81 FR 53486 - Dietary Supplements: New Dietary Ingredient Notifications and Related Issues; Revised Draft Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 156 (August 12, 2016)

The Food and Drug Administration (FDA or we) is announcing the issuance of a revised draft guidance for industry entitled ``Dietary Supplements: New Dietary Ingredient Notifications and Related Issues.'' The revised draft guidance supersedes FDA's July 2011 draft guidance on the same topic. The revised draft guidance, when finalized, will help industry in evaluating whether to submit a premarket safety notification for a new dietary ingredient (NDI), or for a dietary supplement containing an NDI, and in preparing such premarket safety notifications (also referred to as NDI notifications).

[Federal Register Volume 81, Number 156 (Friday, August 12, 2016)]
[Notices]
[Pages 53486-53489]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-19306]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-D-0376]


Dietary Supplements: New Dietary Ingredient Notifications and 
Related Issues; Revised Draft Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or we) is announcing the 
issuance of a revised draft guidance for industry entitled ``Dietary 
Supplements: New Dietary Ingredient Notifications and Related Issues.'' 
The revised draft guidance supersedes FDA's July 2011 draft guidance on 
the same topic. The revised draft guidance, when finalized, will help 
industry in evaluating whether to submit a premarket safety 
notification for a new dietary ingredient (NDI), or for a dietary 
supplement containing an NDI, and in preparing such premarket safety 
notifications (also referred to as NDI notifications).

DATES: Although you may comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that FDA considers your comment on the draft 
guidance before we begin work on the final version of the guidance, 
submit either electronic or written comments on the draft guidance by 
October 11, 2016.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.

[[Page 53487]]

     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2011-D-0376 for ``Dietary Supplements: New Dietary Ingredient 
Notifications and Related Issues; Revised Draft Guidance for 
Industry.'' Received comments will be placed in the docket and, except 
for those submitted as ``Confidential Submissions,'' publicly viewable 
at http://www.regulations.gov or at the Division of Dockets Management 
between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.
    Submit written requests for single copies of the draft guidance to 
the Division of Dietary Supplement Programs, Center for Food Safety and 
Applied Nutrition (HFS-810), Food and Drug Administration, 5001 Campus 
Drive, College Park, MD 20740. Send one self-addressed adhesive label 
to assist that office in processing your requests. See the 
SUPPLEMENTARY INFORMATION section for electronic access to the draft 
guidance.

FOR FURTHER INFORMATION CONTACT: Ali Abdel-Rahman, Center for Food 
Safety and Applied Nutrition (HFS-810), Food and Drug Administration, 
5001 Campus Dr., College Park, MD 20740, 240-402-1853.

SUPPLEMENTARY INFORMATION:

