[Federal Register Volume 69, Number 202 (Wednesday, October 20, 2004)]
[Notices]
[Pages 61680-61684]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-23439]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2004N-0454]


Dietary Supplements; Premarket Notification for New Dietary 
Ingredient Notifications; Public Meeting

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a meeting 
and is soliciting comments on FDA's premarket notification program for 
new dietary ingredients (NDIs). FDA is soliciting comments from 
industry, consumers, and other interested

[[Page 61681]]

members of the public concerning the content and format requirements 
for NDI notifications made under the Federal Food, Drug, and Cosmetic 
Act (the act). FDA is holding this meeting to give the public an 
opportunity to provide information and views on the topics outlined in 
this document. The agency intends to consider all comments received 
during the meeting and made to the docket in determining whether any 
future action is necessary or appropriate.

DATES: The public meeting will be held on November 15, 2004, from 9 
a.m. to 5 p.m. Attendees must register to attend.
    Submit written or electronic comments by December 3, 2004.
    For security and space limitation reasons, you are encouraged to 
register early. You may preregister via phone, fax, or e-mail until 
close-of-business November 10, 2004, or on site on the day of the 
meeting, providing space is available. Those wishing to speak should 
contact Kelly Williams-Randolph (see FOR FURTHER INFORMATION CONTACT) 
before close-of-business, 3 business days before the meeting.

ADDRESSES: The meeting will be held at the Center for Food Safety and 
Applied Nutrition, Harvey W. Wiley Auditorium, 5100 Paint Branch Pkwy., 
College Park, MD 20740.
    Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Kelly Williams-Randolph, Center for 
Food Safety and Applied Nutrition (HFS-810), Food and Drug 
Administration, 5100 Paint Branch Pkwy., College Park, MD 20740, 301-
436-2506, FAX: 301-436-2639, or e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The Dietary Supplement Health and Education Act of 1994 (DSHEA) 
(Public Law 103-417) amended the act by adding, among other things, 
provisions that defined the terms ``dietary supplement'' (section 
201(ff) of the act (21 U.S.C. 321(ff))) and ``new dietary ingredient'' 
(section 413(c) of the act (21 U.S.C. 350b(c))). DSHEA also provided 
that a dietary supplement containing an NDI is adulterated unless it 
meets the requirements set forth in section 413 of the act, which 
requires premarket notification for certain NDIs.
    Under section 413(a) of the act, a dietary supplement that contains 
an NDI is deemed adulterated unless it meets one of two statutory 
requirements. One is that the dietary supplement contains only dietary 
ingredients that ``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.'' (Section 413(a)(1) of the act). The alternative requirement 
is (section 413(a)(2) of the act) that there be:
    [A] history of use or other evidence of safety establishing that 
the dietary ingredient when used under the conditions recommended or 
suggested in the labeling of the dietary supplement will reasonably 
be expected to be safe, and, at least 75 days before being 
introduced or delivered for introduction into interstate commerce, 
the manufacturer or distributor * * * provides [FDA] with 
information, including any citation to published articles, which is 
the basis on which the manufacturer or distributor has concluded 
that a dietary supplement containing such dietary ingredient will 
reasonably be expected to be safe.
    FDA has issued a regulation Sec.  190.6 (21 CFR 190.6) establishing 
the procedure by which a manufacturer or distributor of a dietary 
supplement that contains an NDI must submit the information required by 
section 413(a)(2) of the act.

II. Why Is FDA Holding This Meeting?

    The agency is seeking public comment on several issues that need to 
be addressed to clarify the requirements of section 413(a)(2) of the 
act for NDIs that have not been present in the food supply as an 
article used for food in a form in which the food has not been 
chemically altered. FDA has identified a number of omissions and other 
problems in previous notifications that have been submitted by firms to 
comply with the NDI notification requirements of the act. These 
omissions include a failure to do the following: (1) Adequately 
describe the identity and composition of the NDI, (2) provide 
information that states the basis for a conclusion that the substance 
is an NDI, (3) provide adequate safety information about the NDI, or 
(4) provide other necessary information. The problems with NDI 
notifications described previously suggest that it may be helpful for 
FDA to consider ways to assist submitters of NDI notifications to 
ensure that they contain the information the agency needs to evaluate 
the notification. There is also recognition by the regulated industry 
that the quality of NDI notifications could benefit from FDA 
clarification of the statutory requirements (Ref. 1). Therefore, FDA is 
seeking comments from industry, consumers, and other interested members 
of the public concerning the type, quantity, and quality of information 
that a notifier should provide in notifications under section 413(a)(2) 
of the act.

