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DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

DIETARY SUPPLEMENTS PUBLIC MEETING

PRE-MARKET NOTIFICATION PROGRAM FOR

NEW DIETARY INGREDIENTS

Monday, November 15, 2004

9:04 a.m.

Harvey W. Wiley Building

5100 Paint Branch Parkway

College Park, Maryland 20740

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C O N T E N T S

AGENDA ITEM PAGE

Welcome - Barbara Schneeman, Ph.D., Director,

Office of Nutritional Products, Labeling and

Dietary Supplements 3

Opening Remarks - Michael Landa, Deputy Director of

Regulatory Affairs, CFSAN 4

Meeting Introduction - Susan Walker, M.D.,

Director, Division of Dietary Supplement Programs 7

Moderator - Vasilios Frankos, Ph.D., Special

Assistant to Division Director, Division of Dietary

Supplement Programs 15

Facilitator - Kelly Williams-Randolph, D.V.M.,,

M.P.M., Consumer Safety Officer, Division of

Dietary Supplement Programs 17

Speaker Group 1

Michael McGuffin, President, American Herbal

Products Association 19

Annette Dickinson, Ph.D., President, Council for

Responsible Nutrition 39

David Seckman, Executive Director and CEO, National

Nutritional Foods Association 56

Speaker Group 2

Alan Feldstein, Counsel, and Richard Collins,

Principal, Collins, McDonald & Gann, P.C. 69

George A. Burdock, Ph.D., President, Burdock Group 81

A. Wes Siegner, Jr., Director, Hyman, Phelps &

McNamara, P.C. 96

Speaker Group 3

John L. Zenk, M.D., Chief Medical Officer,

Humanetics Corporation 116

Paul Bolar, Vice President, Regulatory and Legal

Affairs, Pharmavite 121

Willi Hunziker, D.V.M., MBA, CEO, Hunziker

Consulting 132

Closing Remarks - Vasilios Frankos, Ph.D. 143

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P R O C E E D I N G S

DR. SCHNEEMAN: Good morning. If I could

get everyone to please take their seats, I think

we\'d like to get started. We know we have a full

program, and we want to give as much time as

possible for our presenters and commenters so that

FDA has an opportunity to hear what it is you have

to say.

My name is Barbara Schneeman. I\'m the

Director of the Office of Nutritional Products,

Labeling and Dietary Supplements. That is one of

the offices in the Center for Food Safety and

Applied Nutrition, and we are definitely pleased to

welcome you out here to College Park for this

meeting on new dietary ingredients.

As the meeting has been set up, FDA is

here to listen. We\'ll be gathering comments and

analyzing those over the next few weeks, and we

know that many of you also plan to submit written

comments, and we\'re looking forward to those

written comments as well.

Without further, I want to introduce

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someone from the Center Director\'s office, who is

also relatively new to our office, Mike Landa, who

has been with FDA for quite a number of years but

has just recently taken the position of Deputy

Director for Regulatory Affairs in the Center for

Food Safety and Applied Nutrition. And so I\'d like

to ask Mike to make a few opening comments.

Thank you.

MR. LANDA: Thank you. Thanks, Barbara.

First, let me welcome everyone. Thank you

for coming today to share your views with us. We

hope and expect this meeting will be instructive

for us, but let me add we don\'t anticipate that it

will be interactive; that is, what we expect it to

be is in what\'s called listening mode. The \"we,\"

as you will learn later this morning, will consist

of sort of a listening panel, including myself, Dr.

Schneeman, and several others.

With respect to the NDI notice itself, let

me just say we know there have been requests for an

extension of the comment period. We know it\'s a

long-ish notice, at least in terms of the number of

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questions we\'ve asked and areas we\'ve asked for

comment on. We will be making a decision shortly

on the request for extension, and we\'ll let you

know once the decision has been made.

The purpose of the meeting today, as

Barbara mentioned, is for us to hear presentations

on the Pre-Market Notification Program for NDIs.

We\'re soliciting comments from all interested

persons, from consumers, from industry, from

others, concerning the content and requirements,

format requirements for notifications made under

the statute and in the agency\'s regulations. The

Federal Register notice announcing this meeting

sets out the questions we\'re most interested in

hearing your comments on in great detail. Copies

of the notice, by the way, are on the registration

table outside the auditorium.

We\'ll consider the presentations we hear

today and any comments we get to the docket in

deciding what our next step or steps will be. That

makes it, of course, extremely important that you

make sure to get your comments to the

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docket\--closer? Okay. Is that better? Is that

worse?

\[Laughter.\]

MR. LANDA: To briefly recap what I was

saying, but apparently no one heard, a couple of

points. One, we\'re going to be\--\"we\" meaning the

agency folks here\--we\'ll be in listening mode

today. We may ask clarifying questions of the

speakers, but we are here primarily to listen. In

that sense, we don\'t expect the meeting to be

interactive.

The second point I made was that we know

we have requests for extension of the comment

period in-house. The agency has not yet decided

whether to grant that request. We\'ll let you know

as soon as a decision is made.

The third point was that there are copies

of the notice available at the registration desk.

For those of you who don\'t have a copy with you,

perhaps during a break you can grab one out there.

We will, of course, take into accounts presentations we hear

today and any comments we received

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on the docket in deciding what the next step or

steps will be in relation to new dietary ingredient

notifications. It makes it all the more important

that people make sure to get comments to the

docket. If they are sent elsewhere in the agency,

they may or may not work themselves to the docket,

so please send them there.

In just a minute, I\'ll turn the program

over to Dr. Susan Walker, who is in what we call

ONPLDS, with affection. Susan is Director of the

Division of Dietary Supplement Programs in ONPLDS.

But just before I turn the meeting over to her, I\'d

like to publicly acknowledge the work of the

division in making this meeting happen. I think

ONPLDS certainly in general but the division in

particular really drove this meeting. I\'d also

like to acknowledge the work of a couple of lawyers

in the Office of Chief Counsel who do foods work

for us: Irene Chen and Louisa Nickerson.

I think with that I\'ll just turn the

meeting over to Susan.

DR. WALKER: Thank you, Mike, and thank

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you all very much for coming. We\'re truly glad

that you\'re all here today, and we\'ve been looking

forward to this meeting. Let me see if I can

actually remember how to do this audiovisual piece.

Well, maybe we need an AV person. Oh,

there we go.

What I\'m going to do is very briefly just

introduce the members of our panel today, and then

I\'ll give a very short background about how we got

to where we are today and why we\'re having this

meeting. And I\'d actually like these folks to

stand up because they\'ve done so much work in

getting us to this point. As Mike said, the

division is within the Office of Nutritional

Products, Labeling and Dietary Supplements. Our

Office Director, Dr. Barbara Schneeman, has been

extremely supportive and completely behind our

efforts, and we really thank her for that.

There are three branches in the division,

and we\'ve got Dr. Bob Moore, Compliance. I think

you\'re all pretty familiar with Bob. And then Dr.

Linda Pellicore, Regulations and Review, and Linda

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is really the person you have to get through if

you\'re going to get through the NDI program. So

I\'d like to introduce Linda especially. And then

Dr. Jason Woo, who\'s our Clinical Team Leader.

Also we have Dr. Bill Frankos, Special Assistant

for Science Review, and Bill has recently come to

the agency, about a year ago, and he will be

moderating our session. And we\'ll talk more about

that in a bit.

Now, I\'d like to acknowledge Dr. Kelly

Williams-Randolph, who was very instrumental in

setting up our meeting and making sure this

happened today.

Other members of our panel I\'d like to

introduce: Mike Landa, who you just met; Barbara

Schneeman; and then Dr. Jeanne Rader, who is

Division Director for the Research and Applied

Technology Division; and then Dr. Alan Rulis, who

I\'m sure you all know, who is currently the Senior

Advisor for Special Projects.

Now, in our new dietary ingredient

program, basically we have a variety of ingredients

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that are notified to us, but this is our recent

history, which is predominantly botanicals and

botanically derived substances. So as we move

forward, it\'s important to remember this is a very

large part of what we\'re receiving in our

notification process, and this probably reflects

the fact that the complexity of this area really

drives some of the complexity of this entire

process. And we really have to be aware of these

substances as we move forward.

Now, in looking at our notification

program over the past few years, we\'ve noticed that

there have been many more notifications and that

FDA has been objecting to a larger percentage of

these notifications. And looking at these, we

wanted to determine why is this happening, and

we\'ve identified several factors. These are not

all the factors, but basically they\'re issues about

describing the new dietary ingredient. We need to

know what it is, and that actually sounds like a

very simple question, but it\'s a very complex

issue, particularly with botanicals.

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We need to understand how and why it\'s

eligible to be a new dietary ingredient. We need

to understand what\'s an adequate amount of safety

information for the statutory bar in the law which

is establishing reasonable expectation of safety.

And then we\'ve noticed there\'s other necessary

information that\'s frequently not there, just

general identifying information.

All of these are in dockets and they\'re

publicly available. Anybody can go in there, can

see all the notifications and see all the responses

from FDA.

So this is the history in the past ten

years. The notifications, obviously we\'re getting

more and more, and there\'s a higher and higher

objection rate. Some folks have pointed out that

it\'s likely that there are notifications in here

that may not be new dietary ingredients.

So what\'s really the key to the issue

today? It can be summarized in two slides that I\'m

going to put up here. And this is the discussion

we really need to have over the next few weeks and

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months.

The first piece is when is a substance an

eligible dietary ingredient under the statute,

under 201(ff), which has three sections, so it\'s

going to be very important to look at the basic

eligibility of a substance to be a dietary

ingredient.

So once this gate has been opened and gone

through, the next question is: Was the dietary

ingredient marketed in the U.S. prior to October

15, 1994? Because this is the actual statutory

definition of a new dietary ingredient in DSHEA,

and there are really only two answers. It\'s yes or

no. If it was not, then that substance is a new

dietary ingredient. If it was, then it\'s not a new

dietary ingredient.

The ramifications of this are large

because if you\'re a new dietary ingredient, not all

new dietary ingredients have to notify. A subset

of new dietary ingredients has to notify. So the

next question that\'s going to be very important is:

What is the group of substances that does not have

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to notify? The third important question is: For

those that do have to notify, how do we fulfill

both parts of the notification requirement such

that we don\'t reach a status where that product is

adulterated? Because if there exists a history of

use or other evidence of safety, basically

establishing this reasonable expectation of safety

and FDA has been notified, then that\'s a lawfully

marketed product. If either of these is not met,

that product on its face is adulterated.

So the scope of this meeting clearly is to

discuss and receive comments on the status of

substances as new dietary ingredients; questions

about the chemical identity of a new dietary

ingredient; when and under what circumstances does

an ingredient that may have been available prior to

1994, is there a point at which it becomes new

because it\'s been transformed, there\'s been a

chemical alteration, there\'s been a different

extraction process? We\'ve really got to develop an

understanding of what \"marketed prior to 1994\"

really means in terms of safety because we really

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have to bring this all back to safety. The intent

of that section of DSHEA I would imagine\--this is

me speaking personally, but it\'s the safety

gatekeeper. And if we look at 201(ff), the

identity section, and we look at 413, the new

dietary ingredients section, those two pieces taken

together are a very powerful safety tool.

So we need to look at the standard for

establishing a reasonable expectation of safety,

what type of information should be provided. We

need to look at some of the definitions for new

dietary ingredients. And when we look at all this,

as we said in the notice, we\'ll determine if

there\'s a need for guidance or amending the

regulations.

So in order to proceed with this actually

complicated task, we\'re having this public meeting

today to get started. We\'ll receive the comments

to the docket. We\'ll look at those and then

determine next steps. And for today\'s meeting, I\'d

like to actually introduce Dr. Bill Frankos, who\'s

going to serve as our moderator. Bill is a Special

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Assistant for Science Review within the division,

and he received his Ph.D. in pharmacology and

toxicology from the University of Maryland Pharmacy

School. He has over 30 years\' experience in the

toxicological and pharmacological evaluation of

data used to assess the safety of nutritional

supplements, foods and food additives, drugs,

medical devices, cosmetics, pesticides, and

environmental and occupational exposures. And

prior to joining FDA, Bill was a principal in

Environ Corporation and Associate Director, Life

Sciences Division, at Clement Associates.

Previous to joining the private sector, he

was with us in FDA in the Office of the Commissioner as a

senior toxicologist, and previous to

that at the Office of Food Additive Safety, I

believe. So Bill obviously has a lot of

experience. He\'s going to be very helpful in

moving this process along, and I\'d like to

introduce him today as moderator for our session.

Thank you.

DR. FRANKOS: Thank you. I\'m quite

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excited at the prospect of starting to deal with

some of the issues that have been presented in the

Federal Register notice. The list of questions

that you\'ve all seen is a list that was developed

after the whole division went back and carefully

looked at the process of NDI review and the

problems that occurred. We felt that there were so

many issues that we needed to deal with that we

needed to open this up to the public, get input,

and start a process that is certainly going to take

several months, and we feel that it needs to be a

public process. This meeting is the first of what

I think will be other meetings that may have to

occur in order to bring this together.

The panel that Susan introduced is here to

really listen, but if clarification is needed, they

certainly will ask questions. The ground rules for

the questioning is that we will only be asking

questions that are clarifying questions.

Now, if any members of the audience have a

specific question, a clarifying question they would

like to ask, if you come to one of these mikes here

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and introduce yourselves, we can recognize you.

But I would like those questions to be clarifying

questions, not going into areas that have not been

addressed by the speakers.

I\'d like to introduce Kelly

Williams-Randolph. She\'s been doing a great job

coordinating this notice, and she wants to go

through a little bit of the housekeeping, and then

after that we\'ll start with the speakers. Thank

you.

DR. WILLIAMS-RANDOLPH: Thanks, Bill.

Good morning. I\'d like to start off with a welcome

to the members of the FDA panel, the folks from

industry, consumers, health professionals, and

everybody that\'s here in the audience. I\'d like to

go over some meeting logistics with you, starting

with today\'s agenda.

This morning we will spend with

introductory remarks and one speaker group session.

There will be a morning break at 10:30 a.m. for 15

minutes, and then another speaker group session.

After the second speaker group session, we will

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have another 15-minute break, scheduled for 11:45

a.m., and then have our final speaker group

session. Bill Frankos will then give closing

remarks.

