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

 

 

 

 

 

 

 

Friday, July 15, 2005

 

8:00A.M. to 9:45 A.M.

 

 

 

 

Greenbelt Marriott

6400 Ivy Lane

Grand Ballroom

 

Greenbelt, Maryland 20770

 

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

 

       FOOD ADVISORY COMMITTEE STANDING MEMBERS:

 

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

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

       Patrick S. Callery, Ph.D.

       Dennis Gonsalves, Ph.D., M.S.

       Jean M. Halloran (Consumer Representative)

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

       Margaret C. McBride, M.D.

       Mark Nelson, Ph.D. (Industry Representative)

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

 

       TEMPORARY VOTING MEMBERS:

 

       Petr Bocek, M.D., Ph.D.

       Margaret Briley, Ph.D., R.D.

       Erica Brittain, Ph.D.

       Ciaran P. Kelly, M.D.

       Soheila June Maleki, Ph.D.

       David O. Oryang

       Marc D. Silverstein, M.D.

       Suzanne Teuber, M.D.

 

       FOOD AND DRUG ADMINISTRATION:

 

       Robert E. Brackett, Ph.D. - Director

       Food and Drug Administration, CFSAN

 

       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

 

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

 

       FOOD AND DRUG ADMINISTRATION STAFF:

 

       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

 

                             C O N T E N T S

 

                                                                                                   PAGE

Call to Order and Welcome and Introductions                5

 Richard Durst, Ph.D., Acting Chairman                   

 

Welcome                                                                                  6

Robert E. Brackett, Ph.D., Director, CFSAN, FDA            

 

Committee's Discussion and Response to                             7

FDA's Charge and Questions                                  

 

Closing Comments                                                                    85       

Michael M. Landa, J.D., Deputy Director

Regulatory Affairs, CFSAN, FDA                            

 

Adjournment                                                                              87                                          
 

 

                          P R O C E E D I N G S

 

Call to Order and Welcome and Introductions

 

                 CHAIRMAN DURST:  I would like to convene

 

       the final session of our committee meeting this

 

       morning.  Let me begin by again stating that there

 

       are the conflict of interest statements over on the

 

       side table for anyone who wants to avail themselves

 

       of that information.

 

                 Also, rather than waiting for the very

 

       last minute to thank the various people who made

 

       this meeting possible, I just wanted to thank

 

       Marcia and her staff for taking such good care of

 

       us and providing all of the information we needed

 

       to have a successful meeting.

 

                 I also want to thank the USDA Graduate

 

       School for providing support and the Marriott Hotel

 

       of course for providing very nice facilities to do

 

       this work.

 

                 In addition, I would also like to take the

 

       opportunity to introduce Dr. Robert Brackett, who

 

       is the director of the Center for Food Safety &

 

       Applied Nutrition, who was able to join us for a

 

       couple of hours this morning.

 

                 Bob, if you want to say a few words?

 

                                 Welcome

 

                 DR. BRACKETT:  Thanks, Dick.

 

                 The only thing I wanted to say -- I know

 

       you are all in a hurry to get things done and get

 

       to your airplanes this morning, too -- I had hoped

 

       to be here for more of the meeting this week, but I

 

       have been stuck at other meetings.  However, I do

 

       want to let you know how supportive I am of the

 

       advisory committee structure.

 

                 I served on this Committee a number of

 

       years ago, and I know that it is a big time

 

       commitment and there is a lot of studying to be

 

       done, a lot of discussion, so FDA really does

 

       appreciate your participation and your expertise.

 

                 This is something I think that has more

 

       value added to it for us than we could have gotten

 

       individually and breadth of knowledge, and so I do

 

       thank you also.

 

                 I would also like to extend that I hope

 

       that you will continue.  I hope that you will tell

 

       your colleagues, when they are asked to serve on

 

       this Committee, that this is something that they

 

       really do provide a great service to the country

 

       and to the regulated industry that we deal with.

 

                 With that I will let you conclude your

 

       meeting this morning, and thank you for being here.

 

                 CHAIRMAN DURST:  Thank you, Bob.

 

                 Yes?

 

                 DR. TEUBER:  I found out, in my rush to

 

       get over here, one page is still on the printer at

 

       the concierge desk.  If there is a Marriott staff

 

       person who could pick up the third page from the

 

       printer, behind the concierge desk, that would be

 

       fantastic.  It is a printout of just a draft of our

 

       summary here.

 

                  Committee's Discussion and Response to

 

                        FDA's Charge and Questions

 

                 CHAIRMAN DURST:  Okay.  Thanks, Suzanne.

 

                 I assume I don't have to read the charge

 

       again, since we know what we are here for.  We have

 

       been dealing with this for two days now.

 

                 To remind you, we don't have to come up

       with, certainly, a vote.  We don't even have to

 

       come up with a consensus.  What we want to do is

 

       provide the FDA with some guidance and

 

       recommendations on the draft report that we have

 

       been discussing the past two days.

 

                 I have asked several members of the

 

       Committee to try to summarize the remarks or

 

       comments and discussion that has gone on for the

 

       past two days.

 

                 I have asked Marc and Suzanne to summarize

 

       the food allergens part of our first day of

 

       discussions and Ciaran to summarize the celiac

 

       disease, the gluten portion.

 

                 After their presentations, we will open it

 

       for discussion to make any comments agreeing,

 

       disagreeing or just filling in some blanks that

 

       they think are important.

 

                 Then, after that part, we will go back and

 

       deal with the general questions that are on the

 

       charge sheet.  That I think should go fairly

 

       quickly after we have agreed on some of the other

 

       items that we are going to discuss.

 

                 Even though it is out of order, maybe we

 

       will start with Dr. Kelly with the discussion of

 

       gluten, since we are waiting for the page on the

 

       food allergens.

 

                 Ciaran.

 

                 DR. KELLY:  Sure.  Ciaran Kelly here.

 

       Should I read the questions, or just go straight to

 

       the answers?

 

                 DR. TEUBER:  Yes, please.

 

                 DR. KELLY:  So the first question is

 

       regarding gluten and celiac disease.  Is there a

 

       distinct subpopulation of individuals with celiac

 

       disease that have an increased sensitivity to

 

       gluten?

 

                 If so, for the safety-assessment-based

 

       approach, is the proposed uncertainty factor for

 

       intraspecies differences tenfold sufficient to

 

       ensure that exposure levels will be below the level

 

       of sensitivity for this highly sensitive

 

       subpopulation?  If this uncertainty factor tenfold

 

       is not sufficient, what uncertainty factor should

 

       be used?

 

                 Sensitivity to gluten does vary from one

 

       individual to another at the level of clinical

 

       symptoms.  However, symptoms of celiac disease do

 

       not parallel small intestinal mucosal injury as

 

       assessed by small bowel biopsy histology, which is

 

       the widely accepted quantitative method of

 

       assessing gluten-induced injury in celiac disease.

 

                 There are insufficient available data to

 

       state with any certainty or to what extent

 

       individual variations influence the intestinal

 

       mucosal changes of celiac disease in response to

 

       specific levels of gluten exposure.  Thus, it is

 

       not possible currently to assign a reliable

 

       uncertainty factor for intraspecies differences in

 

       gluten sensitivity.

 

                 The Committee is uncertain as to whether

 

       or not it is appropriate to apply an uncertainty

 

       factor for intraspecies variation in the

 

       immunological responses to gluten and celiac

 

       disease that is based on the standards normally

 

       used for toxicology studies.

 

                 The magnitude of the uncertainty factor

 

       will also be influenced by the level of individual

 

       variation observed in the studies used to determine

 

       that threshold.  The choice of an uncertainty

 

       factor for a dietary gluten threshold will also be

 

       influenced by the ability to measure the gluten

 

       content of foods.

 

                 It is likely that the gluten threshold

 

       together with a modest or moderate uncertainty

 

       factor will lie close to the lower limits of

 

       performance of the currently available assays and

 

       this may, at least in the short-term, dictate the

 

       measurable threshold.

 

                 CHAIRMAN DURST:  Okay.  Does anyone have

 

       any comments or discussion on Ciaran's presentation

 

       on that question?

 

                 (No response.)

 

                 CHAIRMAN DURST:  I guess most people are

 

       in agreement on that.  Very good.

 

                 DR. KELLY:  The second question:  Is it

 

       scientifically sound to use data from short-term

 

       clinical studies that evaluate the effects of acute

 

       gluten exposure to predict the effects of long-term

 

       gluten exposure in gluten-sensitive individuals?

 

                 What uncertainty factor is appropriate for

 

       thresholds developed using available short-term

 

       clinical studies in order to prevent adverse

 

       effects associated with chronic effects.

 

                 Data from acute challenge studies that

 

       examine intestinal mucosal changes in response to

 

       brief exposure to gluten peptides of several hours

 

       or days' duration are not widely accepted as a

 

       valid method to determine a gluten threshold.

 

                 However, there is general acceptance in

 

       the medical and scientific community of studies

 

       that examine mucosal responses to several weeks or

 

       months of exposure.

 

                 If threshold values are based on challenge

 

       studies that examine in a quantitative fashion the

 

       mucosal responses to several weeks or months of

 

       gluten exposure, then the uncertainty factor needed

 

       for chronic exposure will be minimal.

 

                 Additional valuable data are also

 

       available from other countries, particularly in

 

       Europe, that have many years of experience with

 

       enacted threshold values.  Those data may also

 

       reduce concerns regarding the need for an increased

 

       uncertainty factor based on prolonged duration of

 

       gluten exposure.

 

                 Since a determination of threshold values

 

       must be made in the context of incomplete and

 

       evolving medical and scientific knowledge, the

 

       Committee endorses the Working Group's finding that

 

       any threshold value that may be set for gluten must

 

       be continually reevaluated, and, if new information

 

       warrants, be adjusted.

 

                 CHAIRMAN DURST:  Erica.