III. Registration, Written Questions, and Requests for Oral 
Presentations

    Persons interested in attending the November 15, 2004, meeting may 
send their registration information (including name, title, business 
affiliation, address, telephone, and fax number) to the contact person 
(see FOR FURTHER INFORMATION CONTACT) by close-of-business November 10, 
2004, or you may register onsite on the day of the meeting, providing 
space is available. To expedite processing, this registration 
information also may be sent to the contact person (see FOR FURTHER 
INFORMATION CONTACT) by fax or by e-mail. If, in addition to attending, 
you wish to make an oral presentation during the meeting, you must 
inform the contact person 3 days before the meeting when you register 
and submit the following: (1) A brief written statement of the general 
nature of the views you wish to present, (2) the names and addresses of 
all persons who will participate in the presentation, and (3) an 
indication of the approximate time that you request to make your 
presentation. Depending upon the number of people who register to make 
presentations, we may have to limit the time allotted for each 
presentation. Interested persons are encouraged to submit their 
presentations and any additional comments to the docket. Any person who 
wishes to distribute written material at the meeting is responsible for 
the copy and distribution of such material. If you need special 
accommodations due to disability, please notify the contact person at 
least 7 days in advance. There is no registration fee for this public 
meeting, but early registration is encouraged because space is limited 
and it will expedite entry into the building and parking area. Because 
the meeting will be held in a Federal building, you should also bring 
photo identification and plan for adequate time to pass through 
security systems.

IV. Scope of the Meeting

    We are holding the public meeting on November 15, 2004, in part, to 
identify and receive comment on the information a firm should provide 
in an NDI notification under section 413(a)(2) of the act. As follows, 
we provide a list of questions intended to focus public comment on 
specific NDI issues.

[[Page 61682]]

A. Status of a Substance as a ``New Dietary Ingredient''

    1. What should FDA consider to determine whether a substance falls 
within a particular category of the statutory definition of ``dietary 
ingredients'' under sections 201(ff)(1)(A) through (F) of the act?
    2. What changes in chemical composition to a dietary ingredient 
would cause it to become a substance that is not a dietary ingredient?
    3. What should FDA consider to determine whether a dietary 
ingredient was not marketed in the United States before October 15, 
1994, and is therefore an NDI?
    4. What changes in chemical composition to a dietary ingredient 
that was marketed in the United States before October 15, 1994, would 
lead to the dietary ingredient becoming an NDI subject to the 
notification requirement in section 413(a)(2) of the act?
    5. What changes to the conditions of use (e.g., serving size, 
duration, frequency of use) recommended or suggested in the labeling 
for a dietary supplement that contains an NDI would trigger the need 
for a separate NDI notification?
    6. Is there an authoritative list of dietary ingredients that were 
marketed prior to October 15, 1994, and therefore are not NDIs? If not, 
should there be? Who should compile such a list and what criteria 
should be considered for placement of the dietary ingredient on such a 
list?