I. Background

    We are announcing the availability of a revised draft guidance for 
industry entitled ``Dietary Supplements: New Dietary Ingredient 
Notifications and Related Issues.'' This draft guidance supersedes the 
July 2011 draft guidance on this topic (76 FR 39111; July 5, 2011) and 
is being issued consistent with our good guidance practices regulation 
(21 CFR 10.115). The draft guidance, when finalized, will represent our 
current thinking on this topic. It will not create or confer any rights 
for or on any person and will not operate to bind FDA or the public. An 
alternative approach may be used if such approach satisfies the 
requirements of the applicable statutes and regulations.
    On October 25, 1994, the Dietary Supplement Health and Education 
Act of 1994 (DSHEA) (Pub. L. 103-417) was signed into law. DSHEA 
amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act) by 
adding, among other provisions: (1) Section 201(ff) (21 U.S.C. 
321(ff)), which defines the term ``dietary supplement'' and (2) section 
413 (21 U.S.C. 350b), which describes requirements for NDIs. Among 
other things, section 413 of the FD&C Act requires the manufacturer or 
distributor of an NDI, or of a dietary supplement containing the NDI, 
to submit a premarket notification to FDA (as delegate for the 
Secretary of Health and Human Services) at least 75 days before 
introducing the NDI or dietary supplement into interstate commerce, 
unless the NDI and any other ingredients in the dietary supplement 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 (21 U.S.C. 
350b(a)(1)). The notification must contain the information, including 
any citation to published articles, which is the manufacturer or 
distributor's basis for concluding that a dietary supplement containing 
the NDI will reasonably be expected to be safe.
    This draft guidance has several purposes. First, it is intended to 
help dietary supplement manufacturers and distributors decide whether 
to submit an NDI notification. In addition, the draft guidance is 
intended to provide recommendations on how to conduct a safety 
assessment for an NDI notification and what to include in the 
notification. In question and answer form, the draft guidance presents 
FDA's views on what qualifies as an NDI; when an NDI notification is 
required; the procedures for submitting an NDI notification; the types 
of data and information that manufacturers and distributors should 
consider when evaluating the safety of a dietary supplement containing 
an NDI; and what should be included in an NDI notification. In 
addition, the draft guidance contains questions and answers about parts 
of the dietary supplement definition (section 201(ff) of the FD&C Act) 
that can affect whether a particular substance may be marketed as a 
dietary ingredient in a dietary supplement.
    We issued the original version of this draft guidance in the 
Federal Register of July 5, 2011 (the 2011 draft guidance). We gave 
interested parties an opportunity to submit comments by October 3, 
2011. In the Federal Register of September 9, 2011 (76 FR 55927), we 
extended the comment period to December 2, 2011. We received numerous 
comments on the 2011 draft guidance.
    Based on those comments and on meetings with industry and other 
stakeholders, we realized that the 2011 draft guidance contained gaps 
and unclear statements that were subject to confusion and 
misinterpretation. Therefore, we decided to clarify and better explain 
our thinking on some critical issues, in addition to explaining their 
public health significance, and to

[[Page 53488]]