 

                 DR. BRITTAIN:  Okay.  I guess I just want

 

       to summarize.  I have a slightly different

 

       perspective on this.  I don't think my bottom line

 

       is really that different.  But from a statistical

 

       perspective, it is hard for me to know that a

 

       three-month exposure study would tell me everything

 

       about the cumulative, chronic exposure; so, I would

 

       be a little more uncertain than some of the people

 

       on the Committee were yesterday.

 

                 However, that concern is softened by the

 

       fact that we do have the observational data that

 

       seem to suggest a similar effect; so, I think my

 

       bottom line is probably pretty similar to yours,

 

       although maybe a little more uncertainty.

 

                 CHAIRMAN DURST:  Thank you.

 

                 Anyone else?

 

                 David.

 

                 MR. ORYANG:  Yes.  David Oryang.  I think

 

       your concern is well-taken.  I think the key thing

 

       here is to remember that if it is clearly

 

       documented or at least if evidence documents how we

 

       came about determining that safety factor, that is

 

       the key thing.

 

                 As long as it is documented and

 

       transparent, then people will be able to comment on

 

       it or provide better information to determine

 

       better safety factors.

 

                 The clear thing is that there should be a

 

       good documentation of how the safety factor came

 

       about.  I think that is the key so that experts and

 

       others who review it can then give better comments

 

       or suggestions on how to improve it, if it doesn't

 

       seem right.

 

                 CHAIRMAN DURST:  Okay.  Thank you.

 

       Any other comments?

 

       (No response.)

 

                 CHAIRMAN DURST:  I guess we can proceed.

 

       Ciaran.

 

                 DR. KELLY:  The third question:  Are

 

       current data sufficient to conclude that a portion

 

       of celiac patients are or are not also susceptible

 

       to gluten proteins naturally occurring in oats,

 

       i.e., prolamines and glutelins, if not, what

 

       additional data is needed to draw such a

 

       conclusion?

 

                 Published data indicate that the majority

 

       of individuals with celiac disease do not

 

       demonstrate significant symptoms or signs in

 

       response to oats.

 

                 A meta-analysis of these published studies

 

       may serve to strengthen this conclusion.  There are

 

       a very small number of documented cases where

 

       individuals with celiac disease showed an

 

       immune-based response to oat proteins.

 

                 However, the low frequency of these

 

       reports indicate that the overall approach to

 

       setting a threshold for gluten should not be unduly

 

       influenced by the relatively minor concern

 

       regarding oat-sensitivity.  Of greater concern is

 

       the issue of cross-contact leading to low-level

 

       contamination of foodstuffs with the known toxic

 

       gluten proteins.

 

                 CHAIRMAN DURST:  Thank you.

 

         Comments?

 

         (No response.)

 

                 CHAIRMAN DURST:  Good.  Thank you.

 

                 DR. MALEKI:  Well, I have one.

 

                 CHAIRMAN DURST:  Oh, I'm sorry.

 

                 DR. MALEKI:  Soheila Maleki.  Just one

 

       comment.  The other concern that I think wasn't

 

       mentioned is that limiting the food choices of the

 

       people that are celiacs is probably self-included.

 

       I just wanted to mention that.

 

                 CHAIRMAN DURST:  Okay.

 

                 DR. KELLY:  Then, the fourth question:

 

       Are all individuals with celiac disease equally at

 

       risk for developing consequences -- for example,

 

       cancer -- and increased mortality from the

 

       long-term ingestion of gluten?

 

                 Are current data from clinical studies or

 

       from individuals with celiac disease on a

 

       gluten-restricted diet sufficient to estimate the

 

       magnitude of any increased risk of mortality for

 

       these individuals?

 

                 The outcomes of celiac disease vary

 

       widely, from lifelong silent disease to fatal

 

       malignancy.  However, at this time the only

 

       identified risk factor for bad outcomes, including

 

       death from malignancy, is poor or absent compliance

 

       with a gluten-free diet.

 

                 Prolonged, strict adherence to a

 

       gluten-free diet clearly reduces the risk for

 

       gastrointestinal symptoms and nutritional

 

       deficiency states such as anemia and osteoporosis

 

       and celiac disease.

 

                 The available data, though limited and

 

       imperfect, indicate that prolonged, strict

 

       adherence to a gluten-free diet also reduces the

 

       risk for malignancy.

 

                 Thus, instituting measures that facilitate

 

       compliance with a strictly gluten-free diet are the

 

       only known approach to reduce the overall risks

 

       associated with celiac disease.

 

       Comments?  Questions?

 

       (No response.)

 

                 CHAIRMAN DURST:  Good job, keep going.

 

       (Laughter.)

 

                 DR. KELLY:  Question five:  Is

 

       evidence of minimal intestinal pathological change,

 

       for example, increased intraepithelial lymphocytes

 

       following a gluten challenge, an appropriate

 

       symptom upon which to base a LOAEL for long-term

 

       consequences?

 

                 Are other biomarkers such as clinical

 

       symptoms or more severe intestinal pathological

 

       changes more accurate predictors of long-term

 

       consequences?

 

                 Yes, the characteristic intestinal

 

       pathological changes of celiac disease, for

 

       example, reduced villus-to-crypt ratio and

 

       increased intraepithelial lymphocyte counts

 

       constitute the widely accepted gold standard for

 

       celiac disease diagnosis.

 

                 These changes are also widely accepted as

 

       the gold standard method for evaluating disease

 

       activity following a gluten challenge.  Other

 

       disease markers such as symptoms, antigliadin

 

       antibody, tissue transglutaminase or endomysial

 

       antibody levels, or measures of mucosal

 

       permeability are considered of secondary value in

 

       quantifying disease activity.

 

                 CHAIRMAN DURST:  Comments?

 

        (No response.)

 

                 CHAIRMAN DURST:  Very good, Ciaran.  Thank

 

       you very much.

 

                 I don't know, as far as what is allowed,

 

       may I ask the Threshold Working Group if they have

 

       any additional questions or clarifications they

 

       need on those points?

 

        (No response.)

 

                 CHAIRMAN DURST:  Well, we are moving,

 

       then.

 

                 Okay.  Suzanne and Marc, are you ready to

 

       present to your comments?

 

                 DR. TEUBER:  Okay.  Suzanne Teuber here.

 

       For this discussion, it turned out as we went

 

       through the questions that there were actually some

 

       that we did not specifically address in the

 

       Committee discussion, and so there will be

 

       discussion that is needed this morning in order to

 

       answer the charge

 

                 For the first question: are there distinct

 

       subpopulations of highly sensitive individuals

 

       within the allergic population for each of the

 

       major food allergens?

 

                 We know that there are huge differences in

 

       threshold doses and a continuum of reaction

 

       severity upon ingestion from mild to

 

       life-threatening for each of the major food

 

       allergens.

 

                 However, it is not possible at this time

 

       to identify "distinct" subpopulations of

 

       individuals by clinical criteria, previous

 

       frequency or severity of allergic reactions, or
 

 

       threshold responses on a double-blind,

 

       placebo-controlled, food challenge within

 

       populations sensitive to specific allergens for

 

       which thresholds or uncertainty factors can be

 

       identified.  That is number one.

 

        Any thoughts on that one?

 

        (No response.)

 

                 DR. TEUBER:  Okay.  Then, number two, I

 

       will hand over to Marc here.

 

                 CHAIRMAN DURST:  Erica.

 

                 DR. BRITTAIN:  Yes, I just want to add one

 

       comment.  In terms of all of these questions about

 

       the food allergies, from my statistical

 

       perspective, again, to me the first step here of

 

       when the Working Group actually is setting a

 

       threshold is to define what the precise goal of the

 

       threshold is; in terms of the sensitive population

 

       or the overall allergic population, what risk level

 

       is acceptable.  I think that is the first step.

 

                 DR. SILVERSTEIN:  Actually, these are

 

       additional comments under one, so why don't I

 

       continue with that.

                                                                 22

 

                 DR. TEUBER:  Okay.

 

                 DR. SILVERSTEIN:  The next part of the

 

       question of number one says:  "If so, for the

 

       safety-assessment-based approach, how to propose

 

       uncertainty factors for intraspecies differences

 

       10-fold, under severity of responses for this

 

       sensitive population tenfold, sufficient to ensure

 

       exposure levels will be below the level of

 

       sensitivity for the highly sensitive populations?"

 

                 The uncertainty factor for sensitive

 

       populations is unknown when considering food

 

       allergy and immune response as compared to classic

 

       safety assessment and toxicology.

 

                 The selection of an uncertainty factor for

 

       allergens should be informed by the distribution of

 

       the NOAELs and the LOAELs using measures of the

 

       spread of data such as standard deviation,

 

       interquartile range or ranges.

 

                 If reproducible, subjective responses in

 

       patients with a history of life-threatening

 

       anaphylaxis are included in setting LOAELs and

 

       NOAELs, the uncertainty factor might be lower than

 

       10.

 

                 The selection of thresholds for allergens

 

       should be informed by evidence of the thresholds of

 

       NOAELs and LOAELs.  However, as we mentioned, bias

 

       due to exclusion of the most sensitive individuals

 

       who have experienced life-threatening allergic

 

       reactions, anaphylaxis, require caution in using

 

       currently available data.

 

                 All currently available published and

 

       unpublished data should be specifically assessed

 

       for potential selection, referral bias, and other

 

       factors that influence the individuals who are

 

       actually studied.

 

                 There is also uncertainty due to variation

 

       between individuals in a population and uncertainty

 

       due to variation within individuals over time.

 

       There are inadequate prospective studies performed

 

       with the goal of seeing if the objective response

 

       thresholds have changed in patients with persistent

 

       food allergy, except in those who are expected to

 

       have developed a tolerance.

 

                 A highly sensitive individual might have a

 

       lower or higher LOAEL compared to baseline

 

       depending on such factors as: the season of year;

 

       theoretically, increased histamine release

 

       potential based on activity of conditions such as

 

       allergic rhinitis and asthma, which might be

 

       seasonal; status of an atopic dermatitis; the time

 

       of day; stability of the patient's underlying

 

       asthma; ingestion of other factors such as alcohol,

 

       exercise, pre- or post-ingestion, matrix effects of

 

       food, processing the food, progression of the

 

       degree of their allergy based on IgE target,

 

       epitope diversification, antibody increases, and

 

       other variables which are known to individuals in

 

       the field.

