consider.

 

                 (Slide.)

 

                 DR. TAYLOR:  Well, classical risk

 

       assessment involves determining the NOAEL for a

                                                                201

 

       food additive or a pesticide residue or something

 

       like that and dividing it by 100.

 

                 Classically, tenfold is for extrapolation

 

       from animals to humans, and tenfold is for

 

       intraindividual variation.  Consequently, what

 

       uncertainty factor should we use?

 

                 (Slide.)

 

                 DR. TAYLOR:  For allergens, since you have

 

       human subjects that can be used, the ideal thing

 

       would be to determine the no observed adverse

 

       effect level for specific allergenic foods among a

 

       human population that is allergic to that food, and

 

       then apply an uncertainty factor to get your

 

       threshold dose.

 

                 (Slide.)

 

                 DR. TAYLOR:  To do that with any degree of

 

       confidence, you have to challenge a fairly large

 

       number of allergic individuals.  You would have to

 

       identify the NOAEL for each patient.

 

                 You would probably also have to identify

 

       the LOAEL for each patient to prove the person is

 

       still allergic to the food that is under

                                                                202

 

       consideration.

 

                 It would be good to determine the

 

       variation between individuals in NOAELs because it

 

       is probably a millionfold.  A standardized protocol

 

       would be handy so that you didn't have uncertainty

 

       about the differences in protocols.

 

                 (Slide.)

 

                 DR. TAYLOR:  There is no animal to human

 

       extrapolation needed for food allergy

 

       considerations because we have human data.  We have

 

       already selected a sensitive subpopulation of the

 

       human population.

 

                 The question arises, Did we include the

 

       most sensitive individual?  I think that is an

 

       important consideration for this panel.  We have

 

       heard several speakers say, "Well, maybe we have

 

       not."

 

                 My argument is that perhaps in terms of

 

       representing the whole allergic population to a

 

       particular food we have actually excluded the other

 

       end of the dose distribution curve, and we actually

 

       have included a number of people from the most

                                                                203

 

       sensitive subpopulation.

 

                 (Slide.)

 

                 DR. TAYLOR:  I want to point to this study

 

       again.  People have interpreted this study as a

 

       publication involving the dose distribution for the

 

       whole food-allergic group allergic to peanuts,

 

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

 

       the most sensitive individuals in clinical

 

 

       population.

 

                 (Slide.)

 

                 DR. TAYLOR:  Well, how much data is out

 

       there?  Is there enough data to make your

 

       decisions?  I think there can be if you can wrestle

 

       with the uncertainty factors and the differences in

 

       protocols from one study to another.

 

                 I just went through what I think is the

 

       most relevant literature.  Some of these are in

 

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

 

       the back that somebody very laboriously put

 

       together.  I think they actually found most of the

 

       relevant studies.

 

                 I congratulate them for that, because that

                                                                204

 

       is not particularly easy to do.  I went through

 

       those studies and added up the number of patients

 

       that are in each one of these studies that were

 

       subjected to double-blind, placebo-controlled food

 

       challenges and for which a published LOAEL exists.

 

                 Now, there are lots of differences in

 

       protocols, so there are uncertainty factors with

 

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

 

       What you can see is there are lots of subjects.

 

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

 

       2002 paper, and that is because that is not

 

       original data.  Some of those patients may also

 

       appear in some of the other studies.  We got

 

       concerned about whether to count them twice.

 

                 (Slide.)

 

                 DR. TAYLOR:  This is for egg.

 

                 (Slide.)

 

                 DR. TAYLOR:  This is for milk.

 

                 (Slide.)

 

                 DR. TAYLOR:  We have got a lot of data

 

       points.  What are the uncertainty factors?  Well,

 

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

                                                                205

 

       Many of the studies have been done on pediatric

 

       populations; fewer studies have been done on

 

       adults.  You can do challenge trials on both of

 

       those.  A lot of the diagnostic challenge trials

 

       are done on infants, but they are not done in

 

       threshold study types of experiments.

 

                 (Slide.)