request additional comments on these issues before publishing a final 
guidance. We have revised certain questions and answers and added a 
number of new questions and answers.
    The major topics on which we have revised or added questions and 
answers are as follows:
     Chemical alteration--Dietary supplements containing an NDI 
are exempt from the notification requirement when they contain 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 IV.B of the revised draft guidance explains 
FDA's interpretation of ``present in the food supply as an article used 
for food'' and the public health basis for that interpretation. In 
addition, section IV.B has been revised to address the question of what 
constitutes ``chemical alteration'' more fully and to explain FDA's 
reasoning on this issue, as well as discussing additional examples of 
when chemical alteration occurs and when it does not. Because no 
guidance document can cover every possible manufacturing scenario, the 
draft guidance encourages industry to consult with FDA in advance on 
such matters.
     Manufacturing changes that create an NDI--A related issue 
addressed in section IV.A of the draft guidance is when a manufacturing 
change alters the structure or properties of an ingredient and creates 
an NDI for which a notification must be submitted. The revised draft 
guidance provides examples of manufacturing changes that alter the 
identity of the ingredient, the key factor in determining whether they 
also change the regulatory status of the ingredient.
     Synthetic substances--Section IV.D of the revised draft 
guidance contains an expanded discussion clarifying FDA's views on when 
synthetic copies of botanical and other dietary ingredients qualify as 
dietary ingredients under the FD&C Act. FDA's thinking is based on the 
text of section 201(ff)(1) of the FD&C Act, which defines some types of 
dietary ingredients by identity and others by function.
     New dietary ingredient definition and list of 
``grandfathered'' dietary ingredients--In section IV.A of the draft 
guidance, we revised our response to the question about whether there 
is an authoritative list of dietary ingredients marketed before October 
15, 1994 (a so-called ``grandfathered list'' or ``old dietary 
ingredient list''). Dietary ingredients marketed before that date are 
not NDIs and therefore are not subject to the premarket notification 
requirement in section 413 of the FD&C Act. Although there is currently 
no authoritative list of ``grandfathered'' ingredients, the revised 
answer notes that FDA is prepared to compile such a list based on 
independent and verifiable data to be submitted by industry. The 
revised answer also discusses FDA's thinking on the regulatory status 
of dietary ingredients that would be on such a list, as well as the 
status of dietary ingredients not on such a list.
    We also revised several questions and answers in section IV.A to 
clarify various matters regarding FDA's interpretation of the terms 
``marketed'' and ``dietary ingredient'' in section 413(d) of the FD&C 
Act, which defines an NDI as a dietary ingredient that was not marketed 
in the United States before October 15, 1994, and we added more 
examples of documentation that can be used to show that a dietary 
ingredient was marketed prior to October 15, 1994.
     Structuring notifications efficiently and relying on data 
from prior notifications and master files--We added several questions 
and answers in section IV.C of this draft guidance to suggest ways 
manufacturers and distributors can reduce the number of NDI 
notifications they must file and to clarify when data and information 
from a previous notification or ``master file'' may be used in a 
notification. For example, the answer to a new question clarifies that 
firms may submit an NDI notification that covers the use of the NDI in 
multiple dietary supplements and includes safety data for a range of 
doses and/or differing conditions of use. This answer also explains 
that a firm may submit a confidential ``master file'' containing 
specifications, manufacturing procedures, and other identity 
information for an NDI, and may incorporate information from the master 
file into its own NDI notification or may authorize another firm to 
rely on information from the master file in a notification for a 
dietary supplement containing the NDI. We also added a question and 
answer to describe when a firm may rely on data in another 
notification. In addition, section IV.C now includes a question and 
answer with six examples distinguishing situations in which separate 
notifications are required for different dietary supplements containing 
the same NDI from situations in which a single NDI notification covers 
multiple dietary supplements containing the same NDI. Finally, section 
IV.C now clarifies that, although a combination of NDIs is itself an 
NDI, a combination of grandfathered dietary ingredients is not, even if 
that combination has not been used in a dietary supplement before.
     Identity information to include in an NDI notification--We 
revised several questions and answers in section VI.A in consideration 
of comments regarding chemical and botanical information necessary to 
determine the identity of an NDI. We also added a new question and 
answer with recommendations about what chemistry information should be 
included in a notification for an enzyme NDI. In addition, since some 
of the standard references on nomenclature of plants and microorganisms 
have been renamed or updated since the 2011 draft guidance, we updated 
the citations to refer to the most recent edition.
     Electronic submission--We updated the question and answer 
in section V.A about electronic submission of NDI notifications. The 
updated answer states that we are accepting NDI notifications 
electronically and provides the Internet address for the electronic 
submission gateway. As before, the answer notes that firms still have 
the option to submit paper notifications to FDA using the procedure 
described in 21 CFR 190.6.
     PDF form for NDI notifications submitted on paper--Because 
our electronic submission gateway for NDI notifications is now 
available, we have decided not to provide a competing form for paper 
notifications. Therefore, we have removed ``Appendix B: 75-Day Pre-
Market New Dietary Ingredient Notification Form'' from the draft 
guidance.
     Safety information to include in an NDI notification--We 
revised several questions and answers in sections VI.B and VI.C to 
clarify our thinking on compiling and evaluating scientific evidence 
about the safety of NDIs and dietary supplements that contain NDIs. In 
section VI.B, we clarified our thinking on the use of foreign history 
of use data. We also added a recommendation to consult ``Principles and 
Methods for the Risk Assessment of Chemicals in Food,'' a joint 
publication of the World Health Organization and the Food and 
Agriculture Organization of the United Nations, as a useful source of 
information on conducting human clinical studies for NDIs and dietary 
supplements. In response to comments, we removed all references to 
FDA's ``Redbook'' guidance, which contains recommendations on toxicity 
studies and other scientific evidence needed to determine the safety of 
food additives. We also revised section VI.B to explain that the NDI 
safety standard is different from the standards for other FDA-regulated 
products and clarify that evidence for an NDI safety evaluation should 
be compiled to meet that standard. Although the revised draft