 

                 The next part of the question:  If these

 

       uncertainty factors are not sufficient, what

 

       uncertainty factors should be used for the

 

       safety-assessment-based approach?

 

                 A concrete number was not offered by the

 

       Committee.  The Committee noted that the

 

       uncertainty levels of tenfold or a hundredfold had

 

       been used in biomedical toxicology.  IgE-mediated

 

       allergic reactions essentially are amplifiers.

 

       They amplify reactions to minute amounts of

 

       allergens.

 

                 So, the application of uncertainty factors

 

       to thresholds on the double-blind,

 

       placebo-controlled, food challenge may not be

 

       sufficiently large to handle this variation of

 

       amplification of an allergic response.

 

                 DR. TEUBER:  That was the entirety of

 

       number one.

 

                 CHAIRMAN DURST:  I beg your pardon?

 

                 DR. TEUBER:  It was the entirety of number

 

       one; it is put out in sections.

 

                 CHAIRMAN DURST:  It is open for

 

       discussion.

 

                 Erica.

 

                 DR. BRITTAIN:  I agree with all that.  I

 

       just want to add one point that as an alternative

 

       to the uncertainty factors another strategy is the

 

       modeling approach that we heard the speaker talk

 

       about.  I think that is a really promising approach

 

       to assessing risk.

 

                 However, even with that, you would need to

 

       make sure that you have data that represents the

 

       entire target population.  I don't know that really

 

       is available at this point.

 

                 CHAIRMAN DURST:  Any other discussion?

 

        Mark.

 

                 DR. NELSON:  Yes, this is Mark Nelson.  I

 

       agree with your synopsis as well, and I think you

 

       have captured a lot of hours of struggle, but one

 

       thing I wanted to clarify.  I do agree that the

 

       uncertainty factors should be based on the range,

 

       the largest range possible, of the sensitive

 

       individuals.  But I heard, and correct me if I'm

 

       wrong, that some of the studies did in fact include

 

       some extremely sensitive individuals.

 

                 DR. TEUBER:  Yes, some did.  And then we

 

       also had the situation where in some studies the

 

       extremely sensitive people challenges were stopped

 

       at subjective which -- well, that was in some of

 

       the hazelnut study.

 

                 But for the Hourihane study, for instance,

 

       they did go on.  It was a twenty-fold difference in

 

       one patient, a fifty-fold difference in the other

 

       between a subjective response and an objective

 

       response.

 

                 DR. NELSON:  Right.

 

                 DR. TEUBER:  We definitely want things to

 

       be based on objective, when possible, but I am

 

       concerned that in the threshold studies that are

 

       going to be done by the consensus protocol there is

 

       still room for a physician or a patient to decide

 

       to stop.

 

                 I mean, they have the ability and informed

 

       consent procedures to stop at any time, and so if

 

       they are recruiting the most sensitive, we may have

 

       folks who back out before an objective response or

 

       where the physician decides, "Ah, you know, they're

 

       complaining of throat swelling, and I can't see

 

       anything, but I'm hesitant to go on."

 

                 There, that data of the subjective I think

 

       should be used.  It doesn't carry the weight of an

 

       objective NOAEL but certainly could be used to help

 

       estimate an uncertainty factor.

 

                 DR. NELSON:  Yes.  I don't mean at all to

 

       imply that people should be forced to participate

 

       in these studies or continue on, if subjectively

 

       they have lost comfort.  What I wanted to point out

 

       was that I understood that the database as it

 

       exists now, there are some studies that do have

 

       very sensitive individuals in them.

 

                 DR. SILVERSTEIN:  I think this is one of

 

       the most difficult -- this is a discussion point

 

       not a summary point -- issues is assessing

 

       potential bias.  There are of course in

 

       randomized-controlled trials a careful focus on

 

       eligibility an exclusion criteria.

 

                 In observational studies and in studies of

 

       diagnostic test assessment, the eligibility and

 

       exclusion criteria may or may not be as explicitly

 

       stated.

 

                 In any case, when a study does have

 

       well-stated eligibility and exclusion criteria, you

 

       often don't get a description of those people who

 

       are referred or screened and not studied.  Because

 

       they are not studied, you usually have less

 

       information.

 

                 Because this is a serious life-threatening

 

       condition, because these studies were done at

 

       distinguished academic centers by individuals who

 

       have distinct experience, to appear in such a study

 

       often you need to be referred; and so the referral

 

       bias, we are often not able to assess it.

 

                 The strongest studies are those that we

 

       would call "population-based studies."  Those would

 

       be the things you would want to look for.

 

       Oftentimes, that is not stated or it is only

 

       implicit in understanding that this study, as study

 

       subjects, the study subjects are often referred to

 

       as "the population," because we are making

 

       inferences about similar subjects.  But the study

 

       subjects, because of referral, weren't truly

 

       representative of the population of allergic

 

       individuals.

 

                 That is the concern, and that is the

 

       challenge the FDA will have in evaluating this

 

       literature, but it needs to be looked at for all

 

       available literature.

 

                 CHAIRMAN DURST:  Dick Durst.  I would also

 

       like to remind the Working Group that when they set

 

       these thresholds they also have to be cognizant of

 

       the analytical methods.

 

                 When you put on an uncertainty factor or a

 

       safety factor onto these thresholds, you have to be

 

       tempered by the knowledge of what analytical

 

       methods can do as far as verifying and making sure

 

       that foods comply to these thresholds.  At the

 

       present state of the art I think there are some

 

       problems in this respect, so that this has to be

 

       taken into consideration.

 

                 DR. TEUBER:  Suzanne Teuber.  When you go

 

       through the back of the binder and look at the

 

       different foods and the sensitivity and actually

 

       for the objective, quantitative measurements of

 

       what can be done, if an uncertainty factor is

 

       applied that is too large, you will be below those

 

       levels.  You end up then with the analytical method

 

       as the method of choice for some of these.

 

                 Additionally, if you consider, the Working

 

       Group should consider, that the serving size may be

 

       subject to discussion when you are determining how

 

       many parts per million may be acceptable.

 

                 I guess I really need to retract that.  It

 

       is just that based on clinical experience now so

 

       many patients go by that first subjective response

 

       in the mouth of having some tingling or some

 

       itching and have been able to stop -- I'm sure if

 

       Anne Munoz-Furlong were here she has thousands of

 

       stories of this; I have hundreds and hundreds.

 

                 So, the serving size where a person may

 

       notice a subjective response may be much smaller

 

       than the 100-gram serving size that may be used to

 

       calculate how many parts per million are going to

 

       be acceptable before a NOAEL with an appropriate

 

       uncertainty factor applied is reached.

 

                 CHAIRMAN DURST:  David.

 

                 MR. ORYANG:  Yes, David Oryang.  Just

 

       adding, I think, yes, if a safety factor is derived

 

       in a science-based way, even if the sensitivity is

 

       much greater than the sensitivity of any of the

 

       test methods.

 

                 I think it should be transparently

 

       communicated, and then the decision will be made,

 

       hopefully, at FDA as to how to resolve that, maybe

 

       through labeling and saying, well, it is clear that

 

       we don't have the methods to be able to detect that

 

       level, those parts per million that individuals are

 

       sensitive to.

 

                 I think the products could be labeled

 

       appropriately so that those at risk can make the

 

       choice whether or not to go ahead and take on that

 

       risk, but I don't think we can temper the science

 

       based on available methods, necessarily.

 

                 They are two different things: there are

 

       the safety issues and then how do we apply what we

 

       know.  If there is no method of applying or

 

       detecting that level of sensitivity, then it needs

 

       to be transparently presented, I think, as opposed

 

       to altering the safety factor so that it is within

 

       a range of detectability.

 

                 CHAIRMAN DURST:  Erica has a comment.

 

                 DR. BRITTAIN:  Yes.  This is touching on

 

       something that I tried to say yesterday, and I

 

       think I said it badly.  Let me take one more chance

 

       to try to say it again.  At some point the FDA will

 

       be establishing a threshold for each allergen.  I

 

       hope it will be a really safe and really

 

       conservative threshold.

 

                 Presumably, it will be above the level of

 

       detection.  It means there will be this gray zone.

 

       Some products will fall in the gray zones between

 

       the level of detection and the threshold that was

 

       set.

 

                 I am wondering if there would be any value

 

       in being able to provide that information to the

 

       consumer that this product say something like

 

       "contains peanuts but below the allergenic level."

 

                 So, that mom who was here on Wednesday who

 

       said, "I don't want this threshold based on a

 

       statistical estimate, I want it based on fact," if

 

       she does not want to take any chance at all, she

 

       can see, "Oh, it's in that gray zone, and I don't

 

       want to take any chance."

 

                 Or, if someone has had experience in the

 

       past with reactions in that gray zone, then they

 

       may think they are the rare individual that cannot

 

       tolerate that level.  I just wanted to throw that

       out one more time.

 

                 CHAIRMAN DURST:  Okay.  Carol and then

 

       Soheila.

 

                 DR. WASLIEN:  Well, one of the problems I

 

       see with the detection method is that we don't even

 

       know what the allergen is in a good number of

 

       cases, so having a good detection method may be

 

       detecting the wrong thing.  It is that kind of

 

       problem with detection methods, too, that lead to

 

       the uncertainty factor.

 

                 DR. TEUBER:  Suzanne Teuber.  I actually

 

       disagree with that.  Because if you have a method

 

       that is just aiming to detect the food, the

 

       proteins in the food that are allergens are going

 

       to track along with that measurement.  Just as the

 

       measurements for gluten, the glutelin fraction

 

       will track along with the gliadin fraction is

 

       measured.

 

                 If all of our tests so far that are

 

       measuring the food given are based on total

 

       protein, it all seems to track together in a

 

       proportionate way.  I think that is okay.