In addition, I would also like to go over

the speaker group session presentation time limits

and time limits for clarification questions from

FDA panel and audience members. Each speaker will

have 15 minutes to present, with a five-minute

follow-up period for clarification questions

regarding the presentation. We will be using a

color card timing formula for keeping speaker

presentations on schedule. A green card will

signal the speaker that they have five remaining

minutes. A yellow card will indicate the speaker

has one remaining minute. And the red card will

indicate that the speaker should finish his or her

sentence.

In closing, you can find bathrooms located

midway between the front entrance of the building

and the registration tables. Signs are also posted

indicating the location of the restrooms, and on

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the back of your agendas you\'ll find a floor plan.

Thank you, and I hope you will find today

useful. Now I\'ll give the floor back to Bill.

DR. FRANKOS: Thank you.

Our first speaker will be Michael

McGuffin, who is president of the American Herbal

Products Association. Michael, can you come up?

MR. McGUFFIN: Thanks, Bill. How do I get

to my presentation here?

\[Pause.\]

MR. McGUFFIN: Good morning. It\'s a

pleasure to be here, and I appreciate the

opportunity to address you all. I really

appreciate the people from FDA inviting me.

I already tried to negotiate an extra five

minutes from Bill, so I hope we can tolerate. I\'ve

got a pretty packed presentation here.

AHPA represents about 200 companies that

sell herbal products, almost exclusively as dietary

supplements, and my primary comments are going to

be the impact of this rule on herbal products.

AHPA will submit substantive comments to the

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docket, and just for the record, we would really

appreciate those extra 60 days. This is a knotty

issue, as you all know, and anything you can do to

give us the time extension will be appreciated.

I\'m going to just move into this in the

interest of trying to get through this in 15 or

maybe 18 minutes, and I want to start with the

definition if a dietary ingredient, specifically as

that applies to botanicals, and I\'m emphasizing

here with these bold lines that there are really

two different classes of botanical ingredients:

the 321(ff)(1)(C), which is an herb or other

botanical, it\'s an unprocessed herbal ingredient;

and then (F) can be a concentrate, a metabolite, a

constituent, an extract, or a combination of any of

the above. And I think it\'s important to think of

these separately. Although much of the information

that\'s required for a new raw material herb or a

new constituent or concentrate or extract are the

same, there are some differences that I\'m going to

point out that I think are important to keep in

mind.

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I\'ll get back to this a little later, but

I want to look, too, at just an overview of what\'s

required in a new dietary ingredient notification.

If you go to 21 CFR 190.6, that\'s where the reg is

written, and I class five different pieces of

information that are required there if you break

down the various subparagraphs. And I don\'t need

to say much about the first or the last. Almost

everybody knows their name and address and

remembers to sign it. But each of these other

things needs some attention: the name of the

ingredient, which with an herb must include the

Latin name; a description of the supplement that

contains the ingredient, including, of course, the

level of use and conditions of use; and the big

deal, the thing that we\'re really after, the

evidence on which a reasonable expectation of

safety is based.

I want to point out something that\'s not

here. It does not specifically state in 190.6 that

you need to identify the dietary ingredient.

There\'s a requirement for a description of the

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supplement. There is not a specified requirement

for a description of the ingredient. I\'m going to

again come back to that later because it\'s

something that we need to pay attention to.

A quick review. As of last week, there

are 249 notices on the docket. Fifteen of these

are for dietary supplements. They don\'t belong

here. There should not be submissions for new

dietary supplements. It\'s not required. It

confuses the system. But where we end up was 194

unique dietary ingredient submissions. There are

also a number of duplicates, a few withdrawn, but

this 249 comes down to 194. And of those 194, I

get slightly different numbers than Susan did, I

think. I count 83 non-herbal dietary ingredients

and 111 herbal. And then the herbal breakdown into

that subparagraph (C), the unprocessed herbs, there

are 33 of those; herbal constituents, which is one

of the words used in subparagraph (F), there are 26

of those, and then there are 52 herbal extracts, or

concentrates or oils or things that aren\'t just the

herb but neither are they constituents.

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I don\'t do as good a job of drawing these

pretty pictures as Susan also, but here\'s just a

pie graph of\--again, you can see over half of these

are botanicals, and they\'re kind of split between

these three subclasses of botanicals.

Then here\'s the outcome, here\'s what

happens if you look at these different subclasses

with regard to the number of notifications, the

number that are filed. And \"filed\" is as close as

FDA gets to \"accepted.\" It means they didn\'t

object to. It means they didn\'t send you back a

letter with the word \"adulterated\" in the letter.

So of the non-herbal ingredients, you can see 63

percent of those are being filed; 65 percent of the

herbal constituents; but the unprocessed herbs,

only one out of five is making it through the

process. And the extracts, it\'s a little greater

than one out of three. So there\'s clearly the

herbal constituents, things like sesamin from

sesame seed, vinpocetine, those are getting

through; whereas, the herbs themselves tend not to.

Now, my interest is herbs, so I\'m, of

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course, concerned about what is it that\'s making it

so that the herbs don\'t get through, and so I\'ve

looked at why FDA refuses to file so many of these.

Some of the issues are very specific to

herbs: plant part not named. Again, though, 190.6

does not specify tell us the part of the plant.

One of the suggestions that AHPA will make, 190.6

should specify name the part of the plant if your

ingredient is a botanical. It\'s obvious. You

don\'t have an ingredient that\'s a botanical without

also naming the part. But it\'s not stated. Some

companies miss that, and we\'d like to help them

address that. This No. 247, that\'s a mushroom, and

FDA said we don\'t know what part of the mushroom.

So those were both objected to or rejected.

There\'s confused nomenclature in the last one

filed, this plum extract, where the filing company

said we\'re not sure if it\'s Terminalia ferdinandiana or

lapides. FDA said, well, if you don\'t

know, then we don\'t know. It turns out those are

two different names for the same plant. They

should have called me and I could have helped them

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with that. But, nonetheless, that kind of

confusion gets an objection notice. Or in the case

of freeze-dried kimchi\--I love it. Somebody wants

to sell us freeze-dried kimchi, but they didn\'t

tell us that it was Brassica, so FDA said we don\'t

know what to do with that.

Many of the other reasons that FDA objects

to herbal filings, though, are the same that they

object to the non-herbal filings, and Susan pointed

out some of these. I\'ve quoted from some specific

notices. \"It is unclear\...whether the test

substances used in the referenced studies are

qualitatively or quantitatively similar to\" to your

new dietary ingredient. So somebody says I want my

ganiderma product to come to market, and here\'s a

whole lot of information about ganiderma extract,

but they don\'t clarify that it\'s, in fact, their

ganiderma extract. FDA says we don\'t have any

information that\'s a basis for knowing that your

ingredient is safe. I\'ve seen that one over and

over and over. And then as Susan also mentioned,

inadequate information to clearly identify the

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ingredient.

There have been other issues. Things have

been rejected just because they\'re frank toxins,

things like extract of oleander\--thank you for

rejecting that one\--pokeweed lectins, illegal

substances like GBL, and then sometimes because the

described dietary supplement is in a form that

doesn\'t fit the definition. My favorite one is an

herbal eyepatch which FDA wisely chose to reject.

With regard to this second point here,

though, the inadequate information presented to

identify the ingredient, I want to repeat, 190.6

does not specifically state identify the

ingredient. Again, it\'s an obvious recommendation

that AHPA will make that 190.6 should, in fact,

state that the identification of the ingredient

must be included.

The next two slides are looking at the

requirements set in 190.6 and breaking it down into

the identity, the description of the supplement in

which the product goes, and the evidence of safety.

And I have two slides here. This one is for

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subparagraph (C), which is herb or other botanical.

And my position is that all you need to identify an

herb is the name of the herb and the part. You

don\'t need chemistry. You don\'t need anything that

goes further than that because peppermint leaf is

peppermint leaf if that\'s what I\'m selling. Now,

that\'s an old ingredient, but just to make the

impression. Whereas, if it\'s anything in (F), if

it\'s an extract, if it\'s a concentrate, clearly you

need a lot more information, and all of these

points are actually from a document that AHPA

produced a couple of years ago, a guidance on

manufacturing of extracts that I will leave a copy

into the record here.

You have to disclose the solvents, the

ratios, all other ingredients. You need to

describe the process. Is it a liquid product or a

solid product? And then these bracketed items\--the

markers, characterization, and purity\--are often

but not always relevant. It\'s a much more dense

process once it moves from an unprocessed herb.

Whereas the dietary supplement description, it\'s

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not any different for the subclass (F), which are

the extracts and concentrates, than it is for the

raw herbs. And the only difference that I have on

evidence is that the evidence of the herb would be

history of use and other evidence, whereas the

extract you can argue that the history of use of

similar dietary ingredients, like the raw herb, has

relevance.

I also want to point out that in the

description I\'ve made a pointed statement that

there is not a requirement to identify the other

dietary ingredients. Most companies want to say,

\"My new dietary ingredient is this ingredient, and

the use is 50 milligrams in a dietary supplement.\"

Most of those submissions have gone through. Most

recently, FDA in one letter said, well, we don\'t

know what the other ingredients are, so how would

we know that the supplement is safe? We want to

argue against FDA taking that any further.

Old versus new, again, the class (C) and

the class (F) are different. With regard to just

herbs\--roots and leaves and seeds and things that

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are just parts of plants\--AHPA in 1995 sent out a

call to industry to identify old herbal dietary

ingredients. The next year we submitted a list of

over 1,600 herbs to FDA, identified those as

believed to be in commerce prior to the date, and

in 2000 we published \"Herbs of Commerce,\" 2nd

edition. We added about 400 other plants in the

meantime, numerous Chinese plants, numerous

Ayurvedic plants, fungi, algaes. It\'s a very

thorough document.

We also disclaimed it in two different

ways. The first disclaimer says just because it\'s

here doesn\'t mean it was marketed prior to the

date. And the second one says just because it\'s

not doesn\'t mean it wasn\'t.

Our thinking here was we accepted

submissions honorably. We believed that they were

submitted honorably. But we didn\'t go out and

double-check or prove that chamomile had, in fact,

been marketed prior to the date. Nonetheless, it

is AHPA\'s position that even though \"Herbs of

Commerce\" may not be authoritative, this disclaimer

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should not be read as a reason to abandon our text.

It should not be seen as assuming that there is no

relationship whatsoever between the listing of an

herb in \"Herbs of Commerce\" and its marketing prior

to the date. That is what we asked people to tell

us. We think it has relevance. We think it does

create a presumption of presence in the

marketplace.

If the agency wants to take it further and

get to something like an authoritative reference,

AHPA is uniquely positioned. We would be happy to

discuss being actively involved in a process or

being contracted for a process to do an old dietary

ingredient substantiation for botanicals. We know

a lot about this issue.

Then with regard to old herb extracts\--and

by extracts I mean everything in (F)\--we didn\'t go

out and say tell us all of the extracts. We didn\'t

ask that kind of thing a decade ago. But there are

standard accepted extract forms: decoctions,

liquid extracts, dry extracts, tinctures. There

are long accepted food-grade solvents, and I\'ve

31

listed numerous of those here; established

extraction processes. And there is a reason to

think that all of the common herbs were

manufactured by all of these common processes with

all of these common solvents. And if I\'ve got a

32-percent ethanol chamomile, I shouldn\'t have to

prove that a 32-percent ethanolic extract of

chamomile was marketed because it\'s in the range of

reasonableness that it was marketed.

I also want to point out there are other

solvents that I didn\'t list here and other

extraction processes that had come into the

marketplace, not as extensively, things like hexane

and acetone, super-critical gases and

super-critical extraction.

Let me move then to suggestions, and the

first few here I\'m just repeating, modifications to

190.6, and an assumption that \"Herbs of Commerce\"

herbs are \"old,\" as are extracts by common

processes. I\'m repeating, we\'d really like to see

the agency just not accept filings for new dietary

supplements. Those are wrong. They create a

32

bizarre record where now there\'s a document that

says that licorice root and ginseng aren\'t allowed

to be sold because somebody submitted\--actually,

they don\'t say that. They say your product may be

adulterated which contains this ingredient. There

are these lawyers in California that will make lots

out of that. We\'d really like to see that stop.

We\'d also like to see the agency refuse

filings for obvious old dietary ingredients, and

I\'ve listed a number of them here.

With regard to enforcement, I think it\'s

obvious that enforcement needs to be prioritized

based on safety concerns, and one point in passing,

Susan mentioned the food exemption if it\'s present

in the food supply and not chemically altered, and

we want to make sure that the agency thinks what we

think, that international food supply counts

against that clause.

We\'d like to see restraint from overly

broad or maybe I mean overly narrow interpretations, but

I\'ve given some examples. For an

herb, for the agency to say you didn\'t give us

33

specifications on purity, that\'s a GMP issue, not a

new dietary ingredient issue. Compositional

analysis, I\'ve made my pitch that I don\'t believe

compositional analysis of chamomile flowers is

warranted; whereas, chamomile extract in a new

solvent and a new extraction method may be. And,

also, this issue about I really strongly argue

against any requirement that the only way I can get

my new dietary ingredient approved is to disclose

every other ingredient that it may ever be marketed

with. That puts an unfair burden on every product

that has a single new dietary ingredient versus the

whole world of products that have only old dietary

ingredients. And we would oppose that.

There\'s a tendency for companies to

resubmit when they change the dose and that I think

is wise, but we\'d like some guidance on that.

There ought to be minimum criteria for FDA to

review a submission. I\'m not sure what those are,

but I\'m sure that they do include all of the

administrative parts of 190.6, if it\'s not in

triplicate, if it\'s not signed, if it didn\'t

34

disclose the plant part, those kinds of what I

called here administrative or technical issues.

And then, of course, the identity of the new

dietary ingredient, if it\'s not identified I don\'t

think the agency should go through that whole

process of sending it back saying your ingredient

is adulterated. I think the agency ought to not

accept it, and I know that the record shows the

agency does go back and ask for more information.

We encourage that. We\'d love to see more timely

access at FDA\'s docket. I notice today it\'s really

up to date. We appreciate that. But I also know

that you pushed a bunch of stuff through in the

last few weeks. We appreciate that.

In closing, AHPA and another organization,

NPI, we\'re in the middle of creating a searchable

database. We\'re going to make it so that you can

go in and search for astaxanthin or licorice or

whatever and find every submission that mentioned

that. We\'ll also search\--we\'ll provide a summary

outcome statement of what happened, was it filed or

was it objected to.

35

A couple things that I didn\'t get on here,

we\'d love to see an opportunity to withdraw that\'s

very similar to what happens in a GRAS notice.

There have been three or four withdrawals, one of

which the agency refused to allow. We think that

it ought to have rules that are a very similar to

the GRAS withdrawal process.