[[Page 53489]]

guidance no longer cites the Redbook, we continue to recommend the use 
of the dietary exposure assessment methodology and some toxicology 
tests that are also used for the evaluation of food additives because 
these are standard scientific methods not specific to any particular 
safety assessment paradigm. Finally, we added a new question at the end 
of section VI.C to emphasize that this draft guidance contains 
recommendations about safety information to include in an NDI 
notification, but these recommendations are not requirements.
     Other changes--We made clarifying changes, explanatory 
changes, and editorial changes throughout the document. We also updated 
references and links and added new references where appropriate.

II. Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 
3501-3520), Federal agencies must obtain approval from the Office of 
Management and Budget (OMB) for each collection of information they 
conduct or sponsor. This draft guidance contains proposed collections 
of information. ``Collection of information'' is defined in 44 U.S.C. 
3502(3) and 5 CFR 1320.3(c) and includes Agency requests or 
requirements that members of the public submit reports, keep records, 
or provide information to a third party. Section 3506(c)(2)(A) of the 
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal Agencies to publish a 
60-day notice in the Federal Register soliciting public comment on each 
proposed collection of information before submitting the collection to 
OMB for approval. To comply with this requirement, we intend to publish 
a 60-day notice on the proposed collections of information in this 
draft guidance in a future issue of the Federal Register.
    This draft guidance also refers to previously approved collections 
of information found in FDA regulations. These collections of 
information are subject to review by OMB under the PRA. The collections 
of information in 21 CFR part 111 have been approved under OMB control 
number 0901-0606, and the collections of information in Sec.  190.6 
have been approved under OMB control number 0910-0330.

III. Other Issues for Consideration

    Although FDA welcomes comments on any aspect of this draft 
guidance, we particularly invite comment on the following:
     What processes alter the identity of an ingredient 
marketed prior to October 15, 1994, and thus create an NDI? We are 
especially interested in recommendations for clearer examples or 
criteria to differentiate changes in manufacturing methods and starting 
materials that alter the identity of the ingredient from changes that 
do not.
     What processes ``chemically alter'' an ingredient within 
the meaning of section 413(a)(1) of the FD&C Act, and why? Conversely, 
what processes do not cause chemical alteration, and why? Are there 
certain processes, such as tinctures, that sometimes result in chemical 
alteration and sometimes do not? What criteria should be used to 
evaluate whether an ingredient has been chemically altered? We are 
especially interested in receiving scientific information that shows 
whether a particular process actually results in chemical alteration.
     What method of compiling independent and verifiable data 
on the marketing of dietary ingredients before October 15, 1994, would 
be most effective? How should an authoritative list of 
``grandfathered'' ingredients based on such data be developed and 
implemented?
    As FDA considers the development of final guidance, we will review 
comments received on this revised version, as well as comments on the 
2011 draft guidance that are still relevant.

IV. Electronic Access

    Persons with access to the Internet may obtain the guidance at 
either http://www.fda.gov/FoodGuidances or http://www.regulations.gov. 
Use the FDA Web site listed in the previous sentence to find the most 
current version of the draft guidance.

V. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at http://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. International Programme on Chemical Safety, ``Principles and 
Methods for the Risk Assessment of Chemicals in Food,'' 
Environmental Health Criteria 240 (2009), available at: http://www.who.int/foodsafety/publications/chemical-food/en/.
2. The official name of the Redbook is ``Guidance for Industry and 
Other Stakeholders: Toxicological Principles for the Safety 
Assessment of Food Ingredients,'' available at: http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm2006826.htm.

    Dated: August 9, 2016.
Jeremy Sharp,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2016-19306 Filed 8-11-16; 8:45 am]
 BILLING CODE 4164-01-P