 

                 DR. WASLIEN:  You don't see a case where

 

       protein would be separated and only one of the

 

       protein fractions would be included in the food and

 

       therefore safe?

 

                 DR. TEUBER:  Well, yes, where you have

 

       casein used or alpha-lactoglobulin or whey as

 

       separate fractions.

 

                 DR. WASLIEN:  Yes.

 

                 DR. TEUBER:  There you do have a situation

 

       where the challenges that are done to determine the

 

       NOAELs and LOAELs have been with the whole protein.

 

       Actually, yes, I do see that as a potential

 

       problem, but the actual challenge dose that would

 

       elicit -- actually, yes, that is a good point, to

 

       think about the separation there.

 

                 DR. WASLIEN:  Yes, particularly with milk

 

       protein.

 

                 DR. TEUBER:  Yes.

 

                 CHAIRMAN DURST:  Okay.  Soheila and then

 

       Petr.

 

                 DR. MALEKI:  Soheila Maleki.  One comment

 

       for Erica.  Well, currently the gray area exists

 

       that is in "may contain" labeling.  You are asking

 

       for something that already exists that the consumer

 

       is asking to take away.  They want a more

 

       definitive response.

 

                 Second, there are analytical methods that

 

       can actually go down to measuring one molecule that

 

       is completely insignificant.  Like I said, on this

 

       tablecloth here somebody can detect peanut or

 

       wheat, if they wanted to.  You can go down to a

 

       molecular level, and washing won't get rid of it,

 

       that these people will not react to it.

 

                 There is a limit where allergic people

 

       will not react, and we do have the detection

 

       methods.  What happens is we don't have the

 

       threshold data on the individuals.

 

                 Still, the consumer is asking for us to

 

       make some kind of decision on the best data

 

       available.  I think that is something important to

 

       think about for the consumer, because that is why

 

       they are frustrated.

 

                 CHAIRMAN DURST:  Petr.

 

                 DR. BOCEK:  Petr Bocek.  Soheila pretty

 

       much said what I wanted to say because that would

 

       apply to every product to assess their methods.

 

       One would be saying, okay, this product doesn't

 

       have, let's say, peanut at the allergenic

 

       threshold, yet it contains.

 

                 Here you go, you are restricting the

 

       consumer from basically anything.  If you take the

 

       PCR, you are going to detect peanut everywhere.  So

 

       I think it is absolutely impossible to apply that

 

       method.  It has to be the allergenic threshold

 

       only.  That is what the consumer wants, and that is

 

       going to make it clear.  I absolutely agree with

 

       that.  I don't think it is practical.

 

                 CHAIRMAN DURST:  All right.

 

                 Mark.

 

                 DR. NELSON:  Mark Nelson.  Just to add to

 

       that from the practical standpoint of actually

 

       manufacturers labeling their products, we want to

 

       communicate clearly to the consumer.  We don't want

 

       to add anymore gray to it, to the situation at all.

 

                 If a threshold can be established where

 

       the great majority of allergic individuals for a

       particular allergen can be benefited by having

 

       that information, great, but we don't want to add

 

       to the gray.

 

                 CHAIRMAN DURST:  Thank you.

 

                 Any further discussion on this question?

 

                 (No response.)

 

                 CHAIRMAN DURST:  That was good.  The next

 

       question.

 

                 DR. TEUBER:  Number two:  “Is the initial

 

       objective response seen in a clinical challenge

 

       study always an adverse effect that poses risk to

 

       human health?,” is the first part of the question.

 

                 We said there was discussion of no, it is

 

       just uncomfortable, but then we kind of wrapped it

 

       up.  We were making comments at the end, so here is

 

       what we ended up writing.

 

                 "Yes, if there is an objective response to

 

       a food in a double-blind, placebo-controlled study

 

       performed in a patient with IgE-mediated food

 

       allergy, this is an adverse effect that poses risk,

 

       albeit usually low.

 

                 "The findings from an objective response

 

       in a double-blind, placebo-controlled, food

 

       challenge is sufficient for physicians to make

 

       recommendations that patients avoid specific foods

 

       and change lifestyle to avoid risk of

 

       life-threatening allergic responses.  This is

 

       sufficient to conclude that objective responses are

 

       associated with allergic reactions that pose risk

 

       to human health."

 

                 Any comment on that part of the questions?

 

                 DR. MALEKI:  Just one quick comment.

 

                 CHAIRMAN DURST:  Soheila.

 

                 DR. MALEKI:  Soheila Maleki, sorry.  One

 

       quick comment that, yes, the subject of milk came

 

       up and I think when Petr and I were making

 

       comments on that we were thinking instead of just

 

       "to human health," we were thinking

 

       "life-threatening."  That is why we said no.  I

 

       agree, I believe that we can forward your response.

 

                 DR. TEUBER:  Okay.  Is it scientifically

 

       sound to use this response to determine a LOAEL in

 

       the absence of a NOAEL?  We said no, reactions to

 

       the first dose, because that was implied in the

 

       question, mean that the LOAEL could be just a trace

 

       lower or conceivably a thousand-fold lower.  Such

 

       data are not useful in the decision-making process.

 

                 Then, the next part of the question:  For

 

       the safety-assessment-based approach, is the

 

       proposed uncertainty factor of tenfold sufficient

 

       and appropriate to use in the absence of a NOAEL?

 

       We said no, such data should not be used at all.

 

                 Then, more on that question:  If a

 

       clinical challenge study reports a subjective

 

       response of a lower dose than the dose that caused

 

       an objective response, should that observation be

 

       taken into account when determining the appropriate

 

       uncertainty factor?

 

                 Again, we have extremely limited data on

 

       subjective responses and the relationship to

 

       objective at this point.  We said yes, if using a

 

       subjective response as the LOAEL, the uncertainty

 

       factor would be lower.

 

                 If using the objective response but

 

       subjective responses were also recorded, the

 

       uncertainty factor -- and this is a point that we

 

       can discuss more today -- should probably extend to

 

       cover the dose at which the subjective response

 

       occurred and likely a bit further to account for

 

       the individual variation.

 

                 I might like to stop right there, because

 

       we did not actually specifically discuss that.  As

 

       we were coming up with this, we wrote that.  Again,

 

       our whole point is that we want the LOAELs to be

 

       based on objective data.

 

                 However, if you have subjective data as

 

       well, which the consensus protocol for threshold

 

       studies they are now going to be recording this

 

       subjective data, this might be very useful in

 

       judging what these uncertainty factors should be.

 

       I had put here that the factor should actually

 

       extend a bit below that.  That was without any

 

       discussion yesterday.

 

                 How do you all feel about that?  Again,

 

       this is just our recommendation.

 

                 CHAIRMAN DURST:  Carol.

 

                 DR. WASLIEN:  Hi, Carol Waslien.  Since we

 

       don't know the individual factors that would

 

       influence the subjective or objective reactions, I

 

       assume that we have to include that.

 

                 I would hope that we would accumulate data

 

       that says this is the kind of range within an

 

       individual that you might see, because that makes

 

       it exceedingly low in a sense or the lower limit.

 

       Over time, I would think that kind of data should

 

       be accumulated in trials.

 

                 CHAIRMAN DURST:  Petr.

 

                 DR. BOCEK:  Well, we didn't discuss it

 

       originally, but I absolutely agree with that.  In

 

       practice, imagine you give a patient in a

 

       double-blind challenge study 100 micrograms of

 

       peanut, and they say, "I'm itching all over.  My

 

       mouth is tingling.  I don't feel well."

 

                 You go on and they develop hives only at

 

       100 milligrams.  There is absolutely no way I will

 

       say that 10 milligram is the norm, because they had

 

       subjective symptoms which to me are significant at

 

       100 micrograms.  I certainly agree with that

 

       approach.

 

                 CHAIRMAN DURST:  Marc.

 

                 DR. SILVERSTEIN:  I would like to make a

 

       comment and an observation.  In our understanding

 

       the drugs, we have had tremendous benefits by

 

       improved methodology that have been developed by

 

       investigators, epidemiologists, and statisticians

 

       in response to regulatory requirements that were

 

       developed and industry was focused on because of a

 

       need to develop drugs to be marketed.

 

                 It seems to me that in the setting of

 

       thresholds for allergens there is an opportunity

 

       here to specify a set of potential biases, a set of

 

       potential confounding factors that the leading

 

       investigators in the allergic diseases would use in

 

       establishing these consensus protocols for

 

       double-blind, placebo-controlled, food challenges.

 

                 If, for example, biases such as referral

 

       bias, selection bias, disease-spectrum bias,

 

       verification bias were judged to be important

 

       factors.

 

                 A set of standards for performing these

 

       studies could include reporting this information.

 

       Journal editors have also been influential in

 

       improving the quality of studies by saying, "As a

 

       characteristic for publication, we would like you

 

       to meet these criteria."

 

                 If there were a set of confounding factors

 

       -- time of day, season, exercise, concurrent

 

       medications -- that are thought to be important by

 

       clinicians, by allergists, if those factors were

 

       specified as factors that should be reported in the

 

       collection of data, then as we go to making

 

       judgments about policy and regulations, we would

 

       have a more uniform and higher quality data to base

 

       those regulations.

 

                 If we think back about the way in which

 

       our knowledge of clinical trials has benefited by

 

       the need to have well-designed Phase I, Phase II,

 

       Phase III clinical trials, I think we are at an

 

       analogous point here.

 

                 These factors that we have, these

 

       potential sources of error and the potential

 

       incomplete data, I think could be used by those on

 

       the cutting-edge in doing these studies or

 

       designing these studies, so that as these studies

 

       are conducted within one, two, three years we would

 

       have a body of data to make better judgments about

 

       the setting of thresholds.  I think there is a very

 

       important opportunity here to influence the type of

 

       data that will be available in a couple of years.

 

                 CHAIRMAN DURST:  Suzanne.

 

                 DR. TEUBER:  A note to file, this would be

 

       an excellent RFA.  Again, these studies are

 

       extremely expensive, and so the only ones that are

 

       underway right now or being planned are those being

 

       sponsored by industry, graciously, to help

 

       determine these thresholds.  This is an excellent

 

       opportunity for us, as a Committee, to have in our

 

       minutes the need for more funding for this.