We need to see consistency. I know that

FDA intends to be consistent, but I can find

examples. Astaxanthin, there have been five

submissions\--the three that were submitted prior to

2002, those were accepted; the two that were

submitted this summer were not. I don\'t know that

they were markedly different, those ingredients.

If they were not, we\'d need to understand did

something change in the policy, because it needs to

be very consistent, and I think you understand

that.

I know that there\'s a new emphasis now on

the agency saying exactly which subparagraph of a

dietary ingredient is it in. I think that\'s a good

question. But I also don\'t think that when

36

the\--that\'s not a reason to object to a filing just

because somebody didn\'t tell you that they believe

that deer antler is in subparagraph (E) or that

carnitine is also in subparagraph (E).

Maybe my last statement. The industry

needs to see the whole process of the new dietary

ingredient notification as a gate through which new

ingredients can come, not as a barrier that refuses

to allow new ingredients into the marketplace. And

we really look forward to working with the agency.

Guidance is definitely needed.

One point I forgot to make, some of these

submissions are just a mess, and that needs to be

acknowledged. Some of them don\'t deserve to be

filed. They\'re embarrassingly narrow in the

information that\'s submitted, and I think I can

close it there.

DR. FRANKOS: Thank you, Mike.

Any questions? Linda.

PARTICIPANT: Mike, I wonder if you could

tell us what NPI stands for on that last slide.

MR. McGUFFIN: You know, on the Metro on

37

the way in, I thought\--I\'m fairly certain it\'s the

Natural Products Institute. I think that\'s what it

is. They\'re a publication company in our trade who

does a lot of work in communication, and we\'re

partnering with them to put this thing together.

DR. FRANKOS: Mike?

PARTICIPANT: When you compiled \"Herbs for

Commerce,\" did you ask for documentation?

MR. McGUFFIN: We did not. We just asked

for people to tell us, some companies provided\--oh,

sorry. Yes, the question was, when we compiled the

information for \"Herbs of Commerce,\" did we ask for

documentation? No, we did not. We simply asked

for people to inform us what they were selling.

Some companies provided us with notarized

statements. Some companies provided us with copies

of their catalogues or advertising. And, also, I\'m

kind of a pack rat. I\'ve got a whole box of

catalogues from \'93 and prior.

DR. FRANKOS: I have one question. When

you said that whole herbs history of use is

relevant for evaluating the safety of extracts, I

38

was curious how you would use that data when there

are so many forms of extracts.

MR. McGUFFIN: I\'ll tell you what. The

question is: How would I use information about

whole herbs to evaluate the safety of an extract of

that whole herb? What I have done, Bill, is I\'ve

looked at all 249 of these. What I haven\'t done is

file one. So I\'m not sure. I think some of the

toxicologists that are going to talk to us might

have more relevant responses to that because I

think the way that you would use it, though, is the

more that you could show that your extract had a

chemical characteristic that was similar to the raw

botanical, then I think you\'re going to be able to

use that as information that suggests that we\'ve

been using that for some number of years or

generations.

DR. FRANKOS: Thank you.

Yes, Jason?

PARTICIPANT: \[inaudible, off microphone\]

you\'re specifying international use as a food, not

as a medicine or\--

39

MR. McGUFFIN: Correct. Yes, the question

is with regard to my call for international use,

there\'s that one\--I forget. What is it? I forget.

The one that says that you\'re not required to

submit a new dietary ingredient that is present in

the food supply in a form that\'s not chemically

altered. That\'s exactly the part I\'m saying. If

it\'s present in the food supply in South Africa,

that\'s okay; it doesn\'t have to have been present

in the food supply in South Dakota.

DR. FRANKOS: Okay. Thank you.

MR. McGUFFIN: Thank you.

Our next speaker is Annette Dickinson.

She\'s president of the Council for Responsible

Nutrition. Annette?

DR. DICKINSON: Good morning, and thanks

to FDA for the opportunity to be here and for

beginning this initiative.

The Council for Responsible Nutrition is

one of the leading trade associations for the

dietary supplement industry. Our members include

mainstream manufacturers of dietary ingredients

40

themselves, as well as manufacturers of both

national brand names and private label dietary

supplements. And we also have a number of members

whose interest is international in scope.

We want to congratulate FDA for the three

documents that were issued in the last few months,

all of which are intended to move the agency and

the industry toward full implementation of DSHEA.

We don\'t believe anything is more important to

solidifying the confidence in dietary supplements

and the confidence both on the part of the

regulators and on the part of Congress as well as

consumers than moving to full implementation, and

we congratulate the agency over the past couple of

years for a number of initiatives toward full

implementation and enforcement, which we believe is

necessary.

At the same time, we are concerned that

that enforcement and implementation be consistent

with the intent of DSHEA, and I know that the staff

at FDA is determined to make that happen. The

purpose of DSHEA was to ensure consumer access to a

41

wide variety of products and also to provide

consumers with more information about the uses of

those products. The intent of DSHEA was to affirm

the safety of a broad array, a very broad array of

existing dietary ingredients and establish a

notification process for new ingredients that was

distinct from, deliberately distinct from and

intended to be less burdensome than the food

additive approach that the agency was using at the

time.

We have also submitted in conjunction with

this meeting a statement prepared by our legal

counsel, Peter Barton Hutt, which was prepared at

the request of both CRN and one of our sister

associations, CHPA, the Consumer Healthcare

Products Association, which presents his legal view

of the status of dietary ingredients and new

dietary ingredients.

The definition of dietary ingredients in

the act is extremely broad and was meant to be

broad, and any discussion of new dietary

ingredients we believe must begin with a discussion

42

of what fits within the rubric of dietary

ingredients in the first place.

While we agree that safety is an important

factor in determining whether an ingredient may be

marketed and also an important factor in

determining whether an NDI notification is adequate

for its purpose, safety is not necessarily a factor

in defining the category per se, that is, the

category of dietary ingredients. And I\'ll offer a

couple of examples of why that must be the case.

One of the categories of dietary

ingredients is minerals. Minerals is an extremely

broad category. Minerals typically occur

naturally, not as elements but as various

compounds. Calcium, for example, is an essential

nutrient, an essential mineral which occurs

naturally as calcium carbonate and some other

forms. However, it has been used for many years in

dietary supplements and is grandfathered in other

forms that actually do not occur naturally, such as

calcium citrate. This illustrates a point, which

is that we do not believe the inclusion of a

43

mineral in this category depends on it being in a

naturally occurring form. In addition, we do not

believe that inclusion in the mineral category is

limited to nutrients that are essential. Calcium

is certainly an essential mineral. But there are

many others, such as tin, vanadium, silicon, and

boron, that have for many years been present in

very popular national and private brands of

multivitamin/multimineral formulations, and we

consider all of these to be grandfathered

ingredients.

Likewise, the area of botanicals is an

extremely broad category. It includes common and

generally safe ingredients such as ginseng, garlic,

and ginkgo. It also includes ingredients about

which some safety concerns have been raised, such

as comfrey, chapparal, and kava. The fact that

there may be safety concerns that need to be

addressed does not mean that the ingredient doesn\'t

fall definitionally into the category. It is an

issue that needs to be dealt with separately, and

we urge FDA in its proceedings to keep these two

44

sides of the issue separate, that is, what falls

within the category of the definition and where

safety issues may arise.

Another category of ingredients in DSHEA

is dietary substances. We believe dietary

substances is an extraordinarily broad category and

must be accepted as broad. There is a colloquy

that we refer FDA to in our written comments that

occurred during the passage of NLEA, not DSHEA,

back in 1990 and that focuses on what might qualify

as a nutritional substance. We believe that all of

the substances mentioned in that colloquy, which

include enzymes, coenzyme Q-10, evening primrose

oil, and various other substances, certainly fall

within this category of dietary substances.

The next question has to do with if

something is an ingredient, is it a grandfathered

ingredient? In order to be grandfathered, there

are three criteria that must be met: the

ingredient must have been on the market in a

dietary supplement; it must have been on the market

in the U.S.; and it must have been on the market

45

prior to October 15, 1994.

The vast majority of dietary supplements

on the market currently contain grandfathered

ingredients, and there is no suggestion in the law

itself that there are any circumstances under which

an old ingredient would become a new ingredient.

This is something that is going to require

considerable discussion within FDA, within our

various associations, and among us all during this

period of comment that we have available to us. We

have discovered in our various conference calls

leading up to this meeting that we don\'t

necessarily have agreement within our association

about the breadth of what might be grandfathered

and whether there are conditions under which an old

ingredient might become a new ingredient. So this

will be, I am sure, a fertile field for further

discussion as we move forward here, and it\'s

another reason why we did join with AHPA and NNFA

and other associations in requesting an extension

of the comment period.

Another issue I\'d like to raise is that in

46

some of FDA\'s recent enforcement actions, warning

letters, FDA has taken the position that certain

ingredients were not grandfathered because they

were not legally marketed before 1994. The term

\"legally marketed\" does not appear in DSHEA, and we

do not believe that necessarily legal marketing is

a criteria for what is grandfathered, and I want to

give you three examples of why that might be the

case.

The first two involve the essential trace

minerals selenium and chromium. On several

occasions during the decades prior to the passage

of DSHEA, FDA took the position that selenium and

chromium were not formally recognized as food

additives and were not formally approved as GRAS

substances and, therefore, were not, technically

speaking, legally marketed as dietary supplement

ingredients. Nevertheless, as we know, these

ingredients were commonly marketed in dietary

supplements prior to DSHEA and are still commonly

marketed in dietary supplements. And, in fact, FDA

has now established an RDI for both of these

47

minerals. Therefore, it cannot be a criterion

chromium and selenium being legitimate ingredients

of dietary supplements and being grandfathered that

FDA should have viewed them to be legally marketed

prior to DSHEA.

Another example is amino acids. Under FDA

food additive regulations, there were very limited

conditions under which amino acids could be added

to conventional foods, and technically FDA viewed

them as not being legal ingredients in dietary

supplements. Nevertheless, they were widely

markets as dietary supplements and still are and,

in fact, now have their own subcategory in the

definition of dietary supplements. Therefore, we

believe this is another illustration that

grandfathering cannot be denied based on a narrow

interpretation of whether an ingredient was legally

marketed prior to DSHEA.

In these comments today, CRN is going to

focus really on some very broad issues and not

delve into most of the detailed questions that FDA

presented in the Federal Register notice, although

48

we will certainly do that before the end of this

process.

In describing the information that should

be provided in a new ingredient notification, we\'re

going to skip over most of those questions, but we

are going to indicate that one of the concerns that

has come through loud and clear from our members is

that FDA should be aware that much of the information they

have requested, particularly regarding

processing, may be proprietary information. And as

we move forward, there will be a need to assure

that proprietary information can be protected.

In addition to requesting information

about the dietary ingredient, FDA requests certain

information regarding the dietary supplement, and

we believe this is entirely appropriate. DSHEA

refers to the new ingredient notification needing

to provide information on the basis of which the

dietary supplement itself can be expected to be

safe. However, as one small part of this section,

FDA asks the question whether a label should be

required to be submitted at this point. We would

49

simply note that in many cases the dietary

ingredient notification is filed by the ingredient

supplier or by a manufacturer during a pre-launch

phase of development of the product, and a label

simply may not be available at that point, so we do

not believe submission of a label should be a

critical part of that process.

Really the core question facing all of us

here and the core question that will need to be

resolved before the end of this process is: What

type of information should be included in an NDI

notification in order to establish a reasonable

expectation of safety? FDA has outlined a number

of questions that are very good questions that

should be considered by every company submitting an

NDI notification. However, we do not believe that

the questions posed should be viewed as an absolute

requirement or an outline for the information that

must be submitted in a notification. We believe it

really goes beyond what we see as the intent of

DSHEA in establishing this notification process.

In particular, members of our association

50

who are very familiar with food additive petitions

look at this list of questions and they see

something very similar to a \"Red Book\" list of what

must be submitted for a food additive. Members of

our association who are on the pharmaceutical side

look at this list and they see great similarity to

what might be required for an NDA filing. And we

do not believe either the food additive model or

the NDA model was intended to be the basis for

describing what needs to be included in a new

ingredient notification.

We would request, as we move forward with

defining what does need to be included, that FDA

express its openness to consultation with companies

who are considering an NDI notification in order to

help them direct their information in such a way

that the NDI notification will include the

information FDA expects to see and that the company

can improve its chances of having the NDI

notification accepted.

Some FDA personnel in the last little

while here, the last month or so, have made

51

presentations in which they have indicated that

they really see no difference in the standard of

safety that is described in DSHEA and the standard

of safety that is expressed for food additives. We

cannot agree with this assumption because we

believe that when Congress wrote DSHEA, it

certainly was aware of the standards of safety that

are set for food additives, and it chose to

establish a different statement. It indicated that

new ingredients should be reasonably expected to be

safe. Furthermore, in terms of the process, it did

not permit or require FDA to actually approve an

NDI; that is, there is no formal approval of the

NDI from FDA once the document is submitted.

What is required is that the manufacturer

or distributor should have in its holdings and

should submit to FDA sufficient information to

support the manufacturer\'s determination that the

ingredient and the product are reasonably expected

to be safe. We believe those are significant

differences from the food additive model and that

FDA should clearly incorporate those aspects into

52

their consideration.

There are other models than the classic

food additive model that we believe bear

consideration here as FDA looks for a model on

which to base the new ingredient notifications. In

particular, the GRAS self-determination process we

believe is an extremely effective and flexible

process. I don\'t know what\'s happening to my\--it

looks fine right here on this screen. I don\'t know

what\'s happening up there. We believe the GRAS

self-determination process is an example of a

highly effective and flexible process which allows

manufacturers to make a determination of safety,

relying heavily on the input of experts or

committees of experts to help them make that

determination and to help respond to any questions

FDA may have.

There are other programs that might be

considered. For example, the EPA has a program

that it puts new chemicals through when it approves

new chemicals for introduction into the

environment, which involves a functional analysis,

53

a functional safety analysis\--a structure activity

analysis, is what I\'m trying to say, of the

compound as it relates to other compounds in the

same class. And we think this might have some

relevance to FDA\'s review as it pertains to new

ingredients that are single chemicals.

Likewise, Canada\'s Natural Health Products

Directorate has recently\--is just this year

implementing a whole new program of review,

including protocols for safety evaluation of

natural health products, and we believe there may

be some elements of this that would be relevant to

this program.

