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