 

                 CHAIRMAN DURST:  Jean.

 

                 MS. HALLORAN:  It does seem like,

 

       following up on this, one of the critical questions

 

       is the relationship of subjective responses to

 

       objective responses.  I don't know whether it has

 

       been studied so far how well these correlate or

 

       whether that is something that needs further study.

 

                 However, if in placebo-controlled,

 

       double-blind studies a subjective response is a

 

       very good indicator of a subsequent objective

 

       response, then that would lend more validity to

 

       using the subjective responses as a factor in

 

       determining a threshold.

 

                 I was wondering if anybody knows whether

 

       that kind of correlation has been done up to this

 

       point; and if not, whether perhaps we might want to

 

       recommend research in this area?

 

                 DR. TEUBER:  Suzanne Teuber.  That

 

       actually is being incorporated into the current

 

       consensus protocol for threshold studies, that

 

       subjective responses will be recorded carefully,

 

       and then the goal is to proceed to an objective.

 

       This will allow us to have data on how those are

 

       related in a wider range of patients.

 

                 Because right now, there are only a few

 

       reports of proceeding on to an objective response

 

       after initially having a subjective one, I should

 

       also note, a subjective response verified by repeat

 

       challenge with negative placebo.  It will come.

 

                 CHAIRMAN DURST:  Any further discussion on
 

 

       question two?

 

                 DR. TEUBER:  Well, actually we have more

 

       on question two.  That was just one little

 

       subsection there.

 

                 (Laughter.)

 

                 DR. TEUBER:  Suzanne Teuber, I should say.

 

                 CHAIRMAN DURST:  I thought we went through

 

       these.

 

                 DR. TEUBER:  Oh, actually, no, you're

 

       right.  That was basically it, but we have one

 

       little bit more that we wanted to add to this

 

       discussion of number two.  We wanted to note again

 

       this recruitment problem.

 

                 Of note, recruitment of the highly

 

       sensitive subpopulations to threshold studies may

 

       be enhanced by recording subjective reactions that

 

       are reproducible to the active dose but negative to

 

       the placebo, two challenges of each, with an option

 

       of stopping at that dose.

 

                 In threshold studies, highly sensitive

 

       patients may or may not be willing to proceed to an

 

       objective response or the physician may not be

                                                                

 

       comfortable proceeding.

 

                 There is acknowledged controversy that is

 

       appropriate about the applicability of LOAELs that

 

       are subjective.  Objective responses are preferred,

 

       with the concern that it be demonstrated in studies

 

       that extremely sensitive subjects have been willing

 

       to participate in, otherwise an uncertainty factor

 

       greater than 10 may be needed because we just don't

 

       have enough data.

 

                 Again, we wanted to note the previous

 

       comments that Mark had made about using a range of

 

       threshold values in determining the uncertainty

 

       factor.  We actually raised these points in our

 

       discussion here again.

 

                 Then, proceeding on to number three:  In

 

       the absence of specific data that would allow

 

       thresholds to be established for each of the major

 

       food allergens, is it scientifically sound to use

 

       the threshold established for a single food

 

       allergen -- for example, peanuts -- as the

 

       threshold for all major food allergens?

 

                 We really did not discuss this much

 

       further.  I think it could use a little bit more

 

       discussion.  I said no, it appears from the

 

       available data that soy thresholds may be higher.

 

       Such labeling would then restrict diets

 

       unnecessarily as well as pose hardships to

 

       industry.

 

                 We really didn't discuss the fact that for

 

       other allergens we don't have much data or adequate

 

       data, and it might be reasonable to use the most

 

       stringent one until other data are available.

 

                 Any thoughts on this?

 

                 CHAIRMAN DURST:  Erica.

 

                 DR. BRITTAIN:  I mean, that sounds good,

 

       just as long as you really are totally competent

 

       about what is the most stringent factors.

 

                 CHAIRMAN DURST:  Carol.

 

                 DR. WASLIEN:  Well, I think there are a

 

       good number of tree nuts, for example, that we have

 

       limited data on.  Hazelnuts, yes; but other tree

 

       nuts, we don't have the data on.  Other allergens,

 

       the other 200 that aren't part of the 7, we have to

 

       use something in their place.

 

                 Perhaps, until those ranges become more

 

       clearly established, we are safer at using a peanut

 

       allergen that is the most likely to show a response

 

       for those foods until they are proven otherwise,

 

       sort of guilty until proven innocent almost.

 

                 CHAIRMAN DURST:  Marc.

 

                 DR. SILVERSTEIN:  Marc Silverstein.  It

 

       seems to me that a parent making a decision about

 

       food exposure for a child, a physician making a

 

       decision to recommend diet for a patient and an

 

       agency making a policy recommendation for consumers

 

       and industry, all are faced with difficult

 

       decisions.

 

                 The decision threshold and the potential

 

       decision you might make might be weighed not only

 

       by the likelihood of making a correct or incorrect

 

       decision, but the consequences of making a correct

 

       or incorrect decision.

 

                 Obviously, a parent making a decision for

 

       a child, a physician making a decision for a

 

       patient, and an agency making a decision for a

 

       population and industry all have different

       thresholds in terms of the value of a

 

       false-positive or a true-positive recommendation to

 

       avoid or not avoid, or to change diet or not change

 

       diet, or to label or not label a specific level.

 

                 I do think that we are, in some sense,

 

       changing our perspective.  We are putting on our

 

       hats or our roles as parents and individuals.  We

 

       are putting on our judgments as clinicians or

 

       health care providers, and we are putting on our

 

       roles as policymakers.

 

                 I actually think we should be cautious in

 

       making judgments about how sensitive or specific

 

       our thresholds would be for a decision about our

 

       children, our decisions about our parents, and our

 

       decisions about our public population.

 

                 I am not sure that I would want -- in

 

       fact, let me phrase it positively -- I would not be

 

       comfortable making a decision to be very

 

       conservative or very liberal, if you will, high or

 

       low, highly sensitive, or specific when I shift my

 

       domain from that what I would do for my child to

 

       that what I might do for my patient or that what I

 

       might do for an agency's decision.

 

                 I do have some sense that I would rather

 

       than say we should be conservative and extrapolate

 

       from what we know about this other class of antigen

 

       I might say that right now we have insufficient

 

       data and cannot make a recommendation.

 

                 CHAIRMAN DURST:  Dick Durst.  Would it be

 

       safe to say that for those allergens for which we

 

       have sufficient data we would set a realistic

 

       threshold based on that; and for those that the

 

       data is currently insufficient, that we would use

 

       the threshold of the most sensitive?

 

                 DR. SILVERSTEIN:  That would be safe to do

 

       that, but I feel that I could make some judgments

 

       with regard to individual patients.  I would be

 

       cautious about making such a recommendation on a

 

       policy basis for that.  The consumer might and the

 

       industry might want guidance.  We may have

 

       insufficient data to be able to provide that

 

       guidance.

 

                 CHAIRMAN DURST:  Soheila and then Jean.

 

                 DR. MALEKI:  Soheila Maleki.  Well, I

       mean, I agree with you, Marc.  I understand your

 

       thought, but, again, going back to what the

 

       consumer wants, the consumer wants us to err on the

 

       side of caution.

 

                 I mean, of course that is something that

 

       you don't want, to lump everybody in.  I a hundred

 

       percent agree with you.  However, when you hear

 

       from the consumers, they would prefer that you err

 

       on the side of caution even in the absence of data,

 

       which is what it essentially is asking.

 

                 In the absence of data to pick the most

 

       sensitive food and set a threshold, I think is more

 

       comfortable to the consumer or probably would make

 

       them feel better than to say nothing on the label

 

       at all.

 

                 DR. HEIMBURGER:  Or, to leave it

 

       ambiguous.  Doug Heimburger.  Or, to leave it

 

       ambiguous, to say "It may contain" or whatever.

 

                 CHAIRMAN DURST:  Jean.

 

                 MS. HALLORAN:  Yes.  I think we should

 

       keep in mind that we are talking about a threshold

 

       for labeling only.  This is not a threshold for

 

       excluding the product or taking it off the market

 

       or anything like that.  Particularly, the problem

 

       comes with what is the threshold for requiring

 

       somebody to say, a company to say that "This

 

       product contains soy"?

 

                 I think to err slightly, perhaps, in the

 

       direction of a lower threshold is the appropriate

 

       course here until it can be shown that certain very

 

       low levels of soy do not pose any hazard to a

 

       person with allergies.

 

                 Because for most people it is not

 

       relevant; it will not be of interest at all.  What

 

       we are trying to do here is to try to provide

 

       information to consumers with a very special

 

       concern.

 

                 CHAIRMAN DURST:  Mark.

 

                 DR. NELSON:  Yes, Mark Nelson.  Earlier,

 

       we were talking about gray areas.  I think if we

 

       went to establishing a threshold based on the most

 

       sensitive or the most problematic allergen we would

 

       be completely in the black area.

 

                 Echoing some of Jean's comments, I think

 

       if we are to establish a threshold based on the

 

       most problematic allergen, I can't imagine there

 

       would be too many companies that would go through

 

       the process of reformulating a product for soy to

 

       meet that lower, tight threshold knowing full well

 

       that there are data that exist that we are getting

 

       close to better information for a higher threshold

 

       for soy, and then going back and reformulating

 

       again to meet that.  In effect, we would be

 

       postponing providing useful information to a good

 

       portion of the allergic population, if we were to

 

       take that tack.

 

                 CHAIRMAN DURST:  Jeff.

 

                 DR. BARACH:  Jeff Barach.  I would

 

       certainly agree with Mark's comments.  One thing I

 

       would say, though, is that we really from my

 

       observation have fairly good data on at least four

 

       of the major eight, and that is comforting to me.

 

       I wish we had more, but that seems to be what was

 

       presented to us.