B. Chemical Identification of the NDI

    1. What types of chemistry information should be included to 
describe an NDI for purposes of the NDI notification? Please consider 
the following types of information:
    a. Chemical name.
    b. Chemical Abstract Service (CAS) registry number (if available).
    c. Empirical formula.
    d. Structural formula.
    e. Quantitative composition.
    f. Chemical characterization.
    g. Chemical specifications.
    2. Are there additional types of chemistry information that should 
be included in the description of an NDI?
    3. What types of information should be included to describe a 
botanical NDI for purposes of the NDI notification? Please consider the 
following types of information:
    a. Botanical family name.
    b. Part(s) of plant used.
    c. Conditions of propagation.
    i. Sexual reproduction (propagated from seeds).
    ii. Seeds produced through selective breeding--variety and 
cultivar.
    iii. Seeds are bioengineered.
    1. Variety, cultivar and seed producer.
    2. Asexual reproduction by cloning.
    3. Vegetative propagules.
    4. tissue culture.
    d. Geographical location of cultivated or wild harvested plant.
    e. Conditions of cultivation.
    i. Time of cultivation--month and year.
    ii. Field cultivation--soil pH, fertilizers, pesticides and 
herbicides.
    f. Greenhouse cultivation.
    i. Soil pH, fertilizers, pesticides and herbicides.
    ii. Hydroponic growth media--nutrients, growth hormones and 
minerals.
    g. Method of drying--air or heat.
    h. Processing information--hand or machine sorted, chopped or 
milled.
    4. Is there other information that should be included in a 
botanical NDI notification due to unusual production conditions of the 
botanical? Please consider the following possible situations:
    a. Saccharomyces cerevisiae is cultured in medium with unusually 
large amounts of selenium. Should the notification describe the degree 
of selenium uptake as well as the levels of selenium compounds in the 
final dietary supplement product?
    b. Traditional or bioengineering methods are used to produce a 
plant variety with novel properties. What chemistry information is 
needed to describe the plant variety in sufficient detail to identify 
the botanical product?
    5. Is there processing information that should be included in the 
description of a botanical extract in order to adequately describe the 
NDI? Please consider the following types of information:
    a. Description of the method of preparation (e.g., extraction) in 
sufficient detail so as to make clear:
    i. The identity of the source material (dietary ingredient).
    ii. How the extract (NDI) is obtained from that source material.
    iii. How the extract is standardized from batch to batch.
    iv. How potential adulterants such as nonfood solvents, pesticides, 
heavy metals and filth are excluded.
    b. Documentation of the absence of toxins or other by-products that 
may affect the safety of the ingredient produced by fermentation or 
bioengineering.
    c. Documentation that the extracts of cultured isolates are neither 
infectious nor toxic.
    6. Are there additional types of information that should be 
included in the description of a botanical NDI?

C. Information About the Dietary Supplement

    1. What types of information about the dietary supplement product 
should be included in an NDI notification?
    2. Please consider the following types of information:
    a. Composition/formulation of the dietary supplement product, 
including any contaminants.
    b. A copy of the proposed product label and of any other labeling 
that recommends or suggests conditions of use in addition to or 
different from those recommended or suggested in the product label.

D. Establishing a Reasonable Expectation of Safety

    1. What types of information should be included in an NDI 
notification in order to establish a reasonable expectation of safety 
based upon history of use? Please consider the following types of 
information:
    a. A description of the population that consumed the food or 
dietary supplement containing the NDI.
    b. The consumption levels (per serving and total exposure).
    c. How often and how long the population consumed the food or 
dietary supplement containing the dietary ingredient.
    d. The number of independent references documenting history of safe 
use.
    e. The number of consecutive years of exposure.
    f. Documentation of the health monitoring system(s) and database(s) 
associated with the consumption of the NDI during the historical period 
of safe use.
    g. Reliability of historical safety information if no health 
monitoring system is in place to detect adverse effects that may be 
associated with the human consumption of the dietary ingredient.
    2. Are there additional items that should be included to establish 
a reasonable expectation of safety based upon history of use?
    3. What quality and quantity of data and information are needed to 
establish a reasonable expectation of safety based upon evidence other 
than history of use?
    4. In considering the data and information necessary to establish 
reasonable expectation of safety, how would the following differences 
in the use of the NDI in the dietary supplement from historical use 
affect safety determinations?
    a. Significantly higher serving level (e.g., twice the serving 
level historically used).

[[Page 61683]]