FDA itself has adopted on occasion other

methods than the food additive method for looking

at safety of various ingredients in evaluating

health claims for psyllium and stanol and sterol

esters. FDA found that those ingredients did not

have official regulatory status at the time the

health claim was evaluated and required the

companies to submit certain additional information

on the safety of those ingredients, and we think

54

the nature of those submissions may be relevant to

this process.

Finally, FDA\'s guidance on new plant

varieties produced through biotechnology also

relies heavily on manufacturer determination of

safety and on comparability to existing plant

varieties with a minimal or no reliance on actual

clinical testing to go along with that.

FDA addresses the need for definition of

certain other terms that appear in DSHEA, and we

will reiterate here the same point that we made

with regard to dietary ingredients. All of the

terms should be understood broadly and literally,

terms such as extract, constituent, metabolite, and

the issues having to do with safety or other

considerations that arise because of the breadth of

some of those definitions we believe should be

dealt with directly and separately and not used as

reasons for restricting the definition itself.

We do endorse the seven recommendations

FDA made in the Federal Register notice for

improving the format and content of notifications,

55

and we will be addressing those in more detail in

further iterations of our comments on this issue.

Finally, we congratulate FDA for

undertaking this initiative and also for fully

involving all stakeholders, which we believe is

critical to the successful outcome of this

discussion. And we look forward to future

opportunities to work with FDA to improve the

confidence with which consumers, regulators, and

legislators can view this product category.

Thank you very much for this opportunity.

\[Applause.\]

DR. FRANKOS: Any questions?

\[No response.\]

DR. FRANKOS: Annette, I have one

question. With respect to using a GRAS

self-determination process, how would you see that

fitting into the NDI notification process?

DR. DICKINSON: I would see that fitting

in in a way similar to the current GRAS

self-determination process where a company may

submit their determination to FDA and request

56

listing of that GRAS notification. In that process

also, FDA does not formally approve the GRAS

ingredient, but simply arrives at a point where it

has no further questions. But the company would

ahead of time do its analysis of the safety,

including relevant involvement of experts.

DR. FRANKOS: Thank you.

Okay. Our next speaker is David Seckman,

and he is Executive Director and CEO of the

National Nutritional Foods Association.

MR. SECKMAN: I\'m David Seckman, Executive

Director and CEO of the National Nutritional Foods

Association. NNFA was founded in 1936 and is the

oldest and largest trade association in the natural

products industry. We represent the interests of

more than 8,000 retailers, manufacturers,

suppliers, and distributors of health foods,

dietary supplements, and related items. I

appreciate being able to submit this testimony in

response to the FDA\'s request for input on

pre-market notification for new dietary

ingredients. And I think I\'m glad I didn\'t have

57

slides today.

\[Laughter.\]

MR. SECKMAN: Just kidding.

NNFA has consistently supported FDA\'s

ability and efforts to enforce the Dietary

Supplement Health and Education Act of 1994 and to

ensure that dietary supplements continue to be

safe. In fact, in May of 2002, we submitted

comments to FDA suggesting ways for FDA to enhance

the quality, utility, and clarity of the pre-market

notification requirements for a new dietary

ingredient under Section 413. We continue to

believe that FDA could use public comments on

Section 413 to provide the industry with much

needed guidance on NDI submissions. Of course, any

guidance will apply to any company putting dietary

ingredients on the market, whether they be the

manufacturers of finished products or raw

ingredient suppliers who need to guarantee safety

to their customers.

What everyone in the industry needs is

clear guidance. Specifically, NNFA believes that,

58

as written, Section 413 is unclear both as to when

a new dietary ingredient notification is required

and the type of information to be included if a

pre-market notification is filed. In light of

FDA\'s November 4th publication of its major

initiatives for dietary supplements, NNFA

specifically urges FDA to use caution in enforcing

on NDI issues before it offers clarification to

industry as to when a pre-market submission is

required. Although NNFA will be commenting in more

detail later, the following are a couple of key

issues and comments that we think that need to be

addressed in the guidance.

Our first issue concerns the not

chemically altered exemption. According to Section

413, a dietary supplement containing an NDI is not

adulterated if the dietary supplement contains only

dietary ingredients which have been presented in

the food supply as an article used for food in the

form in which the food has not been chemically

altered. Thus, the chemically unaltered

ingredients from the food supply does not require

59

NDI filings to be made before being used in a

dietary supplement.

The legislative history of DSHEA offers a

small bit of clarification of what is meant by

chemically altered, and I quote: \"The term

\`chemically altered\' does not include the following

physical modifications: minor loss of volatile

components, dehydration, lyophilization, milling,

tincture or solution in water, slurry powder, or

solid in suspension.\" Clearly, many forms of

processing have been left off this list, and FDA

has not offered industry guidance of how to

determine whether a process would or would not be

considered chemically altered.

NNFA takes the position that a dietary

ingredient should fall within its not chemically

altered exemption as long as the resulting dietary

ingredient is found in nature. Supplements are a

subset of food. They need to be regulated

accordingly. If it can be shown that an ingredient

either is a single entity or complex, can be found

in our diets, and there is no evidence of ill

60

effects, that ingredient should be allowed for

sale. Moreover, FDA should not assume that changes

in the processing or formulation always result in a

change in the chemical structure that would require

an NDA filing. Such an interpretation is

consistent with the intent of Section 413 in that

it would require exempt entities which known safety

records based on food usage from the NDA pre-market

submission requirement.

Our next concern in regard to Section 413

is the lack of clarification as to whether

components of food, such as the lycopene found in

tomatoes are subject to the pre-market notification

requirement. NNFA takes the position that

components would also be subject to the not

chemically altered exemption in Section 413(a)(1);

thus, if the extraction method used to isolate

components does not results in the chemical

alteration of the component, the component should

be exempt from the NDA filing requirement.

Moreover, the 413 exemption should extend to the

components to the components that are chemically

61

altered during the extraction process but are in a

form that is found in nature. Such components,

again, have been proven safe within the food

supply.

NNFA\'s next concern is in regard to how

the NDI substance should be chemically identified,

an issue FDA raised in numerous questions about it

in the Federal Register notice. NNFA takes the

position that chemical identifications of a

substance must reflect the level of variation of

the substance that is found in nature. For

example, botanical ingredients vary in composition

depending on where in the world they are grown.

Certainly the agency would not require an NDI

notification for each region unless there are

significant differences that result in a safety

issue. In addition, other ingredients may vary as

percentage of certain confirmations. Again,

however, this level of differences should not

trigger the new NDI requirements as long as the

variation reflects that which is found in nature.

Next I would like to comment on the type

62

of information about a dietary supplement product

that should be included in the NDI notification.

NNFA has some specific concerns about conditions of

use and labeling as put forth by the FDA in its

notice. NNFA would like to point out that when the

agency raises such questions, it blurs the line

between an NDI and a dietary supplement product as

a whole. FDA should not be concerned with how an

ingredient was used unless it was previously used

as a drug, which raises other sections of DSHEA or

how it was labeled. This information does not go

to the safety of the dietary ingredient and should

not alter the review process as to whether a

specific dietary ingredient is safe for use.

My final comments have to do with

establishing a reasonable expectation of safety.

FDA raises the question of what quality and

quantity of data and information are needed to

establish a reasonable expectation of safety based

upon the history of use. NNFA takes the position

that FDA should establish clear parameters

regarding what kinds of evidence would sufficiently

63

demonstrate reasonable evidence of safety.

However, NNFA cautions that FDA\'s guidelines should

not be so rigid so as to establish inflexible

requirements. The kinds of data available for

dietary ingredients vary widely, from very long

documented history of use to clinical studies to

observational reviews. The kinds of data available

may also change over time. NNFA is concerned that

the NDA process, along with the FDA\'s recently

issued initiatives, does not become a mechanism to

stifle or halt NDI submissions by presenting an

almost insurmountable barrier for acceptance. To

adequately reflect this reality, FDA should

continuously exercise flexibility in the types of

evidence required, for example, where an NDI does

not have a long history of consumption by human,

such as novel extractions of grandfathered

botanicals. Moreover, an NDI that is an extract

from an old dietary ingredient and is significantly

similar to the old dietary ingredient might require

less safety data than a new one. To respond

otherwise would result in the stifling of research

64

and development for the use ingredients.

FDA also raises questions about what

quality and quantity of data and information are

needed and to establish a reasonable expectation of

safety based upon information other than a history

of use. Here, NNFA would simply like to point out

that while a certain amount of scientific evidence

is certainly necessary to establish safety, the

burden should not be so high as to mirror a drug

safety review. NNFA submits that information to

establish a reasonable expectation of safety should

suffice. This may include animal and in vitro

studies conducted in an appropriate model or other

test.

Finally, the FDA specifically questioned

what types of documentations are necessary to

establish that an ingredient was marketed in the

U.S. before October 15, 1994, and thus

grandfathered. NNFA and other industry groups in

1994 took the lead in developing lists that

reflected products marketed prior to that year.

Those lists have been relied on by industry, by

65

industry lawyers, consultants, and presumably even

the FDA. NNFA submits that they have achieved

authoritative status and should continue to be

available to be relied upon for confirming

grandfather status. I\'d also like to point out

that if an ingredient does not appear on one of

these lists, it may also be grandfathered if there

is evidence of marketability prior to October 1994.

Examples of such evidence may include human

studies, product advertisement, product catalogues,

order forms, and invoices.

Again, in closing, I\'d like to thank the

FDA for the opportunity to comment on the NDI

process.

DR. FRANKOS: Thank you.

Any questions? Jason?

PARTICIPANT: \[inaudible, off microphone\]

variation in nature. Does that mean just in one

species or parts or portions of the plant or

\[inaudible\]?

DR. FRANKOS: Can you repeat the question,

please? Or go to a mike, yes.

66

MR. SECKMAN: You want clarification of

what\--

PARTICIPANT: Clarification to variation

in nature, extending to just the different growing

conditions you might find in botanicals, or

different portions of the plants being used?

MR. SECKMAN: Both.

DR. FRANKOS: Any other questions?

PARTICIPANT: How did you postulate human

studies that may have been done on an ingredient

prior to October of \'94 would constitute reason for

those ingredients to be grandfathered in?

\[inaudible\] on ingredients never led to or related

to those ingredients being sold in the marketplace?

MR. SECKMAN: Did everybody hear the

question?

DR. FRANKOS: No. I think paraphrase it.

MR. SECKMAN: Studies done on humans

before 1994, is what your question really was, how

does it relate to the new dietary ingredients for

the new dietary ingredient requirements?

PARTICIPANT: Right. I asked \[inaudible\].

67

DR. FRANKOS: Mike, please.

PARTICIPANT: Okay. I asked you how is it

that you could postulate that human studies or

studies\--you know, clinical trials perhaps, done

prior to October of \'94 on certain dietary

supplements or ingredients should be equivalent to

those ingredients being grandfathered in if those

ingredients were never sold on the marketplace?

MR. SECKMAN: I mean, there are valid

studies that were done prior to. They just haven\'t

been used in the filing of the new dietary

ingredient. I think you can make a fair argument

to that sense and be able to file it based on that

information. I think that should be able to be

used.

PARTICIPANT: Will the person who just

asked the question identify himself, please?

MR. KALMAN: The person that asked the

question was Douglas Kalman from Miami Research

Associates.

DR. FRANKOS: Any other questions?

\[No response.\]

68

DR. FRANKOS: Okay. We\'re on time,

actually a little early. I think we could just go

right into a 15-minute break and then start again.

I would like to point out that the next speakers

can go to a breakout room during the break and

prepare their slides. There\'s a room set up. I

don\'t know what room it is, but it\'s next door to

the auditorium.

PARTICIPANT: 1A-001.

DR. FRANKOS: 1A-001.

\[Recess.\]

DR. FRANKOS: We\'re having some

audiovisual problems, so I\'d like it if everybody

could come back together, we\'ll have Alan Feldstein

give an oral presentation, so he is the slides, and

so we can start, and hopefully they\'ll get the

audiovisual stuff together shortly.

And one other thing: There is overflow in

Room 1A-001, if there are not enough seats or if

anybody is feeling hot, there is a room that has

been set up, and there is an audiovisual connection

in that room as well. So there are also chairs

69

that are open down here at the bottom, up front.

I think we will start then with Alan

Feldstein. He is counsel with Collins, McDonald &

Gann. Alan, I think they\'re working there. Maybe

you could sit here.

MR. FELDSTEIN: Sure, that would be fine.

Good morning. Can everybody hear me okay?

Great. Collins, McDonald & Gann is a law firm

located in the State of New York that represents

manufacturers, distributors, marketers, and

individuals in the sports and fitness supplement

industry. Again, my name is Alan Feldstein, and I

am your slides today. And with me is my colleague

Richard Collins, principal of the firm; I\'m of

counsel of the firm.

Again, as everyone has said, we appreciate

the opportunity to share our thoughts, and we

welcome the opportunity to present our comments on

this matter, which is of great importance not only

to our clients but to the segment of the industry

we represent as a whole.

We have reviewed the Federal Register

70

notice of this meeting, and we have also read with

great interest the recent Guidance for Industry on

Substantiation for Dietary Supplement Claims, as

well as Dr. Crawford\'s recent statements before the

Council for Responsible Nutrition. And while

today\'s meeting is on the topic of new dietary

ingredients and the 75-day pre-market notification

process rather than substantiation of label claims,

our comments address a fundamental issue that is

relevant to both topics. And that issue is the

perception\--and I underline that, the

perception\--that both FDA and the sports and

fitness supplement industry have of each other and

how that perception impacts the actions,

philosophies, and attitudes of both sides.

One of the threshold questions that

remains a mystery is, Under what circumstances must

a pre-market notification be filed? According to

the Overview of Dietary Supplements posted on

January 3, 2001, on FDA\'s website, DSHEA \"requires

that a manufacturer or distributor notify FDA if it

intends to market a new dietary supplement in the

71

United States that contains a \`new dietary

ingredient.\'\" However, the law appears to say

something a bit differently.

DSHEA actually says that a District which

contains a new dietary ingredient shall be deemed

adulterated unless it meets one of two criteria.

One of those criteria is the submission of a proper

pre-market NDI notification 75 days before

marketing the product. The other, however, is that

the dietary supplement \"contains only dietary

ingredients which have been present in the food

supply as an article used for food in a form in

which the food has not been chemically altered.\"

Industry has widely interpreted this

language to require pre-market notice only if the

product\'s new dietary ingredients are not present,

unaltered, in the food supply. In fact, many

manufacturers have chosen to decline to submit

pre-market notice based upon their belief that

their products comply with this provision under

DSHEA, and it appears that in ten years, FDA has

never taken an action under this provision with

72

respect to a single product other than the recent

action involving androstenedione. If FDA has an

alternative interpretation of the statute, it has

never explained that to industry, and that is an

example of the problem\--a classic failure of

communication which escalates distrust on both

sides.