 

                 If we think about what could happen to

 

       those other four and we use, say, the lowest level

 

       for the allergen of highest activity, that bothers

 

       me a little bit because of what Mark said.

 

                 I think what we should recognize, though,

 

       is that we do have sort of a default position.

 

       Unfortunately, we have a zero tolerance now for

 

       those allergens, so those products would be

 

       labeled.

 

                 It is not like they wouldn't be labeled;

 

       it is just that they don't have a threshold.  If

 

       there is any there, any detectable, then it would

 

       have to be labeled.  There is a default.  We don't

 

       have to in my mind assign a threshold for

 

       everything at this point and still protect the

 

       consumer.

 

                 CHAIRMAN DURST:  Further discussion?

 

                 Ciaran.

 

                 DR. KELLY:  So is the default threshold an

 

       analytical de facto?

 

                 DR. BARACH:  I would say it is more

 

       ingredient-based than analytical.

 

                 CHAIRMAN DURST:  Petr.

 

                 DR. BOCEK:  Petr Bocek.  When you say

 

       "ingredient-based," so that goes back to "may

 

       contain," or what does it mean?

 

                 DR. BARACH:  It goes back to the system

 

       that we are currently using.

 

                 DR. BOCEK:  Okay.  That is the system we

 

       are trying to change.

 

                 DR. WASLIEN:  Don't you mean that you have

 

       to list all of the ingredients of a food, so it is

 

       not the "may contain"?  Is it the list of

 

       ingredients?  Isn't that what you are referring to?

 

       It doesn't mean he is saying we will stick with the

 

       "may contain" labeling option.  It is if soybean

 

       lecithin is added to a food, it is on the list of

 

       ingredients.

 

                 DR. BARACH:  That's right.  The "may

 

       contain" part covers the possibility of

 

       adventitious presence or a contamination during the

 

       manufacturing as well.  We have the list of

 

       ingredients, and then we have the "may contain" for

 

       small amounts that may enter the product.

 

                 CHAIRMAN DURST:  That was Carol and Jeff

 

       responding.

 

                 Now, Mark.

 

                 DR. NELSON:  It also covers not only

 

       additives and potential cross-contact, but it also

 

       includes the processing aids which are

 

       intentionally used but really serve no function in

 

       the finished product, but there may be trace

 

       amounts of it in the product.  At this point the

 

       law requires us to do it, to label those as well.

 

                 DR. TEUBER:  Suzanne Teuber.  Actually,

 

       for those processing aids, many of them will fall

 

       under the petitioner notification process.

 

                 DR. NELSON:  They could.

 

                 CHAIRMAN DURST:  Any further discussion?

 

                 (No response.)

 

                 CHAIRMAN DURST:  No?  We will move on.

 

                 DR. TEUBER:  Suzanne Teuber going on here.

 

       The next part of that question was actually: if so,

 

       which food or foods could serve this function; if

 

       not, is there a more appropriate method to be used?

 

       I think people discussed that here.

 

                 The question is, though, do we have a

 

       consensus on that for Dr. Durst to write up a

 

       statement?  I'm not sure that we do.  Do you feel

 

       that we do?  Because basically this might or might

 

       not be an appropriate way to proceed.  There were

 

       concerns raised for and against.  I don't think we

 

       had really consensus.

 

                 CHAIRMAN DURST:  Yes.  Well, as I say, I

 

       don't think we have to reach a consensus as long as

 

       we can provide some guidance to the FDA as far as

 

       directions for them to go.

 

                 I could ask Steve at this point if he

 

       wants any further clarification on that point.

 

                 DR. GENDEL:  No, you are correct, it is

 

       not necessary to reach a consensus but simply

 

       stating the range of opinions and the basis for

 

       those opinions.

 

                 DR. TEUBER:  All right.

 

                 CHAIRMAN DURST:  Okay.  Thank you.

 

                 DR. TEUBER:  Suzanne Teuber.  Continuing,

 

       number four, the draft report discusses the

 

       available data on the levels of protein present in

 

       highly refined oils, that is, oil that is

 

       hot-solvent extracted, refined, bleached and

 

       deodorized.

 

                 Is there any physiologic reason -- for

 

       example, food matrix effect denaturation of protein

 

       -- why the protein levels in highly refined oils

 

       could not be used as the basis for establishing a

 

       threshold for other allergenic foods?  Are there

 

       any other limitations that should be considered in

 

       applying this approach to the eight allergenic

 

       foods?

 

                 With this there was complete consensus

 

       that the levels in oils did not apply.  The reasons

 

       that were raised included the fact that we have

 

       extremely poor measurement of proteins in oils.  It

 

       is very unclear as to their validity.

 

                 Secondly, the points raised about

 

       denaturation, changing of epitopes and whether the

 

       proteins in oils actually reflect what folks really

 

       act to.

 

                 Then, third, the matrix effect was felt to

 

       be extremely important and has been backed up by

 

       studies showing that fat can affect the threshold

 

       for response.

 

                 In addition -- let's see was there yet

 

       another, this is where the printer didn't work on

 

       that -- we had the configuration changes, we had

 

       the measurement problems, and then the matrix.  I

 

       believe those were the three that we had covered.

 

       That one we were in complete consensus agreement

 

       on.

 

                 CHAIRMAN DURST:  Has anyone changed his or

 

       her mind on that?

 

                 (No response.)

 

                 CHAIRMAN DURST:  Well, I guess we are

 

       still in consensus.  Okay, that takes care of those

 

       specific questions.  Again, I will refer back to

 

       Steve, if he has anything that he would like

 

       further discussed on the food allergen part?

 

                 DR. GENDEL:  I don't believe so.

 

                 CHAIRMAN DURST:  Okay.  Then, we can move

 

       on to the general questions on the first page of

 

       our charge.  I think some of these should be able

 

       to go fairly quickly, since we have laid all of the

 

       groundwork now for it.  The first one I will read

 

       the questions, and then we can discuss.

 

                 "In addition to the four approaches

 

       identified by FDA for establishing thresholds

 

       (i.e., analytical methods-based, safety

 

       assessment-based, risk assessment-based and

 

       statutorily-derived) are there other approaches

 

       that FDA should consider?  If so, please describe

 

       and explain why FDA should consider them."

 

                 As I recall, there really weren't many

 

       other options.

 

                 Erica.

 

                 DR. BRITTAIN:  I just have a really brief

 

       comment.  It is not really another method, but just

 

       that to me the safety assessment-based and the

 

       risk-assessment based are sort of part of a

 

       continuum.

 

                 I don't see them as, necessarily,

 

       completely distinct in that I would like to see

 

       more statistical principles brought into the

 

       safety-assessment-based approach.

 

                 CHAIRMAN DURST:  Okay.  Soheila.

 

                 DR. MALEKI:  Soheila Maleki.  I think I

 

       just brought up one method about celiac disease

 

       measurements, and that is, possibility for looking

 

       at T-cell activation, which is more likely to catch

 

       that amplification of response than analytical

 

       methods might.  It was just a suggestion, if

 

       anybody else has any ideas.

 

                 CHAIRMAN DURST:  David.

 

                 MR. ORYANG:  Yes.  I would just like to

 

       echo that.  Yes, the risk-assessment based and the

 

       safety-assessment-based methods are really distinct

 

       and separate.

 

                 However, I think more statistic[s] could

 

       be brought into the safety assessment-based such as

 

       using distributions within the safety factor or the

 

       uncertainty factor, or, for that matter,

 

       incorporating uncertainty into the threshold by

 

       using a distribution, and then using Monte Carlo

 

       simulation to come up with a result, which is a

 

       distribution, and then maybe looking at the 95th

 

       percentile or whatever values come up from that

 

       modeling to set what the ultimate threshold should

 

       be.

 

                 It is really just adding some aspects of

 

       risk-assessment into, some methods of risk

 

       assessment into those factors within the

 

       safety-assessment methodology, because there are

 

       two dimensions of uncertainty.

 

                 If you look at the studies that were done,

 

       from what I could see there is, first of all,

 

       uncertainty about how closely or how well we

 

       capture symptoms or signs.  They observe signs.

 

       When do the observed signs occur?  Should we use

 

       the subjective or objective?  Because there is a

 

       range there as to when the sensitivity is

 

       different.

 

                 Then, the second part of it is you take

 

       this study population, does that study population

 

       truly represent the overall population?  Can you

 

       then take what you have observed here in this study

 

       group and project it to the population?

 

                 We can't say a hundred percent of the

 

       study population represents the other population,

 

       so there is uncertainty there.  There are really

 

       two dimensions of uncertainty as well as, of

 

       course, the model that we are using.

 

                 There is uncertainty based on the method.

 

       There are multiple dimensions of uncertainty.

 

       Unless we incorporate some statistic[s] into this,

 

       I don't think we are doing a good job.  I really

 

       suggesting adding some statistic[s] to some of the

 

       factors.

 

                 CHAIRMAN DURST:  Good.

 

                 Carol.

 

                 DR. WASLIEN:  Carol Waslien.  I also think

 

       I'm not sure if population-based studies of groups

 

       exist that are living on gluten-free diets and are

 

       included in the risk and safety kinds of categories

 

       and studies, because they are not clinical trials.

 

                 I think there is some value to be added to

 

       looking at population-based evaluations to increase

 

       your ability to include highly sensitive, to

 

       increase your ability to ask or collect more data

 

       on range of responses.

 

                 Population-based studies such as that,

 

       although they are crude and messy, would give you a

 

       better idea of the kinds of ranges of responses

 

       that you would see in the free-living population as

 

       opposed to a sample, challenge trial kind of

 

       clinical study.

 

                 CHAIRMAN DURST:  Well, Marc and then

 

       David.

 

                 DR. SILVERSTEIN:  I don't have a

 

       suggestion for another approach.  However, within

 

       the approach, I was struck by the choice of a 10

 

       percent proportion, a population that would respond

 

       to a milk allergy in an identification of a

 

       hypoallergenic formula to derive a buff sample size

 

       of about 29 subjects using a conventional

 

       95-percent confidence interval to identify a

 

       proportion or a rate of 10 percent as a basis for

 

       what has become an accepted sample size for these

 

       sorts of studies.

