1
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
5
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
9
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
12
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
15
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
17
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
20
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
24
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
25
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
26
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
27
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
28
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
29
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
30
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
102
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
113
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
115
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.
126
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
127
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
128
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
129
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
130
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...
131
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
132
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
133
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
134
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
135
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
136
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
137
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
138
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
139
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
140
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.
142
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
144
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.]
145
[Whereupon, at 12:31 p.m., the
meeting was
adjourned.]
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