Further, in situations where all sides

agree that pre-market notice is required, what sort

of safety data does FDA require? One only has to

look at FDA\'s website on new dietary ingredients to

understand the communication problem. If you look

at the FDA website to obtain guidance on

information that the agency requires to approve or

at least not object to a pre-market NDI

notification, you will find this language: \"To

date, we have not published guidance defining the

specific information that the submission must

contain. Thus, you are responsible for determining

what information provides the basis for your

conclusion.\"

And while I appreciate that the meeting

73

today is the start, that is another example of the

communication problem that I think persists today.

The law states that new dietary

ingredients which are not in the food supply can be

introduced when there is a history of use or other

evidence of safety establishing that the dietary

ingredient, when used under conditions recommended

or suggested in the labeling of the dietary

supplement, will be reasonably expected to be safe.

Despite pronouncements otherwise, the law does not

state that there should be a risk/benefit analysis,

as was done with ephedra. It does not suggest a

requirement of zero risk, as an FDA working group

was asked to determine. The process should not be

a roundabout way of allowing the agency to say no,

as is perceived by many of our clients. If the NDI

process is to work within the parameters of DSHEA,

then we would submit that the following steps need

to be taken:

Any guidelines that are propounded by FDA,

and actions undertaken by FDA, must adhere to a

reasonableness standard, as was intended by

74

Congress.

And, equally important, the standards must

be applied in a transparent and reasonable manner

with specific guidelines. In other words, we

believe that if you submit the proper materials,

your ingredient will be either approved or not

objected to.

In addition to these specific steps, it is

our sincere hope that our comments today and this

meeting today will also be the beginning of a

dialogue to help change perceptions that exist

about FDA\'s attitudes towards supplements. The

debate here today is not whether or not there is a

negative bias by FDA but, rather, again, the

perception that such a bias exists and the

perception that there is no one within the agency

that is an advocate or supporter of the industry.

We believe many of the issues raised by FDA for

this meeting and in recent draft guidance documents

on substantiation can be resolved with improved

cooperation and communication.

In speaking with our clients and other

75

members of the sports and fitness supplement

industry, there is a sense of mistrust or that the

process is stacked against anyone who wishes to

file a pre-market notification. That is not true,

you might hear people within the agency say. And

you may be right. But if you were to poll our

clients and others in the industry, you would find

that the perception exists. Why does it? For a

moment I ask you to put yourself in the shoes of a

company in the sports and fitness supplement

industry. Here are some of the things you have

seen in the last ten years:

You have witnessed the publicizing of a

group of anecdotal adverse event reports in such a

manner as to give the impression that they

conclusively support a claim that dietary

supplements containing ephedra are dangerous. You

then learn that the GAO in 1999 in its report

concluded that FDA failed to establish that the

proposed rule would have any public health benefit

and that FDA did not establish that there was, or

is, the need of any regulation. Now, one may argue

76

that this is old news and FDA was eventually right

in banning the product, but since then the same

issue arose with respect to Kava, and as recently

as several months ago FDA was criticized by the

American Herbal Products Association on AERs

involving bitter orange. AHPA was quoted as

stating FDA is willing to regulate by anonymous

press release and be cavalier in its approach to

informing the public about the safety profile of

bitter orange. And while there have been

announcements recently of a change in this policy,

it is these cumulative actions that contribute to

industry\'s perception.

Number two, you are viewing FDA\'s newly

heightened attention toward dietary supplements

from a historical perspective dating back to a

period before DSHEA, when legislators and federal

judges were expressing concerns over FDA\'s

activities against dietary supplements. For

example, a Senate committee found FDA was

\"distorting the law\" to prevent safe supplements

from being marketed, and a federal judge, in

77

adjudicating a seizure action by FDA of

encapsulated black currant oil, chided FDA for

engaging in an \"Alice in Wonderland approach\" to

make an end run around the statutory scheme.

You have also seen androstenedione sold

openly as a dietary supplement for many years, then

suddenly removed from the market not only for

safety reasons but for failure to file a pre-market

NDI notification. Industry is suspicious of FDA\'s

claim of safety because of the long delay. And

even more puzzling is FDA\'s claim that it was not

aware of evidence that the compound is present in

the food supply. Studies have confirmed its

presence in meat. The literature is there.

And, finally, as an example that has just

recently occurred with one of our clients, you are

a company that obeys the laws and has ceased

selling ephedra in the United States. Further,

you\'ve complied with all the procedures necessary

to permit you to sell your product overseas to a

country that permits the sale of ephedra. Yet

despite this fact, you are visited no less than

78

three times over a period of two weeks by FDA field

inspectors who continually are looking for a way to

prohibit you from selling your product overseas.

Thus, from our client\'s perspective, they

have seen FDA take actions that they believe were

not based on science, and when they ask what are

the rules that they have to play by, they are told

there is no guidance for determining what

information needs to be provided. Or if they play

by the rules, they still encounter resistance.

This fosters a climate where many people believe

that no matter what is submitted, you will not get

a fair hearing. Some industry representatives have

told us that they believe that virtually all NDI

notifications submitted in the past year have been

rejected. That perception creates an atmosphere

fostering noncompliance with the law in which no

one benefits.

Recently, Dr. Crawford echoed these

sentiments when he stated that the agency in the

past had said \"we are going to enforce the law, but

you are going to have to guess what the standards

79

are.\" We admire Dr. Crawford\'s candor, and he

zeros in on the exact kind of atmosphere fostering

this perception. Our industry members are

concerned because of the perception that the

rulemakers are biased against them. The question

being asked by them is: \"Are these guidelines and

proposed rules being drafted in the spirit of DSHEA

or in the spirit of pushing the industry to a

pre-market approval drug model?\"

The latter would be detrimental to the

American public. The economic, technological, and

innovative advances which have guided this country

and made it a leader happen when the framework of

the rules are clearly set, while at the same time

there is cooperation between industry and the

government agencies that regulate them, allowing

ample room for innovation. Given our growing

health crisis, FDA should be encouraging, not

discouraging, innovation within a framework of

safety.

Therefore, in addition to our specific

proposals about NDIs, we would ask that FDA give

80

serious considerations to three other proposals

that we believe will go a long way in improving its

relationship with the sports and fitness supplement

industry in general:

It must, in a meaningful way, create lines

of communication with all segments of the industry

to better understand the different segments of the

industry and their needs and desires;

It should take steps to communicate with

and learn about the segment of the American

population that uses sports and fitness nutritional

supplement products so that it can create and

implement its policies and procedures in a manner

consistent with the public that is serves;

And, finally, we\'d also recommend strongly

that FDA have an ombudsman within CFSAN, as it does

with many other industries that it regulates. This

would be someone who will investigate complaints

from outside FDA and facilitate the resolution of

disputes between CFSAN and the industry it

regulates. Having someone who can help with

communication between industry and CFSAN will go a

81

long way toward achieving a balance between the

need to keep Americans safe and the right of

Americans to make their own health decisions about

dietary supplements.

Until there is better cooperation and

communication between FDA and industry and until

there are people within the agency who support the

use of supplements, we believe this will continue

to be a problem. To begin to solve the problem,

there needs to be an effort to change the

perception that exists. And in any relationship,

there\'s always somebody who has to take the first

step, and I would ask that FDA be the one that

takes that first step.

Thank you very much.

DR. FRANKOS: Any questions?

\[No response.\]

DR. FRANKOS: Okay. Now, our next speaker

is George Burdock, President of the Burdock Group,

and, George, you can sit here and then she can

change your slides, or stand there and she can

change your slides.

82

DR. BURDOCK: Good morning. Thank you for

the opportunity to allow me to speak to you on this

very important subject. My name is George Burdock.

I am a toxicologist and consult in the food

ingredients and dietary supplements business. My

company has offices in Florida and Washington, D.C.

My contact information is available at my website

appearing at the bottom of each slide or overhead

here, and if you would like a copy of these slides

in living color, please come to my website and

request one, and we\'ll be glad to send you one.

Because it is not in color, any refunds for

admission will have to be coordinated through Mr.

Frankos.

I would like to address today the dietary

supplement issue as a whole, to include review,

safety, and claims; that is, the claim as to

supplement or nutritional status and possible

structure/function claims, which I refer to in this

talk as efficacy claims.

I am concerned that in response to what

may seem to be a crisis, FDA may be persuaded to

83

take an overly conservative path which may place

safe and efficacious dietary supplements out of the

reach of consumers. This raising of the bar will

almost certainly result in an underground/unregulated market

populated by charlatans, with spurious

claims of potentially unsafe products. I believe

an overly conservative path is supported by several

diverse groups, many of which share our sincere

belief that the public deserves a safe and

efficacious product. There are others, however,

whose goal is not as sincere, and among these the

most zealous supporters of an overly conservative

pathway are those that will gain most financially,

the charlatans of the underground market.

The dietary supplement market is a

strongly consumer-driven market, and the public has

long demonstrated a profound willingness to obtain

benefit from substances outside of mainstream drugs

or food. There are many driving forces behind this

demand, and they included a demand for improvements

in the quality of life, a lionizing of natural

remedies, and a reaction to the high cost of drugs.

84

A strong consumer market encourages enterprise,

investment, and competition within the supplier

community, as long as there is adequate return on

investment.

The wants and needs of the various players

have created tension. This tension begs for

resolution. In this graphic, consumers, industry,

and the agency are depicted as the intersections of

a triangle, each with examples of driving forces

between the two. In this graphic, the relationship

between industry and the consumer is depicted by

consumer demand on the one hand and the need by

industry for a return on investment. Between

industry and the agency is a demand by industry to

exercise its freedom of speech, and the response by

the agency that only efficacious products may be

marketed. Between the consumer and the agency, I

have shown a demand for greater access to fulfill

the wants and needs described earlier by consumers,

or of consumers, and the pushback from the agency

that only safe products should be allowed in the

marketplace.

85

The tension demonstrated in the graphic

sets the stage for a possible response by the

consumer; that is, if an overly conservative

pathway is taken by the agency, it will affirm the

beliefs of many who preach there is a conspiracy to

keep inexpensive natural substances off the market

by \"big pharma\" and by regulators. And it will

also give affirmation to those who want to believe

that we are all witless incompetents that ignore

the lessons of our forebears about the natural

remedies of \"Mother Earth.\" Setting the bar too

high will ultimately result in the loss of our

credibility and the faith of the consumer.

The last time the bar was raised and

threatened to cut off the source for consumer

satisfaction resulted in the passage of DSHEA,

which was meant as a safety valve to ease the

tension between the public and what was seen as an

overregulation by the agency. Locking down this

safety valve with an overly conservative response

will cause consumers to lose faith in the very

agency responsible for their protection, and with

86

the aid of the Internet, give rise to an

underground, uncontrolled, unsafe wild, wild West

of a marketplace.

Maintenance of the faith of the consumer

is essential, but in order to achieve this goal,

the agency, as the key player, needs the active

involvement of industry. Only FDA can elevate the

role of industry from producer to participant, and

in so doing, FDA becomes the engine for resolution.

To do so, FDA must take three steps.

First, the promotion and use of

independent expert panels for the determination of

safety and efficacy; second, initiate a

notification program and post the results on the

Internet so consumers will know what is safe and

efficacious and debunk illegitimate or copycat

products; third, provide a term of exclusivity for

industry. This period of exclusivity will allow

industry an opportunity to return on investment

without which there will be very little R&D and

only the wild, wild West that I mentioned a few

minutes ago.

87

There is precedent for the use of

independent experts, such as GRAS panels, generally

recognized as safe for food ingredients; GRASE,

that\'s generally recognized as safe and effective,

for drugs; and any number of FDA advisory

committees on FDA issues, including OTC drugs,

dietary supplements, food ingredients, and others.

The FDA fact sheet describing a strategy for

dietary supplements includes a statement that

third-party reviews will be permitted. There are

other examples of involvement by independent expert

groups, and I implore the agency not to follow an

overly conservative path as exemplified by

significant scientific agreement where only

institutions could approve claims. If the

precedent of SSA is followed, then something like

the Health Independence Information Act will be

passed, which essentially takes all authority out

of the hands of the agency.

The second of the three steps forward is a

notification program. There is precedent here with

the GRAS notification program and the program for a

88

new dietary ingredient. The results are posted on

the agency website, and the public would be

informed about what was safe and efficacious, and

retail merchants could self-police, knowing what is

legitimate and what was not. Simply put, a

notification program rewards the legitimate players

by letting the public know who plays by the rules

and who does not.

The third of the three steps forward is to

allow a legitimate manufacturer a period of

exclusive marketing rights. That is the period

when safety information on the product is made

public, but information supporting efficacy remains

embargoed by the agency. Also, any other

manufacturer wishing to sell an identical product

using the same claim during the period when

efficacy information is embargoed must present his

own efficacy information to the agency. While

immediate release of safety information is

essential, immediate release of the data supporting

efficacy does not help the consumer. It only

eliminates the incentive for investment.

89

There is precedent for embargoed

information as seen with the food master files

where safety information is released while

manufacturing and other key information may not be.

And we all know about drug master files where all

information is held secret, and for the same

reason: to allow the manufacturer a reasonable

period for return on investment. Without return on

investment, there is no incentive for performance

of safety or efficacy studies and we are back again

to the wild, wild West scenario.

Without possibly jumping the gun or

belaboring the issue, but to illustrate a point,

consumer demand and the promise of reward motivates

manufacturers to fund R&D, safety testing, and

efficacy testing to support claims.

The agency with the notification system

can inform the manufacturer that it has no

objection to the finding that the product is safe

and the claim is adequately supported.

Following this positive feedback from the

agency, the manufacturer can crank up his

90

marketing, manufacturing, and distribution arms to

respond to consumer demand.

If, however, as illustrated above where

the no-objection notice has a lot of little arrows

coming off of it, if this is where the no-objection

notice is publicly broadcast and the information is

not embargoed, then for lack of a better term,

pirates can share the claims support information,

and because the pirates\' only expense is marketing,

manufacturing, and distribution, the pirates can

sell at a cheaper price and consumer dollars go to

someone other than the manufacturer that paid for

the R&D, safety, and efficacy testing.

Therefore, there will be no return on

investment. Funding for R&D, safety testing, and

efficacy testing will dry up.