 

                 Indeed, it is difficult to do the studies.

 

       They are expensive; they are risky; and it takes

 

       time to recruit subjects.  These conditions perhaps

 

       are not very common; so, referral in the collection

 

       of an adequate number of patients means that, by

 

       and large, investigators are performing studies of

 

       about that size.

 

                 We have a collection of literature which

 

       is maybe sufficient for one purpose but may not be

 

       sufficient to make estimates of thresholds.

 

       Estimates of thresholds are not estimates of a

 

       certainty about an incidence rate of 10 percent,

 

       but it is a measurement of a quantity around which

 

       we can decide the amount of precision needed, and

 

       then derive sample size estimates.

 

                 Now, indeed, when those sample size

 

       estimates begin to be large, we have to face the

 

       challenge of how do we do those studies.  Do they

 

       require multicenter studies?  Do they require

 

       longer periods and more effort to recruit?  Do they

 

       require larger budgets?

 

                 These are real factors.  In the real

 

       world, of course, we must live with the available

 

       data and the available resources as we collect

 

       information.  I do think there is an important

 

       distinction between the sample needed to estimate

 

       with fairly reasonable or conventional confidence a

 

       rate of 10 percent and the sample needed to make

 

       estimates of thresholds.

 

                 Depending on how precise your estimates

 

       could be, your samples might be about that size or

 

       they might be much larger.  There should be more

 

       conscious decision making in setting the size of

 

       those samples as well as thinking about the

 

       thresholds themselves.

 

                 CHAIRMAN DURST:  David and then Erica.

 

                 MR. ORYANG:  Yes, David Oryang.  Further

 

       about some of the methodologies, a lot of times if

 

       the resources are available, time being one

 

       resource, and the need is there to really go do a

 

       more in-depth analysis, then the risk-assessment-

 

       based approach, looking at dose response and

 

       exposures, would be the method to go, but the data

 

       is not currently available.

 

                 I will just suggest that sometimes if one

 

       does take the risk-assessment-based approach, you

 

       can still do it, but there would be a lot of

 

       uncertainty in a lot of the parameters.

 

                 To the extent that they can be

 

       transparently presented, maybe it is still viable.

 

       I haven't really seen the evidence that we have

 

       enough on some of the dose responses and exposures.

 

                 I know that in this report there is enough

 

       stated in there, and it is suggested that the

 

       risk-assessment-based approach be the preferred

 

       approach for the allergens but not for the glutens.

 

                 Maybe that is also because of the acute

 

       nature of the allergens.  I mean, the consequence

 

       of not looking further into it seems to be more

 

       acute than in the gluten case.

 

                 I concur with FDA in some of these

 

       recommendations.  I would just say that if the

 

       resources are available and more information is

 

       available, the risk-assessment-based approach is

 

       the better approach.

 

                 CHAIRMAN DURST:  Erica.

 

                 DR. BRITTAIN:  Yes, I really want to echo

 

       what Marc said.  This magical sample size of 29

 

       that we kept hearing I really think is not quite,

 

       even if you want to just exclude a 10 percent rate,

 

       which doesn't seem like really enough for the

 

       threshold setting, it is not set up the way I think

 

       people would normally want to set things up to have

 

       appropriate statistical power.  That is one

 

       relatively minor point.

 

                 It all goes back to what I said originally

 

       that I think you need to set a precise goal of how

 

       much risk is acceptable, and that will drive the

 

       sample size.  If that sample size is way beyond

 

       what can be done, then I think you have to go to

 

       the modeling approach with the right data.

 

                 CHAIRMAN DURST:  Further discussion?

 

                 Ciaran.

 

                 DR. KELLY:  Ciaran Kelly.  I just wanted

 

       to reinforce the comment that has already been made

 

       of the value of including population experiences

 

       within the safety assessment.

 

                 Unfortunately, not only is there a wealth

 

       of experience, but there are also a number of

 

       publications that document the efficacy in a

 

       population of certain levels of gluten exposure.

 

                 I think that if one were to consider the

 

       more conservative thresholds that are currently in

 

       use, there would be the likelihood that those

 

       thresholds would be dangerous as opposed to safe

 

       would seem to be very low.

 

                 CHAIRMAN DURST:  Mark.

 

                 DR. NELSON:  Yes, Mark Nelson.  I wanted

 

       to come back to comments that Marc and Erica made,

 

       but maybe emphasize it a little differently.  I

 

       fully agree with basing this all on science and

 

       having statistical rigor, but we also have to make

 

       sure we are not having to prove we're the enemy or

 

       the good.

 

       We may need to adjust the studies for different

 

       allergens, for example, depending on the severity

 

       of the response, and so on.

 

                 We shouldn't forget that the sample size

 

       used to support the hypoallergenic infant formula

 

       was also for a population whose sole source of

 

       nutrition was the infant formula that they were

 

       taking in.  I mean, safety was clearly considered

 

       in that situation, and, again, it serves the

 

       greater portion of that population.

 

                 CHAIRMAN DURST:  Any further discussion?

 

                 (No response.)

 

                 CHAIRMAN DURST:  We are ready to move on

 

       to the second question.  I will read it again:

 

                 "Are FDA's criteria for selecting and

 

       evaluating the available data appropriate?  If not,

 

       should any of the criteria be modified or deleted?

 

       Please describe any changes you would like to see

 

       and why.  Are there additional criteria FDA should

 

       consider?"

 

                 Who would like to start that off?

 

                 DR. BRITTAIN:  I think we have already

 

       covered all of this.  I don't know if there is

 

       anything else?

 

                 CHAIRMAN DURST:  Yes, I don't know if

 

       there are any more.

 

                 Marc.

 

                 DR. SILVERSTEIN:  Mark Silverstein.  There

 

       was a very useful document prepared and funded by

 

       the Agency for Healthcare Research and Quality.  I

 

       mentioned it yesterday, and it was "Methods for

 

       Evaluating the Strength of Evidence."  It was I

 

       think prepared by one of the evidence-based

 

       practice centers under contract from the Agency for

 

       Healthcare Research and Quality.  It has been

 

       published, and it is available on their Web site.

 

       It basically summarizes a set of methodologic

 

       criteria that you would use in doing, evaluating,

 

       grain- or mice-controlled trials, cohort studies,

 

       studies or diagnostic tests.

 

                 In looking through the list of the

 

       criteria that are in the FDA report, almost all of

 

       the criteria are mentioned, maybe not in exactly

 

       the same format as in that publication.  It seems

 

       to me, that since it is our taxpayer dollars at

 

       work and other agencies have already developed

 

       this, it would be useful to look at it.

 

                 I do believe the diagnostic test section,

 

       which would be relevant for some of the food

 

       challenges, has a different way of phrasing some of

 

       the focus on the selection of the patients.

 

                 I do think it would be a useful resource

 

       both to cite and perhaps to look at to see that the

 

       categories suggested by that thoughtful review are

 

       well covered in all of the categories.

 

                 CHAIRMAN DURST:  Okay.  Ciaran and then

 

       Erica.

 

                 DR. KELLY:  Ciaran Kelly.  Yes, I have

 

       just one comment, and it has to do with the

 

       criteria for evaluating analytic methods.  To my

 

       mind, transparency of the method, an adequate

 

       description of the specific methodology, would be

 

       important so that potential biases or weaknesses

 

       that are inherent within the methodology could be

 

       examined in addition to the other criteria that you

 

       list.

 

                 CHAIRMAN DURST:  Erica.

 

                 DR. BRITTAIN:  I just have a very brief

 

       comment.  In terms of beefing up the summary of

 

       studies in the appendix, maybe along the lines that

 

       Marc suggested, one thing that is not in there is

 

       number of patients in each study.  That seems like

 

       a critical omission.

 

                 CHAIRMAN DURST:  Anything else?

 

                 Jean.

 

                 MS. HALLORAN:  Jean Halloran.  I was

 

       intrigued by the suggestion from Dr. Taylor who

 

       mentioned that clinicians have data on NOAELs and

 

       LOAELs for their patients in their records.  This

 

       is certainly not data which is a

 

       placebo-controlled, double-blind study; it is not

 

       peer reviewed; and it is not many other things.

 

                 Given that there seems to be such a dirth

 

       of data, especially for certain allergens, I am

 

       wondering whether any effort could be made or

 

       whether there would be any value to FDA asking for

 

       such data just to somehow get a vague idea of what

 

       is going on in those areas, whether it is possible

 

       to do that, or whether once data is submitted, it

 

       gets a life of its own and it is more trouble than

 

       it's worth?

 

                 CHAIRMAN DURST:  Okay.  That actually

 

       leads us into the third question.

 

                 DR. BRITTAIN:  Well, I mean, it relates to

 

       this, which is that my concern about that is that

 

       if those studies were done almost exclusively on

 

       patients for whom they were trying to confirm a

 

       diagnosis, they would be really biased.

 

                 Even if there is a large number of them,

 

       if the information came from it is really biased

 

       and is wrong, then it doesn't really help that you

 

       have a lot of data.

 

                 CHAIRMAN DURST:  Soheila.

 

                 DR. MALEKI:  Soheila Maleki.  Just one

 

       comment.  The studies that they used for a

 

       challenge, and I think Suzanne can confirm that, is

 

       the doses that are used are often much higher than

 

       threshold doses.  Actually, if you use that data,

 

       you would be targeting people that have really high

 

       threshold doses, if they didn't react at that

 

       level.

 

                 CHAIRMAN DURST:  Margaret.

 

                 DR. McBRIDE:  I think, though, that those

 

       concerns about that kind of data could be handled

 

       by only including subjects who responded.

 

       Obviously, you don't want subjects that didn't

 

       respond, because you don't even know if they are

 

       sensitive.  There are ways still of looking at that

 

       data and possibly having something.

 

                 CHAIRMAN DURST:  Suzanne.