    b. Longer duration of consumption than historically used (e.g., 
instead of recommending that a consumer drink an herbal tea for a few 
days or occasionally, the label of the dietary supplement containing 
the NDI label suggests or recommends continuous daily use for improved 
digestive function).
    c. Different route of administration (e.g., the dietary ingredient 
was historically administered by poultice or injection, whereas the 
dietary supplement containing the dietary ingredient is ingested).
    d. Change from historical use that might increase potential toxic 
effects (e.g., an NDI that will be consumed as ground root in capsules 
when the historical use was a tea made from the roots).
    e. Change in consumer target group (e.g., from general population 
to young children, pregnant women, lactating women).
    5. What criteria should FDA use to evaluate whether preclinical and 
clinical studies are of sufficient duration to establish a reasonable 
expectation of safety?
    6. When notifications do not provide any information concerning 
recommendations for length of product usage, should FDA assume chronic 
use (i.e., daily) and evaluate safety on that basis?
    7. What types of studies, if any, should be included in order to 
establish a reasonable expectation of safety when the proposed daily 
serving amount is comparable to or less than the safe historical daily 
serving amount? What if the proposed daily serving amount is greater 
than the safe historical daily serving amount? Please consider the 
following types of studies:
    a. Genetic toxicity 2-3 study battery (e.g., a bacterial gene 
mutation assay, mammalian cell gene mutation assay, or deoxyribonucleic 
acid (DNA) repair assay).
    b. Short-term feeding studies (<30-day) (rodent).
    c. Subchronic feeding studies (90-day) (rodent, nonrodent).
    d. Single dose human tolerance studies.
    e. Repeat dose human safety studies (30- to 90-day duration).
    f. Teratology studies (rodent, nonrodent).
    g. Multigeneration reproduction studies (rodent, nonrodent).
    h. Special studies (e.g., carcinogenicity, absorption, metabolism 
and distribution and excretion).
    i. Other studies.
    8. How would the evaluation of such studies (previously listed) to 
establish reasonable expectations of safety, differ under varying 
duration and frequency of use scenarios such as the following:
    a. The labeling of the dietary supplement containing an NDI 
recommends or suggests daily chronic use, and the documented historical 
duration and frequency of use support safe daily chronic use.
    b. The labeling of the dietary supplement containing an NDI 
recommends or suggests intermittent use, and the documented historical 
duration and frequency of use support safe intermittent use.
    c. The labeling of the dietary supplement containing an NDI 
recommends or suggests intermittent use, and the documented historical 
duration and frequency of use support safe daily chronic use.
    d. The labeling of the dietary supplement containing an NDI 
recommends or suggests daily chronic use, and the documented safe 
historical duration and frequency of use support intermittent use.
    e. There is no history of use data to establish safe intermittent 
or chronic daily use.
    9. What are appropriate and authoritative references for notifiers 
to consider when developing protocols for collecting safety data in 
support of NDI notifications?
    10. What considerations should apply to FDA's evaluation of the 
safety of a dietary supplement containing an NDI with respect to the 
following special populations?
    a. Women of child bearing potential.
    b. Pregnant women.
    c. Lactating women.
    d. Children.
    e. Geriatric adults.
    f. Other.

E. The Role of Definitions in Evaluating NDIs

    1. Are there terms that should be defined so that the NDI 
notification program can be more transparent and consistent?
    2. FDA seeks comment on how the following terms should be defined:
    a. Amino acid.
    b. Botanical.
    c. Chemically altered.
    d. Concentrate.
    e. Constituent.
    f. Extract.
    g. Ingestion.
    h. Metabolite.
    i. Mineral.
    j. Salts of dietary ingredients.
    k. Tincture.
    l. Vitamin.

F. Is There a Need for Guidance or Amendment of Current Requirements?

    The information presented as follows, could assist FDA in 
efficiently reviewing NDI notifications. Comment is invited on whether 
FDA should consider the issuance of draft guidance or amendments to 
current requirements to include the following:
    1. Table of contents and ``continuous pagination'' in the 
notification;
    2. A discussion that clearly indicates why the notifier has 
concluded that the ``new dietary ingredient'' is a dietary ingredient 
under 21 U.S.C. 321(ff)(1);
    3. Detailed requirement for chemical characterization of the NDI;
    4. Requirement for composition/formulation of the dietary 
supplement containing the NDI;
    5. A tabular listing of studies, articles and other scientific 
information provided in the notification to support a conclusion that 
the NDI, when used under the conditions recommended or suggested in the 
labeling of the notifier's dietary supplement, will reasonably be 
expected to be safe, with an indication of whether the test material in 
these studies is the same substance as is used in the notifier's 
dietary supplement;
    6. A safety document'' that clearly describes the scientific 
reasoning used by the notifier to establish a reasonable expectation of 
safety, based upon the data provided in the notification; and
    7. Option for electronic submission of notifications.

VI. Transcripts

    You may request a transcript of the meeting in writing from the 
Freedom of Information Office (HFI-35), Food and Drug Administration, 
rm. 12A-16, 5600 Fishers Lane, Rockville, MD 20857, approximately 15 
working days after the meeting, at a cost of 10 cents per page. You may 
also examine the transcript of the meeting at the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday, as well as 
on the FDA Internet at http://www.fda.gov.

VII. Reference

    We have placed the following reference on display in the Division 
of Dockets Management (see ADDRESSES). You may see it at that office 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. M. McGuffin and A. L. Young, Premarket Notifications of New 
Dietary Ingredients--A Ten-Year Review, Food and Drug Law Journal, 
59(1): 2004.

VIII. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that

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individuals may submit one paper copy. Comments are to be identified 
with the docket number found in the brackets in the heading of this 
document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: October 13, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-23439 Filed 10-15-04; 2:59 pm]
BILLING CODE 4160-01-S