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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