 

                 DR. TEUBER:  Suzanne Teuber.  That data,

 

       it actually would be very useful to have if we are

 

       trying to start characterizing subpopulations of

 

       patients.  Because we know that the vast majority

 

       of patients where there is likely this NOAEL data

 

       that just wasn't published are patients who are

 

       children with atopic dermatitis.

 

                 That is a distinct subgroup with usually

 

       not as severe a reaction, and so it might be very

 

       useful to have that, because we still need more

 

       data.  We can help characterize more, then.

 

                 CHAIRMAN DURST:  Since we are dealing with

 

       question three, let me just read it into the

 

       record.

 

                 (Laughter.)

 

                 CHAIRMAN DURST:  "Recognizing that some of

 

       the key studies (i.e., challenge studies) are

 

       ongoing, what if any use of preliminary data that

 

       have not been peer reviewed for establishing

 

       thresholds is appropriate?"

 

                 Now we can continue.

 

                 David, did you have your hand up?

 

                 MR. ORYANG:  Yes, I did have my hand up.

 

       Just briefly, about the data.  I don't see very

 

       much put in there about expert opinion and clear

 

       methods of being able to elicit some of this kind

 

       of information that is kept in records, and so

 

       forth, from a panel of experts and clearly

 

       documented in a way that can be presented

 

       scientifically in the document to be included as

 

       part of the record in how the decision came to be.

 

                 I think it would be useful if there was a

 

       formal process for getting that kind of information

 

       from doctors and other people who can be considered

 

       experts on those specific areas, elicit that

 

       information formally and document it, and then show

 

       a clear method of how you came from the broad

 

       opinion to the narrowed result or determination

 

       that was made.

 

                 I think that is also a good process of

 

       getting that kind of unpublished or informal

 

       information which can be looked at as a knowledge,

 

       which is important in decision making.

 

                 CHAIRMAN DURST:  Soheila.

 

                 DR. MALEKI:  Soheila Maleki.  Again, I

 

       mean, of course any data that any scientist is

 

       beautiful and wonderful to get.  But, again, I

 

       don't think that in establishing thresholds, which

 

       is what we are looking at, that the challenge

 

       studies would be.

 

                 Again, it is wonderful, yes, if we were

 

       going to divide people into subpopulations.  Bottom

 

       line, we are looking at the most severe reactions,

 

       which I don't think will be included in that data

 

       because of the high doses of the challenge, or

 

       often higher doses.

 

                 DR. BRITTAIN:  And the populations that

 

       would undergo those challenges.

 

                 DR. MALEKI:  Yes.  Essentially for this,

 

       yes.  I mean, of course it is wonderful to have the

 

       data.  What scientist or doctor or agency doesn't

 

       want more data?  But bottom line that is --

 

                 CHAIRMAN DURST:  Suzanne.

 

                 DR. TEUBER:  Suzanne Teuber.  Just to

 

       address Mr. Oryang's comments, actually the First

 

       Threshold Conference that was held, the paper by

 

       Steve Taylor and all, that was bringing together

 

       people who had unpublished data about thresholds,

 

       and from there it has gone on to the current

 

       consensus protocol.

 

                 The data that was referred to by Dr.

 

       Taylor was something that was brought to the table,

 

       but again it was this population that was more

 

       atopic dermatitis.  I still think it would be

 

       interesting to have it.  It would cost money to get

 

       it, to pay somebody.

 

                 However, it is true it would not give

 

       information directly related to the

 

       safety-assessment threshold information we want.

 

       It is just population data that is of interest.

 

                 CHAIRMAN DURST:  Mark.

 

                 DR. NELSON:  Mark Nelson.  I guess I would

 

       echo Jean's comment and a lot of other people, to

 

       try to get more data.  What I understood Steve

 

       Taylor to describe, the specific example he gave,

 

       was Hugh Sampson's work.

 

                 This is the extra data from a

 

       peer-reviewed study, which strikes me, hearing the

 

       clinicians speak and others, that this would be

 

       very useful for helping specify the uncertainty

 

       factors we have talked about and also help us maybe

 

       with some of these subjective responses.  I don't

 

       know, I haven't seen the data.

 

                 CHAIRMAN DURST:  Jeff.

 

                 DR. BARACH:  Jeff Barach.  As we heard,

 

       other countries are struggling with the issues of

 

       allergens also.  I would just make note that the

 

       European Food Safety Authority and the European

 

       Commission have put together a Directive

 

       2005/26/EC.

 

                 I would encourage the FDA to contact the

 

       European Food Safety Authority to find out if they

 

       have any data that would be of interest to our

 

       group as they work on the issue.

 

                 CHAIRMAN DURST:  Soheila.

 

                 DR. MALEKI:  Soheila Maleki.  I think that

 

       is a really good point, and I also think Health

 

       Canada, but I think they have already talked to

 

       them about it.  That is a very good point.

 

                 CHAIRMAN DURST:  Margaret.

 

                 DR. McBRIDE:  I understand the concern

 

       about the difference, the potential difference, in

 

       dosing for challenge tests versus threshold

 

       testing.  We have already established that if there

 

       is a LOAEL in the absence of a NOAEL, that is not

 

       very useful.

 

                 On the other hand, if within that data

 

       there are individuals that prove to be sensitive to

 

       whatever is being test and the NOAEL is available

 

       as well as the LOAEL, that is clearly relevant

 

       data.

 

                 CHAIRMAN DURST:  Petr.

 

                 DR. BOCEK:  Petr Bocek.  Just a quick

 

       comment to that.  Yes, it is very valuable, but it

 

       has to be done with the right population.  If that

 

       was a patient where it was a diagnostic challenge,

 

       a question of biology, it is not as valuable as

 

       somebody who has a clear-cut clinical presentation

 

       of anaphylaxis to a food allergen.  Yes, that is

 

       the right person to look for a threshold.

 

                 CHAIRMAN DURST:  Any further discussion?

 

                 Ciaran.

 

                 DR. KELLY:  Ciaran Kelly.  I just wanted

 

       to perhaps more directly address the question about

 

       non-peer-reviewed experimentation.  Clearly, the

 

       presentation that Dr. Fasano gave to us yesterday

 

       is not peer reviewed and published, but,

 

       nonetheless, it is directly pertinent and relevant

 

       to the question at hand and also is performed by a

 

       well-recognized, expert group of investigators.

 

                 Clearly, that is a double-blind,

 

       randomized-controlled trial.  Clearly, those data

 

       are highly relevant.  Although it is likely that

 

       they will be published within the next year, that

 

       publication process is sometimes very hard to

 

       predict, and it could be much longer than a year.

 

       I would feel personally, and I don't know if the

 

       rest of the Committee agrees, that those data are

 

       highly relevant.

 

                 CHAIRMAN DURST:  Any further discussion?

 

                 (No response.)

 

                 CHAIRMAN DURST:  Before we wrap things up,

 

       I would also like to ask does anyone have any

 

       specific comments on anything in the report,

 

       anything that jumped out at them that needs some

 

       modification or correction?

 

                 Yes, Ciaran.

                 DR. KELLY:  Ciaran Kelly.  I do have some

 

       minor suggestions, but I don't want to take up the

 

       Committee's time with it.  What is the mechanism?

 

       Should I submit some --

 

                 MRS. MOORE:  He has asked the question, so

 

       go ahead.  Go ahead.

 

                 CHAIRMAN DURST:  I mean, is it proper just

 

       to provide that to the Working Group?

 

                 DR. KELLY:  I don't want to waste the

 

       Committee's time with very, very minor things.

 

                 MRS. MOORE:  Okay.  You can send it to me.

 

                 DR. KELLY:  I can provide that in the form

 

       of a memo.

 

                 MRS. MOORE:  Okay.

 

                 CHAIRMAN DURST:  Again, I want to refer

 

       back to Steve.  Any specific questions that you

 

       might have before we wind things up here?

 

                 DR. GENDEL:  (Off microphone.)  Yes, I

 

       just want to remind everyone that there is a

 

       mechanism for submitting information through the

 

       docket.  You can access that through the FDA

 

       homepage.  Any information that is relevant can be

       put in there.

 

                 MRS. MOORE:  Steve, start from the top

 

       because you weren't heard from the beginning of

 

       your statement.

 

                 DR. GENDEL:  Okay.  This is Steve Gendel.

 

       The response was that any information can be

 

       submitted through the docket, which is available.

 

       Any relevant information can be submitted through

 

       the docket available through the FDA homepage.

 

                 CHAIRMAN DURST:  Okay.  I think we are at

 

       the point now that I can ask Mr. Landa to make some

 

       closing comments.

 

                             Closing Comments

 

                 MR. LANDA:  Thank you, Dr. Durst.  I will

 

       be very brief.  First, I just want to reiterate Dr.

 

       Brackett's thanks to all of the members of the

 

       Committee for lending us your expertise for these

 

       several days.  We rely heavily on experts from

 

       outside as well as within the Agency.  Of course,

 

       this is one of the principle ways in which we

 

       obtain outside expertise.

 

                 The second point, just in case not

                                                                 

       everyone heard it, the point Steve Gendel made.

 

       The docket will remain open for another several

 

       weeks until the middle of August.  Anyone who has

 

       comments on the report please get them to us

 

       through the docket.

 

                 We will consider any comments from the

 

       public as well as the results and the comments,

 

       sort of consensus statements, from this meeting in

 

       making any changes to the draft report and in

 

       taking our next steps after the draft report is

 

       finalized.

 

                 The last thing is I would just like to

 

       reiterate the thanks noted earlier to Marcia Moore

 

       and her colleagues for putting on the meeting.

 

       Thank you.

 

                 MRS. MOORE:  Thank you.

 

                 CHAIRMAN DURST:  Thank you.

 

                 I believe Marcia said the transcript of

 

       this meeting would be available at the end of

 

       August?

 

                 MRS. MOORE:  Yes.

 

                 CHAIRMAN DURST:  Without any further

 

       comments, I will declare this meeting adjourned.

 

                 Thank you very much everyone.

 

                 (Whereupon, at 9:37 a.m., the meeting was

 

       adjourned.)