Now, if I haven\'t gotten too far ahead of

myself on exclusivity, to get back to the three

steps forward program, we need to examine the use

of independent experts and the notification

program, for both of which we are showing adequate

precedent.

91

First, in this regimen for independent

expert review and FDA notification, a dossier is

prepared and reviewed by a group of independent

experts to determine if the information supply

supports safety and a specific claim.

Once approved by the experts, the dossier

is then provided to the agency on a non-public

basis and is reviewed by the agency within certain

boundaries. The object here is not to have the

agency reinvent the wheel or take full ownership of

the decision by an examination of all the data as

it might do for a food additive petition, but

maintain the spirit of the notification program by

paying closest attention to three points: first,

the credentials of the experts. Are these

reviewers qualified by training and experience to

make this sort of decision? Secondly, is the

rationale provided logical to support the claim?

That is, if the evidence is narrow and specific and

supports an equally narrow and specific claim,

where is the claim is overly broad? Lastly, is the

supporting evidence credible? Not all studies need

92

to be double-blind, placebo-controlled studies, but

does the information provided have adequate rigor

to support the claim made? The goal for the agency

here is not to abdicate its authority but to

provide oversight to ensure that legitimate experts

are approving equally legitimate claims.

The oversight function will also allow the

agency to get along with its other work at hand and

not become bogged down in the details, the very

problem that plagued the GRAS affirmation process.

Upon completion of its review, if the

agency determines the notification is inadequate,

the agency offers a description of the deficiencies

and an opportunity for withdrawal of the

notification. If withdrawn, the information in the

notification is not made public and the submitter

has an opportunity to remedy the deficiencies

without loss of the proprietary information

therein.

If the agency determines the opinion of

the experts is sound, the agency responds to the

submitter with a no-objection, followed by a public

93

notice on the FDA website.

The public notice would consist of the

name of the manufacturer, the product identity, the

truthful statement or claim, and the safety data.

Not made public nor shared outside federal agencies

for at least five years would be the efficacy data,

the time and investment by the manufacturer to

prove the claim, and should not be dissipated to

the pirates.

Again, the FDA should make public the

safety information, the claim, the product name and

the manufacturer. The evidence for a claim should

not be released for at least five years. This is

the same as with the food master file or a drug

master file, and the option of releasing the data

would be at the election of the submitter.

Now, what benefit would be derived from

independent expert review and FDA notification?

First, the agency would be relieved of a possible

logjam of petitions. Second, the agency and public

would benefit from the addition insight provided by

experts outside the agency. Third, consumers would

94

know that the agency and industry were taking

reasonable steps to respond to their demands for

empowerment and access.

How would ensuring return on investment to

industry benefit anyone else in the triad of

players I talked about earlier? First, consumer

demands for a variety of safe and effective

products would be met. Second, the agency and

consumers would know that products were properly

examined for safety and efficacy, that consumers

would get not only value for their dollar but safe

products as well. Lastly, return on investment

would ensure competition and new products in the

marketplace.

If FDA acts to take the three steps, all

the players will benefit. Consumers will be

empowered with more and better products. Industry

will be assured of its right of free speech and a

legitimate need for return on investment. FDA will

know that consumers are protected from unsafe or

fraudulent products. This is a win-win resolution.

Thank you for your attention and allowing

95

me to address you today. I\'d be delighted to

answer any questions and, again, if you would like

copies of any of these slides, in color as well,

please contact me at my e-mail or website.

Thank you.

DR. FRANKOS: Any questions? Please come

to the mike.

PARTICIPANT: George, you ushered in a

topic that is outside the scope of this focus, but

I\'ll address you on it, and that is efficacy. What

would you qualify as a sufficient amount of

evidence to support an efficacy claim that would be

overseen and reviewed or allowed by the FDA on a

dietary supplement?

DR. BURDOCK: Something that meets the

criteria of a structure/function claim. I\'m not

trying to avoid your question, but I don\'t see what

are the grounds on which I could answer.

PARTICIPANT: Structure/function claims do

not have to be supported by a clinical trial for an

actual finished good.

DR. BURDOCK: They don\'t have to be

96

supported by a clinical trial, that\'s for sure.

But there are other methods that support a

structure/function claim.

PARTICIPANT: So I\'m still asking for an

exemplification of what you think would be

sufficient for efficacy claims to be allowed or

approved.

DR. BURDOCK: Adequate animal studies,

proof of absorption, proof of mechanism. There are

a lot of ways to get to it. It doesn\'t always have

to be\--in fact, I think for a structure/function

claim, adequate human data may not be necessary at

all.

DR. FRANKOS: Anyone else?

\[No response.\]

DR. FRANKOS: Thank you.

Good, we\'ve got color. Our next speaker

is Wes Siegner, and he is with Hyman, Phelps &

McNamara, and hopefully things are working now.

MR. SIEGNER: It must be my lucky day

here. I was actually looking forward to using the

overhead because I used to be a teacher, and my

97

first year one of my important lessons I learned

was never turn your back on the audience, being the

class. So overheads were my favorite tools. We

didn\'t have computers back in those days.

Well, thank you for this opportunity to

speak, and welcome to this meeting. Before I start

here, I just want to note that there seems to be a

lot of agreement in what we\'re seeing in this

notice, and that makes me very happy. I think

industry recognizes what the stakes are here.

I have a presentation which I typed out,

which is a little different than my overheads. I

noticed that there\'s no copies left out on the

table. I have a few copies here for people who are

desperate to read it before they go home tonight.

But if you want to give me your card or give me a

call, I can give you another copy if you\'re

interested.

Just starting out, the issues that are

presented in this notice are very, very significant

for the industry. And as I said, I\'m glad to see

that trade associations and others recognize that

98

because one of the things, I think, that we need to

fix immediately is that not enough time has been

given to allow people to consider what the issues

are. There won\'t be enough time to prepare

comments by the 3rd of December, certainly, and I

think actually my feeling is it ought to go well

beyond February 3rd. But whether that\'s on the FDA

table at the moment or not is an issue, but we can

fix that.

The other thing I want people to

understand is that it\'s not that FDA is doing

anything wrong in what is going on here with NDIs.

I have a very strong feeling that it\'s becoming a

food additive approval process. That will be the

natural tendency of FDA if we leave them to their

own devices, not because they\'re not doing their

job but because they are doing their job.

If you put safety in FDA\'s hands and say,

look, we want you to go out there and enforce the

law and protect consumers and make sure that the

products are safe, you can\'t imagine that they\'re

going to say, well, we\'re just going to kind of

99

gloss over these safety reviews. They\'re going to

do a hard-nosed food additive type approval of

those safety reviews. And you as industry and I as

a lawyer for industry need to find ways to give FDA

an option to get out of that box. I think we\'ve

seen some good ones today in terms of suggestions.

My other point\--oh, sorry. I\'m already on

the next slide. What do we do here? There we go.

Sorry. No? There were are.

I\'m the ten-year issue. Basically what

has been happening here with the development of NDI

policy is that over a ten-year period, people have

been submitting NDIs without the rules being known.

FDA has been writing back, and the process has been

evolving over this ten-year period, and there\'s a

lot of important information in those NDI reviews

and objections and filings. I commend Michael

McGuffin and Tony Young for trying to parse through

all that\--there\'s a huge volume of material\--and

pulling out some important lessons. But I\'m going

to go through a few important things that I\'ve seen

in these notifications and correspondence. I think

100

industry deserves a fair break here in terms of

being able to respond to all this. We can\'t do it

in 45 days. My feeling is we need at least six

months to really put this all together and get good

comments in.

I\'m also encouraged by Bill Frankos\'

comment that this is maybe the beginning of a

process, that there may be other meetings. My

concerns would be less strong on the comment period

if the plan is going forward to say, okay, this is

the initial review, we\'re going to consider these,

give you some more chance to comment and to have

public meetings.

The other argument for more time here is,

of course, all the other things that are coming

down the pike. We have the substantiation

document, which has a 60-day comment period. We

have GMPs coming out. We have new FDA directives

in terms of their strategies for regulating

supplements. And I don\'t know how many people have

read all that, let alone absorbed it. I have read

it; I\'m not sure I\'ve absorbed it.

101

I\'ve tried to boil this notice down into

five issues. They\'re not all the issues, of

course, that are in this NDI notice, but to me

these are really the most important issues for the

industry looking forward and wanting to market as

many safe dietary ingredients as the industry can

market and that consumers deserve.

The first issue here is that FDA is going

to have a tendency to restrict the market by very

narrowly defining \"dietary ingredient,\" and I\'m not

going to go into all the shades of that, but I\'ll

bring up one issue relating to that definitional

issue.

Annette Dickinson broached on this second

point, which I think is critical. There\'s this new

standard creeping into the old dietary ingredient

category where they\'re saying that the ingredient

has to be lawfully marketed before 1994. And if we

go that route, there\'s some big problems for

industry.

Third, this issue with \"present in the

food supply,\" FDA wants to narrowly define that to

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mean just foods, not components of foods. David

Seckman picked up on this to some extent in his

discussion. That would be a very narrow

interpretation of that. I\'ve got to be honest, the

statutory language, as is typical of statutory

language, is not entirely clear on this point. But

the goal here should be to assure safety but permit

the broadest definition we can.

The fourth issue is what does \"reasonably

expected to be safe\" mean. You know, I think

industry would all agree that it means something

less than a food additive safety standard. But

it\'s not defined, and, you know, there\'s no actual

precedent in the act for this standard, and we can

talk a little bit about that. But the bottom line

is people need to come to an agreement in the

industry and at FDA what it all means.

Then the last thing I\'ll touch on briefly

is this issue of risk/benefit, which has come into

play through the ephedra final rule and how it

might apply to NDIs.

The issue of narrowing the definition,

103

we\'ve already been through the dietary ingredient

definition several times. This is just a

paraphrasing of it without all of the statutory

sections. I want to focus on the underlying

language, which is \"a dietary substance for use by

man to supplement the diet by increasing the total

dietary intake.\"

Now, if you know exactly what that means,

raise your hand. It\'s a lot of words. I\'m not

sure what it means myself. The problem here is

that FDA wants to define it in a way that\'s very

narrow. My view of this is that that was put in

there as a phrase to kind of say, okay, we have

amino acids, botanicals, herbs, vitamins, minerals;

here\'s a phrase that\'s going to capture everything

else that might be suitable for people to eat. And

\"suitable\" is kind of a nebulous word, but, you

know, you don\'t want people eating unsafe things.

That\'s captured in the safety review.

Now, of course, the statutory definition

also excludes ingredients that are being

investigated as new drugs or were on the market as

104

drugs before they were on the market as

supplements. But barring that, we should have a

big, broad array of substances that we can market

as dietary ingredients. There will be new things

discovered down the road, and we want to keep that

door open.

What FDA is saying in these letters back

in the NDI process is that in order to qualify to

be a dietary substance, it has to be part of man\'s

usual food or drink. Now, I\'m not sure what that

means either, but it doesn\'t signal to me that

they\'re headed in the right direction. I think

that\'s a very narrow reading of the word \"dietary

substance.\" We need to make sure FDA doesn\'t go

down this path, that we keep that door open.

And in the end, I can\'t estimate it. You

know, it could be several hundred ingredients. It

could be thousands of ingredients that the industry

could lose if we don\'t get the right interpretation

here.

This is something that Annette hit on. I

won\'t go into it in great detail. But, again, we

105

have all assumed that there are a lot of

ingredients out there that FDA and industry would

view as old. If we allow this lawfully marketed

interpretation to creep into what FDA\'s thinking,

what\'s going to happen is a lot of these old

ingredients will suddenly become not legally

marketed pre-\'94 ingredients, and that means\--not

that they\'re necessarily going to come off the

market, but they have to go through the NDI

process. And a lot of the old ingredients I don\'t

think would make it, would have a tough time, and

we\'d end up losing a lot of ingredients.

I have a list in the last point here of

some of the ingredients that FDA, I believe, would

view as illegal food additives, pre-\'94, and if

that\'s the case and the lawfully marketed standard

is the one FDA is going to apply, all of these

would need to come off or go through the NDI

process. And I think a lot of the herbs would

suffer the same problem.

Moving on to the next point, this

narrowing of the \"present in the food supply\"

106

definition, this is really a simple matter. How

are you going to interpret the statutory language?

The statute says \"dietary ingredients which have

been present in the food supply as an article used

for food in a form in which the food has not been

chemically altered.\" Well, we\'ve had a lot of long

discussions in our firm about what this means, and,

again, it\'s not exactly clear. You can subject it

to several interpretations. FDA wants to focus on

the words \"article used for food\" meaning that if

you have a potato, it\'s only the potato that is

subject to this exemption from NDI notification.

It\'s not any of the ingredients in the potato, the

components, not the carbohydrates in there, not the

proteins in there, not the vitamins or minerals in

the potato. It\'s just the potato.

Again, the problem with this is that if we

go down this route, we\'re going to lose a lot of

dietary ingredients probably, but the real

importance is that it forces a huge number of

ingredients into the NDI review process. And, you

know, there ought to be some logical conclusion we

107

could come to or interpretation with FDA that

everybody could agree to. And if it\'s a de minimis

ingredient in a food that\'s been marketed forever,

that doesn\'t give you any assurance that the

ingredient might be safe. But if it\'s a very

substantial substance within a food that\'s been

widely consumed, that really gives you an assurance

of safety. And why would we as industry need to

spend the time to put together a panel of experts

to review those? And why should FDA have to review

those types of substances? My view is they

shouldn\'t.

This is the whole thing here: What does

\"reasonably expected to be safe\" mean? Yes, it was

great, we pointed out through DSHEA that FDA was

not supposed to treat dietary supplements as food

additives. We have a different standard for NDIs.

But Congress didn\'t really define it. As a matter

of fact, in this case, Congress decided that the

legislative history wasn\'t going to be legislative

history, so they in passing the law said, well,

none of this that we\'ve said about this law that

108

you might use to interpret it really should count.

You know, we still read it and put meaning into it,

but, you know, this is a problem. And I think that

several people\--Annette and others\--have kind of

hit the nail on the head that industry needs to do

good self-reviews, either in the context of the

GRAS self-affirmations, with panels of experts, or

setting up their own panels of experts, like the

cosmetics and flavors industries have done.

Somehow industry has got to take this thing by the

horns and do their own safety reviews, because if

you don\'t, what\'s going to happen is, again\--and

it\'s not that FDA is doing anything wrong. But if

they have to protect the public and declare things

safe or not safe, they\'re not going to say

half-safe, they\'re going to do a full-blown safety

review. There\'s no other way around that.