 

                 DR. TAYLOR:  You've got the problem with

 

       the nature of the challenge material and the

 

       allergen content of that challenge material.  This

 

       is again from our 2002 study from Threshold 1.

 

                 You can see the number of different

 

       materials: ground peanut, peanut flour, peanut

 

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

 

       dried whole egg, and raw versus cooked for most all

 

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

 

       milk and even infant formula as the milk challenge

 

       materials.

 

                 In many of these cases, the physicians

 

       didn't determine the protein content of the

 

       challenge materials, so you've got to make

 

       glorified guesses.  There are uncertainties about

                                                                206

 

       the challenge materials.

 

                 (Slide.)

 

                 DR. TAYLOR:  I would argue that studies

 

       should be compared using protein content.  This

 

       failure to provide that data makes the evaluations

 

       really difficult.  If the protein content of the

 

       challenge material was not determined or cannot be

 

       determined using reliable data in the literature,

 

       then the study probably has to be rejected from

 

       consideration by groups like this.

 

                 There are well-characterized challenge

 

       materials like non-fat dry milk, dried egg white

 

       and soy flour that I think you can assume what the

 

       protein level is based on standardized industry

 

       data.  Thresholds should be established in terms

 

       that can be related to analytical methods like

 

       milligrams of food or milligrams of food protein.

 

                 (Slide.)

 

                 DR. TAYLOR:  There are also issues related

 

       to blinding that Stefano already talked about.

 

       Some clinicians use labial challenges.  They put a

 

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

                                                                207

 

       That is often used for young infants.

 

                 I think that is particularly difficult to

 

       interpret what the dose was.  However,

 

       diagnostically it is good procedure, but otherwise

 

       it is kind of difficult to figure out what was

 

       going on.  Then, there is the choice of dosages

 

       used for the challenges.

 

                 Probably the biggest uncertainty is this

 

       issue of the fact that most of the publications

 

       were done for diagnostic purposes, and so when you

 

       look at the published literature you get the LOAEL

 

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

 

       NOAELs are clinically available; they are just not

 

       published.

 

                 There is more uncertainty in using a LOAEL

 

       rather than a NOAEL to established threshold doses;

 

       there is patient selection criteria; exclusion of

 

       people on probably both ends of the curve; and

 

       there is variability in individual threshold doses.

 

                 Diagnostic challenges tend to report only

 

       the LOAELs; the NOAELs in some cases may not be

 

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

                                                                208

 

       study, in many cases the patient reacted to the

 

       lowest dose administered.

 

                 However, if it was 400 or 500 milligrams,

 

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

 

       lot of uncertainty if you use that as your LOAEL to

 

       try to try and figure out what the threshold dose

 

       might be.  You are much better off to focus on

 

       lower dose challenges where there is less

 

       uncertainty even if you have to use the LOAEL.

 

                 How far above the NOAEL is the LOAEL; and

 

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

 

       think that is the question that they wanted me to

 

       try to answer.

 

                 (Slide.)

 

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

 

       answer it.  If the LOAEL is based on subjective

 

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

 

       have to be very concerned about uncertainty

 

       factors, because in the limited experiences that

 

       exist in the literature there is a ten- to a

 

       hundredfold variations between the doses that begin

 

       to provoke subjective symptoms and the doses that

                                                                209

 

       tend to provoke objective signs.  I learned

 

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

 

                 Now then, if you have a LOAEL based on

 

       objective reactions, what uncertainty factors

 

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

 

       to have very careful expert analysis of the

 

       clinical study you are looking at.

 

                 I could argue that if you looked at one of

 

       these clinical threshold trials that have been done

 

       using microgram and low-milligram dose level, that

 

       you could use a very low uncertainty factor.

 

                 However, if you are going to rely on

 

       publications like Perry, et al., from 2004 where

 

       you only have data on the reactions that occur at

 

       the lowest diagnostic challenge dose and it is 400

 

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

 

       uncertainty factor because you could be a long ways

 

       above the NOAEL.

 

                 I don't know what you would do in this

 

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

 

       actually think those kinds of studies are not very

 

       helpful.