Then the last thing here is risk/benefit.

This is something that I think a lot of people

haven\'t thought about, but there\'s a problem that

comes into play as a result of the risk/benefit

standard that FDA created through the ephedra rule.

109

The problem is that if you look at 402(f) or

342(f), as it\'s in 21 U.S.C., (A), the section of

the law that applies to adulteration has a section

in it that applies to the adulteration of NDIs.

And that section applies the same unreasonable risk

standard to NDIs as it does to any other dietary

supplement. And I\'m not saying this is going to

happen, but I can very well see down the road,

again, if we leave FDA to kind of run this safety

review, they\'re going to say, well, it doesn\'t make

sense to put an NDI on the market under just a

safety review. When it\'s on the market, we have to

judge it by safety and benefits. So what we\'re

going to do is require NDI notifications to prove

benefits. They\'re not doing this now. I hope it

never happens. But this is just something

that\--another problem we need to keep an eye on.

I just want to bring some notice to

something here. My first point, my conclusion, is

that industry is at a crossroads. Peter Hutt\'s

conclusion is FDA is at a crossroads. Well, so

industry and FDA are meeting at the crossroads, and

110

we need to through this notice get together and

decide what the best path is. And I\'m confident

that if we have enough time to parse through these

issues and work them out with FDA, we can come to

conclusions that are going to be benefiting

industry and that are going to be benefiting FDA

and not wasting a lot of your time, because I think

that if you really get into this as a food additive

review process, it\'s going to be very hard for you

in terms of having to review things, and it\'s going

to be terrible for industry, because in the end

we\'ll be back where we were in the \'80s and early

\'90s where the whole system kind of bogs down and

we can\'t get anything on the market.

Thank you.

DR. FRANKOS: Any questions? Yes, can you

come to the mike down here, please? And please

identify yourself.

DR. BECHTEL: I\'m Dave Bechtel, senior

toxicologist with Cantox. Wes, interestingly, I

totally agree with the issue of FDA\'s review of

data for a new dietary ingredient. I would ask you

111

the following question: Under DSHEA, it is my

clear understanding that there are two options for

new dietary ingredients: one is a notification,

the other is a new dietary ingredient submission.

And that\'s in the regulations.

Do you see any advantage or any

opportunities in the existing regulations in the

format to be able to deal with defining how FDA

operates with the notification versus a submission?

MR. SIEGNER: Answering from where we

stand right now and in terms of how I would advise

a client to go forward, our view toward this is

that we do treat them very much like GRAS

self-affirmations and prepare the NDIs in a very

thorough manner with a panel of experts or however

many experts you need to address the safety issues

that the ingredient raises. And I don\'t really see

the difference, unless FDA tells us otherwise, as

to whether you do the notification or submission

process. It\'s all really the same thing. You

know, we can\'t really say what \"reasonable

expectation of safety\" is, but if the industry or

112

the company submitting the ingredient really takes

it on its shoulders to get the experts lined up

that FDA is going to say, okay, these are really

qualified experts in the industry, they know their

stuff, that\'s immediately going to set FDA at ease,

more so than if they get a submission that\'s, you

know, got some studies attached to it and says

we\'re safe.

So I think answering your question, I

don\'t really see a difference between the two

processes. I think it\'s really more focused on

right now how do we make FDA happy.

DR. FRANKOS: Wes, I\'m a little confused.

Once you determine you have a new dietary

ingredient, I\'m only aware of one process that you

have to notify. So you were talking about another

process?

MR. SIEGNER: Well, actually I\'m familiar

with the notification process, and\--

\[Inaudible comment.\]

DR. WALKER: This is Susan Walker. There

is only one notification process. Basically the

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75-day notification process is a process where you

send in a submission. So unless someone has

clarification on something else, there\'s really

just one process.

MR. SIEGNER: I think we\'re all talking

about the same thing.

DR. FRANKOS: Okay. I do have one

question. You brought up the issue of a de minimis

level of a constituent of a food, let\'s say. Could

you define \"de minimis\"? Is there a way to define

that for us? We would be very happy\--

\[Laughter.\]

MR. SIEGNER: Bill, I thought we were

friends.

\[Laughter.\]

MR. SIEGNER: I think my main point is

that we ought not to be saying component or, you

know, non-component. And that, I recognize, does

lead FDA into another, you know, part of the woods.

I think we can get out of it. But my point is I

don\'t\--let me be truthful. I can\'t answer your

question.

114

\[Laughter.\]

DR. FRANKOS: Very good.

MR. SIEGNER: Very unlawyerly, but I\'ll be

honest. But the point is let\'s not review

ingredients that we know people have been exposed

to at significant levels for, you know, forever. I

think that\'s something that should not be in the

NDI review process. Things that, you know, don\'t

warrant that kind of safety presumption, then we

ought to figure out what they are.

DR. FRANKOS: Okay. Any other questions?

Yes?

MR. SIEGNER: Now I\'m really in trouble.

\[Laughter.\]

DR. DICKINSON: Annette Dickinson with

CRN. As a regulatory wonk, I can\'t resist looking

up the answer to this question that you were just

asked. In DSHEA, under the new dietary ingredient

section, after it talks about the notification

part, there\'s a separate section on petitions,

which says, which appears to say that apart from

the requirement to submit a notification from an

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NDI, any person may file with the Secretary a

petition proposing the issuance of an order

prescribing the conditions under which a new

dietary ingredient under its intended conditions of

use will reasonably be expected to be safe.

So I assume that\'s the separate thing that

he was talking about.

PARTICIPANT: That would be like getting a

regulation\--

DR. DICKINSON: It would be like

requesting a regulation right.

DR. FRANKOS: Okay. That\'s what you\'re

talking about.

MR. SIEGNER: Has anybody ever gone that

route?

DR. DICKINSON: We\'ve ignored that.

DR. FRANKOS: We\'re not aware of any.

MR. SIEGNER: Well, I guess I didn\'t

answer that question very well either.

\[Laughter.\]

DR. FRANKOS: Any other questions?

\[No response.\]

116

MR. SIEGNER: Thanks.

DR. FRANKOS: Well, thank you.

We\'re actually moving along pretty well,

and we\'re on time. So let\'s take a 15-minute break

and come back and finish up. Let\'s meet at 20 of.

\[Recess.\]

DR. FRANKOS: Okay, we\'re into the home

stretch here. Our next speaker is John Zenk, and

he is chief medical officer of Humanetics

Corporation.

DR. ZENK: Thanks. Five minutes left of

the morning, so good morning.

I\'d like to begin by thanking the agency

for allowing me to be here and have some input into

this very important subject. My name is John Zenk.

I am a board-certified, licensed physician in

Minnesota. My specialty is internal medicine. I

also have a degree in pharmacy and actually was a

practicing pharmacist before I started medical

school. I\'m currently the chief medical and

scientific officer for Humanetics Corporation in

Eden Prairie, Minnesota.

117

Humanetics is a privately held company

that discovers, researches, develops, and

commercializes new ingredients for the dietary

supplement and drug industries. We have made a

substantial investment in the research of our new

dietary ingredients, and our company has more than

20 patents. Our current ingredients include 7-Keto

DHEA, which is a metabolite of DHEA; D-Pinitol,

which is a naturally occurring methyl inositol

which comes from legumes and the heartwood of pine

trees. We also have MicroLactin, which is a

specially processed dairy protein, and I\'d like to

point out that the MicroLactin ingredient does not

meet the definition of a new dietary ingredient.

Our direct investment in research

associated with our ingredients is in excess of \$10

million. Much of the investment has gone toward

well-designed human clinical trials to establish

safety and efficacy of our products. To date, more

than 16 clinical trials have been performed on our

ingredients.

When Humanetics made a decision to enter

118

the dietary supplement market, the company looked

at the Dietary Supplement Health and Education Act

and saw that our 7-Keto ingredient met the

definition of a new dietary ingredient. With our

first customer, General Nutrition Corporation, we

notified the agency, as required by law, in May of

1997 prior to commercial sales of this ingredient.

We appear to have been the 14th company to actually

file a pre-market notification for a new dietary

ingredient at that time. Our company has now filed

or supported the filing of six new dietary

ingredient notifications. Two of these were for

our patented ingredient 7-Keto DHEA. Another was

for our D-Pinitol ingredient for which we presently

have three U.S. patents. Another was for D-ribose,

and two were for a polyphenolic extract of the

evening primrose plant. Four of these NDIs were

filed by the agency without objection, and the new

dietary ingredients were introduced to the market

by our company.

As I mentioned, the company completed two

NDI filings for the polyphenolic extract, and the

119

agency concluded that the ingredient was not shown

by the data submitted to be reasonably expected to

be safe for use in dietary supplements. Although

we didn\'t agree with the assessment, out of respect

for the agency and the provisions of DSHEA, neither

Humanetics nor the New Zealand company that

developed that ingredient introduced it for sale as

a dietary ingredient in the United States.

DSHEA established the shape and the

contour of the playing field for new dietary

ingredients. The agency promulgated implementing

regulations in September of 1997, and we have

structured our business model for dietary

ingredients around these regulations. As

competitors in the marketplace, however, we are at

a disadvantage because others ignore this important

part of the law, and the agency has only once (in

the case of androstenedione) invoked this part of

the law in its ten-year history. Although we have

followed the NDI provisions of DSHEA, we compete

with many who do not. I am sure many of us in the

room today are aware of ingredients that would be

120

considered new dietary ingredients for which no

pre-market notification was filed. We are also

aware of ingredients for which pre-market

notifications were filed, subsequently objected to

by the FDA, and the ingredients are sole on the

market in the United States.

This public meeting appears to approach

the new dietary ingredient provisions of the law as

if they were just discovered and need to be

explained. These provisions have been in the law

since 1994. They became effective upon enactment.

We are here today to express our opinion that the

agency should focus its efforts on the enforcement

of this most important aspect of DSHEA. We believe

that it is a good provision, we support it, and we

feel that it is critical for many reasons,

including the most important reason of, to protect

the safety of consumers.

Thank you again for allowing me to be here

and provide this input. I\'d be happy to entertain

any questions.

DR. FRANKOS: Thank you.

121

DR. ZENK: Thank you.

DR. FRANKOS: Our next speaker is Paul

Bolar, Vice President of Regulatory and Legal

Affairs with Pharmavite.

MR. BOLAR: Good morning, with about one

minute to spare. Someone mentioned to me earlier

today that all these flashings of red and blue

colors up on the screen are symptoms,

after-symptoms of the election. Being in the

Washington area, we\'re still undergoing some of the

convulsions, I guess, the aftermath.

Pharmavite is a 33-year-old company based

in Los Angeles, and we manufacture a broad line of

vitamins, minerals, botanicals, and a wide range of

other dietary ingredients. Our products are sold

in food, drug, mass merchandise, and chain stores

throughout the United States. I should mention

that we have also submitted three NDI notices to

the agency, so we\'re somewhat familiar with the

process that we\'re discussing today.

We\'re pleased that FDA is taking steps to

clarify the regulatory requirements related to new

122

dietary ingredients, and we support FDA\'s efforts

to develop a more structured framework for the

submission of NDI notifications. As a result of

these efforts, we believe consumers will benefit

from a higher assurance of product safety and

responsible companies will benefit from operating

on a more level playing field resulting from a

clearer understanding of the requirements.

We will submit more detailed written

comments to the docket on a variety of issues

raised in the Federal Register notice, but for

today I would like to specifically address three

important issues related to this topic. I\'ll first

address the types of changes that should influence

whether an old ingredient should be considered as a

new ingredient; secondly, the type of information

that should be required in NDI notifications; and,

finally, some points about enforcement.

With respect to the statute of new dietary

ingredients, determining all of the variables that

may impact whether a dietary ingredient is

considered new is a difficult undertaken, and no

123

single answer will satisfy all situations.

Furthermore, DSHEA does not clearly define the

types of changes to a so-called old dietary

ingredient that would result in a new dietary

ingredient. Given the broad diversity of

substances that potentially qualify as dietary

ingredients and the wide range of possible effects

that ingested substances may have on the human

system, we believe it is better to err on the side

of caution when determining whether an ingredient

is a new ingredient and subject to the FDA

notification requirements.

Therefore, we believe that in many

situations changes to the chemical composition or

structure of an old ingredient should cause the

altered substance to become a new dietary

ingredient. This would include modifications to

existing ingredients that result in new salt forms,

new esters, chelates, complexes, and other

chemically modified or stabilized forms of old

ingredients.

For example, and ignoring for the moment

124

whether or not an ingredient is old or new, zinc

sulfate is markedly different from zinc chromate.

Chromium chloride is significantly different from

chromium picolinate. We think there are any number

of other examples that could be cited where

different salts and complexes and so forth may have

different safety profiles associated with them.

This reasoning would also extend to old

ingredients produced through new or unique

manufacturing processes if the new processes result

in significant alterations to the composition or

chemical structure of the old ingredients.

Additionally, botanical ingredients obtained from

plants used in dietary supplements before 1994, but

obtained from parts of the plant not previously

used should be considered new dietary ingredients.

In contrast, old ingredients that undergo changes

in their manufacturing process that do not alter

the chemical structure of the ingredients should

not be considered new ingredients. Such changes

may include the use of different synthetic pathways

to achieve the same ingredient or the use of

125

different filtration or purification techniques,

but may not necessarily alter the basic chemical

structure of the dietary ingredient.

While we support a broad interpretation of

what constitutes a new dietary ingredient, we feel

it is equally important that requirements for NDI

notifications should be sufficiently comprehensive

but not overbearing. We believe that notifications

should contain sufficient information to clearly

characterize the substance in question. As a

general rule, more information is always preferred.

There was a whole series of possible types of

information suggested and asked to have comments

submitted on. We think as much information that

can be provided certainly provides more certainty

of what is being discussed. But at a minimum,

notices should include a clear description of the

chemical structure of an ingredient containing a

single compound and provide a reasonably complete

characterization or profile of major constituents

for more complex substances, such as fatty acid

complexes and botanical extracts.

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Recommendations for conditions of use by

the consumer and the amount of the new dietary

ingredient contained in a proposed dietary

supplement should be clearly stated in the notice.

However, the formulation of the finished dietary

supplement and copies of the actual labeling of the

product should not be required because in many

cases the formulations of labeling just simply have

not been created at that point in time. We also

feel that there needs to be flexibility in the

manner in which new dietary ingredients may be

combined with other ingredients, and it should not

be a process wherein the use of a new dietary

ingredient is locked into just one particular

combination of ingredients.

The level of evidence needed to establish

a reasonable expectation of safety should remain

reasonable and flexible. For instance, the nature

and amount of evidence sufficient to satisfy a

reasonable expectation of safety may vary according

to the degree of knowledge about the composition of

the substance or whether the NDI is closely related

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to other known substances with known characteristics. In

cases where a modification to an old

ingredient results in a new ingredient, required

safety evidence should generally focus on the

impact of the change in the new ingredient. We

believe that appropriate data comparing the new

form of ingredient to the existing ingredient

generally should be sufficient for acceptance by

FDA rather than the kind of data package needed for

a completely new substance.

In order to reduce unnecessary burden on

dietary supplement and dietary ingredient

companies, we believe that FDA guidance should

affirm that redundant NDI notices do not have to be

submitted for ingredients for which another company

has already submitted a satisfactory notice. This

assumes that the ingredient is essentially

identical to and used for the same conditions of

use specified in previous filings. For example,

while data submitted by the ingredient manufacturer

covers those who use and distribute the substance

in various dietary supplements, it should also be

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made clear that a submission by one distributor of

a dietary supplement also covers the same use by

other distributors of the same substance whether or

not in the same chain of distribution. However,

this is not to say that one size fits all.

Previous notice submissions should only be relied

on if the levels of consumption and other

conditions of use are consistent with the

limitations specified in previous submissions.

Where significant changes occur, new NDI

notifications should be required for the new

ingredient.

Now I\'d like to turn lastly to the issue

of enforcement, and I\'ll probably echo some of the

sentiments already presented by Dr. Zenk.

We also believe that enforcement of the

NDI notice provisions is an important issue for FDA

to begin to address at this time. Consistent and

evenly applied enforcement of the NDI requirements

will be a key factor in creating meaningful

guidelines and a level playing field for

manufacturers of dietary ingredients and dietary

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supplements. A number of products exist on the

market today that contain new dietary ingredients

for which NDI notices have not been filed. In some

cases, the companies may either be ignorant of the

notice requirements or they may have simply

proceeded on the basis of liberal interpretations

of the law. Unfortunately, there are others who

are blatantly cutting corners and exploiting the

lenient enforcement environment that we have today.

These situations have resulted in an unfair playing

field for companies that attempt to uphold their

end of the bargain. As an example, Pharmavite

recently considered an opportunity to market a

supplement that included what we believe to be

clearly a new dietary ingredient. Upon diligent

review, we declined to market this product because

we did not feel that there was sufficient data at

this time to submit a satisfactory NDI

notification. We are, therefore, pursuing

additional studies to verify the safety of this

ingredient. However, others in this industry,

including major competitors, have chosen to market

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this same product without filing an NDI

notification. This obviously is putting us at a

significant competitive disadvantage.

We urge FDA to establish reasonable

guidelines for NDI notices and to institute

enforcement measures as soon sa possible.

Recognized that FDA has limited resources to police

this situation, we suggest that FDA consider using

an enforcement approach similar to the issuance of

\"Courtesy Letters\" that are used for structure/function

claims. Such letters have been used

effectively to advise companies about FDA\'s

interpretation of appropriate dietary supplement

claims, and we believe that a similar approach

could be effectively implemented to notify

companies who have failed to meet their obligation

to file NDI notices, without a large investment in

time and resource by the agency.

Now, I recognize that there is a process

by which FDA issues warning letters, but what I\'m

suggesting here is something a step back less\--I

guess less\...

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PARTICIPANT: Formal.

MR. BOLAR: Less formal, yes, than a

warning letter.

In conclusion, I\'d like to say that we

believe it is in the long-term best interest of

consumers and of responsible businesses to

carefully review the safety of all dietary

ingredients. We believe that a conservative

approach is preferred when determining the status

of new dietary ingredients. However, this should

be balanced with reasonable and focused NDI

notification requirement. Finally, efforts to

enforce the NDI notice provisions will help assure

broader compliance within the industry, promote a

fairer markets environment, and ultimately assure

the availability of safer products for consumers.

Thank you.

DR. FRANKOS: Any questions?

\[No response.\]

DR. FRANKOS: Thank you.

Let me just reiterate that it\'s very

important that any comments or ideas you have get

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submitted to the docket. The docket is the only

place we can officially look at information, so

please get your submissions in. Everything that is

being discussed today will be documented, so part

of the discussion here is also important to the

deliberation.

Our next speaker is Willi Hunziker, and he

is CEO for Morpho (ph).

DR. HUNZIKER: Okay. I guess I\'m the

first one in the afternoon, so good afternoon,

everybody. I put my talk under the name \"the Swiss

perspective,\" and that has actually two reasons:

first of all, I am Swiss, so my perspective is the

Swiss perspective; but not only that, I also used

to work for a long time for one of the big Swiss

pharmaceutical and nutraceutical producers, and now

I also run my own consulting business consulting

for people in that area.

What I would like to present is a little

bit an outside view and my personal view. If you

just look at nutrition and health, a large body of

evidence, as I\'m sure you\'re aware, substantiates a

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relation between nutrition and health. And the

health benefits are the result of a continued

ingestion of specific substances or combination of

substances contained in the food chain or in

related areas. And I\'m mainly concentrating today

on the food chain, and I\'m mainly concentrating on

pure substances derived from the food chain. So

it\'s a subset of the whole thing.

The health benefits are mostly disease

reduction, although there are others, but to a

large extent, for example, cardiovascular risk,

cancer risk, Alzheimer risk and so forth. And the

nutraceuticals, how we call them, are the active

ingredients that kind of provide those health

benefits.

Now, looking from a public health point of

view, the disease risk reduction at low cost is an

attractive way to slow the continuous rise in

health care costs of the aging population in the

Western world, provided that these substances are

safe and efficacious, I would say. The safety,

first, the food chain is a positive selection of

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substances having a low toxicity profile, either

it\'s by selection or it\'s by co-evolution between

the food chain and the human species. There is,

thus, the history of safe human use of these

substances at the exposure levels obtained by the

respective food, and I stress the exposure levels

because I think that\'s an important kind of

criteria. And I think that\'s a good basis, this

history of safe use is a good basis for assessing

safety, but it might not be enough in all cases.

The efficacy should be substantiated by a

mechanism of rationale, and all clinical studies

and mechanisms of rationale can be, of course,

rather broad, can go from in vitro studies looking

at mechanism, can be in animal studies, and so

forth. At the end, I think it would make sense to

have authorized health claims that guide the

consumer if we want to fulfill what I said about

the public health of these products.

Now, what package would one want to have?

From a scientist\'s point of view, I would say

substance source and available data, the presence

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in the human food chain, as I said, is a subset

that I\'m mainly dealing with, the documented

evidence of safe human use, its documented evidence

for efficacy, mechanistic plausibility and/or

clinical data, and the safety profile of the

substance.

The conditions of use, those should be

guided by the level of chronic exposure and, again,

plasma concentration via the respective diet, so we

want to be in a similar range as with the

respective food.

The target issue concentration reached by

the respective diets, the safety profile of the

substance, and the target organ concentration

needed for efficacy, because if we want to have

efficacy, of course, we need to have the

concentrations required for efficacy at the target

organs.

Now, from the industry point of view, it

looks a little bit different. Establishing safety

and efficacy data you might argue is fine, but how

do we get investment back? And that point has

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already been raised once before, because in the

present situation, competitors can piggyback on

established safety and efficacy data, and the tight

patent protection is rarely possible for these

kinds of products. So that also kind of invites

competitors to come in. And that\'s why to a

certain extent the industry shies away from making

the necessary investment in safety and efficacy

data.

So a proposal would be, as already

mentioned before by coincidence, a time-limited

marketing exclusivity for the first mover in the

field, similar to, for example, in the drug area.

The orphan drug, somebody who develops a drug for

an orphan indication has market exclusivity for a

certain period of time. Other possibilities would

be prohibition of (?) piggybacking, altering

brand-specific claims, and maybe other ideas, with

the goal to kind of allow the first mover to get

his investment back in the solid data that he has

created.

Now, nutraceutical, as I said before, we

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use for substances having a health benefit coming

from the food chain. Regarding the DSHEA

regulation, they can fall in two categories, the

dietary ingredients or the new dietary ingredients,

as was discussed before.

A question that came up is when does a

dietary ingredient become a new dietary ingredient,

and I would say by a significant change in the

conditions of use leading to an increase in

exposure. So if the human body is exposed to a

much higher degree by the new conditions of use

than the old one, I think then that

warrants\--because of safety consideration warrants

a new dietary ingredient status. And, of course,

also the safety profile, if it\'s a critical

substance, then smaller increases in exposure might

already trigger that. Or by a significant chemical

modification of the dietary ingredient, and there I

see a little bit more from the liberal side that

modifications, chemical modifications, for example,

esters and so forth, which are readily cleaved on

ingestion, they should not necessarily be

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considered as a new dietary ingredient; whereas

other chemical modifications which are not readily

cleaved or even lead to different metabolites in

the body, of course, those should be looked at more

carefully.

What information on the chemical nature of

the NDI should be provided? Of course, origin,

extract, raw, enriched, purified, fermented,

chemically synthesized, chemical name of the

efficacious molecule, as I said before. My

interest is mainly in the purified chemicals, so

the impurity profile will only be a few percent in

the normal case, at max.

In the case of non-single compound NDI,

one would have to look at the standardization

question, the dose content of the efficacious

molecule, provide evidence on the role of the other

molecules in the mixture, what they contribute to

the effect in the body, and the stability of the

compound in the (?)-enic form and the

bioavailability in humans.

Now, another question is: What is an

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acceptable ratio of the intended dose to the

dietary intake? If we assume that the safe human

use of an NDI is documented by food-based exposure

data on, again, plasma levels, because depending on

the formulation with the same milligram amount of

compound, you get highly different exposure levels,

and additional pre-clinical tox and clinical safety

data is available, like single ascending dose in

humans or multiple ascending dose, then the dietary

intake of the population with the highest safe

beneficial intake should be used as a basis to

define the intended dose so that kind of sets the

bar. And depending on the data situation, the bar

can be raised, also the situation if you need

higher levels for efficacy, the bars can be raised

to even higher than three-fold if supported by

additional safety data. But the recommended dose

at the end must be at least a small multiple below

the safe upper limit of the dietary ingredient.

So quite a few times it was discussed what

is an adequate safety evidence, and I think that

safety is a must for nutraceuticals, provided that

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for food chain compounds there is evidence for a

beneficial effect and it has a wide safety window.

I think, on the other hand, it should be approvable

a NDI.

So what specific type of safety data would

I suggest? I think to know the fate of the

molecule in the mammalian species, I would like to

have an ADME started. That means an absorption,

distribution, metabolism, excretion study in rats,

normally done with C14-labeled nutraceutical, a

13-week oral tox in rats, then developmental tox,

teratogenicity studies in rats, and tension of

toxicity tests like the Ames test or a mouse

lymphoma test. That would be a first package to

look at the safety to get some indication if there

is a problem somewhere and at what dose.

And then depending on the outcome of the

first set of studies would be additional studies if

required, and here it would help to have guidance

from the agency kind of like a decision tree to

say, okay, if you have a problem in that assay,

then you might have to do this additional kind of

141

study. For example, a 52-week toxicity study in

rats, two-generation study in rats. Standard

carcinogenicity study, we kind of consider

overkill. We would rather see a SHE assay done.

That\'s the Syrian hamster embryonic cell assay,

which shows actually a good correlation in the data

to the standard carcinogenicity assay. And as I

said before, we would like to have some guidance on

what to do if one of the tests shows positive

effects.

Now, another thing is safety factors. In

the food additive, it\'s clearly stated that the

safety factor of 100 is applied for estimation of

an upper safe level in humans from the no observed

adverse effect level found in rodent studies. We

think that this factor cannot be transformed into

the nutraceutical area because the food additives

are new to the human body, the human body was never

exposed to them; whereas, the nutraceuticals you

have a history of safe human use over centuries and

centuries. So I don\'t think that they should be

treated the same way.

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So the proposal is to have no standard

safety factor. I\'m not saying no safety factor,

but no standard safety factor. The upper safe dose

is derived from pharmacokinetic data in both humans

and rodents, plus data from rodent tox studies,

also considered the exposure needed to have the

desired efficacy. And from that data compiled

should allow to determine an upper safe dose, which

in humans leads to plasma levels not exceeding the

no adverse effect level observed in the rodent tox

studies. The intended dose should then be a

multiple below that level, for example, three times

below the upper safe level, and it should also, of

course, allow for the desired effect.

I maybe will just skip that one in regard

to the time. So, in summary, nutraceuticals can

provide the risk reduction for disease. Thus, they

may sense from a public health point of view. They

must be safe in the recommended dose as evidenced

by appropriate safety data. Efficacy should be

evidenced by a mechanistic plausibility and/or

clinical data serving as a basis for honest claims,

143

and I would kind of stress the term \"honest

claims.\"

Legislation together with the industry has

to find ways that allow the first mover to protect

his investment in safety and efficacy.

Thank you.

DR. FRANKOS: Thank you.

Any questions?

\[No response.\]

DR. FRANKOS: Well, thank you. That

brings us to the end of our meeting, and I just

have a few comments. I\'m absolutely thrilled at

the kind of dialogue we\'ve started here, and I hope

that we can continue more of this dialogue. As a

lot of you alluded to, there are quite a few

questions that are in the Federal Register notice.

Those questions were put together because there is

a lot that\'s still to be done as far as coming up

with more consistency in the NDI process.

I encourage you each to address those

questions individually. Today we had a lot of

general discussion, but I think it\'s important that

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we get direct answers to the questions we\'ve

presented.

As far as timeline goes, we\'ll wait to

hear about extending the comment period, but we\'ve

heard quite a few suggestions here as to why we

might want to extend it. And I don\'t know about

this last suggestion about going to six months, but

we will\--I don\'t think that\'s been officially

submitted yet.

The other thing that I\'m very hopeful

about is this whole idea of continued dialogue.

I\'ve heard quite a few commenters indicate that

more dialogue is needed, and I would have to agree

with that, and I\'m looking forward to more

meetings. We may have to look at more specific

questions based on the comments that we get.

So I\'d like to thank everyone. It was

really a very good meeting for me and for our

panel. I\'m sure each of us has learned something

today.

So we\'re finished. Have a great lunch.

\[Applause.\]

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\[Whereupon, at 12:31 p.m., the meeting was

adjourned.\]

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