[Federal Register Volume 81, Number 173 (Wednesday, September 7, 2016)]
[Notices]
[Pages 61700-61703]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-21350]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-N-2523]


Request for Comment on the Status of Vinpocetine

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or we) is requesting 
comments related to the regulatory status of vinpocetine. Specifically, 
we request comments on our tentative conclusion that vinpocetine is not 
a dietary ingredient and is excluded from the definition of dietary 
supplement in the Federal Food, Drug, and Cosmetic Act (FD&C Act). This 
action is being taken as part of an administrative proceeding to 
determine the regulatory status of vinpocetine. All comments submitted 
by the comment deadline (see DATES) will be accepted as part of the 
official record for this proceeding.

DATES: Submit either electronic or written comments on the notice by 
November 7, 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

[[Page 61701]]

identifies you in the body of your comments, that information will be 
posted on http://www.regulations.gov.
     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-2016-N-2523 for ``Request for Comment on the Status of 
Vinpocetine.'' 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.

FOR FURTHER INFORMATION CONTACT: Cara Welch, Center for Food Safety and 
Applied Nutrition (HFS-810), Food and Drug Administration, 5001 Campus 
Dr., College Park, MD 20740, 240-402-2333.

SUPPLEMENTARY INFORMATION:

I. Introduction

    We are initiating an administrative proceeding under 21 CFR 
10.25(b) to determine the regulatory status of vinpocetine (chemical 
name: Ethyl apovincaminate). Specifically, we are trying to determine: 
(1) Whether vinpocetine is a dietary ingredient within the meaning of 
the FD&C Act and (2) whether it is excluded from being a dietary 
supplement under the FD&C Act.

A. Statutory Background

    Under section 201(ff)(1) of the FD&C Act (21 U.S.C. 321(ff)(1)), 
the term ``dietary supplement'' is defined in part as a product (other 
than tobacco) intended to supplement the diet that bears or contains 
one or more of the following dietary ingredients: (A) A vitamin; (B) a 
mineral; (C) an herb or other botanical; (D) an amino acid; (E) a 
dietary substance for use by man to supplement the diet by increasing 
the total dietary intake; or (F) a concentrate, metabolite, 
constituent, extract, or combination of any ingredient described in 
clause (A), (B), (C), (D), or (E).
    Additionally, under section 201(ff)(3)(B)(ii) of the FD&C Act, a 
dietary supplement cannot include ``an article authorized for 
investigation as a new drug . . . for which substantial clinical 
investigations have been instituted and for which the existence of such 
investigations has been made public'' unless the article was marketed 
as a dietary supplement or as a food before such authorization.
    Recently, questions have been raised as to whether vinpocetine is a 
dietary ingredient and is excluded from the definition of dietary 
supplement under sections 201(ff)(1) and (3) of the FD&C Act, 
respectively.

B. Factual Background

    According to records on file in FDA's Center for Drug Evaluation 
and Research, vinpocetine was authorized for investigation as a new 
drug in 1981.\1\ A trade press article from 1985 reported that four 
single-center phase 3 clinical trials \2\ of vinpocetine had been 
completed and that two major multicenter studies were ongoing (Ref. 1). 
A 1986 article in a major newspaper reported that Ayerst had recently 
completed a study of vinpocetine for the treatment of multiple-infarct 
dementia at eight institutions in the United States (Ref. 2). An 
article published in a medical journal in 1986 reported on the results 
of a double-blind study of vinpocetine in elderly patients with central 
nervous system degenerative disorders (Ref. 3). A trade press article 
published in 1988 reported that vinpocetine was in phase 3 clinical 
trials for Alzheimer's disease (Ref. 4). These articles document that 
substantial clinical investigations of vinpocetine were instituted and 
that the existence of these substantial clinical investigations was 
made public.
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    \1\ An article becomes ``authorized for investigation as a new 
drug'' after the sponsor has submitted an investigational new drug 
application (IND) to FDA and the IND has gone into effect. Unless 
FDA notifies the sponsor that the clinical investigation described 
in the IND has been placed on clinical hold, the IND goes into 
effect 30 days after being submitted to FDA (21 CFR 312.40(b)). 
Although FDA will not disclose the existence of an IND that has not 
previously been publicly disclosed or acknowledged (see 21 CFR 
312.130), the existence of the 1981 IND for vinpocetine was publicly 
disclosed in the press no later than 1986 (Ref. 2).
    \2\ Generally speaking, under our regulations pertaining to 
investigational new drugs, there are three phases of a clinical 
investigation of a new drug; phase 3 trials are the last in the 
sequence and are ``expanded controlled and uncontrolled trials'' 
that are ``performed after preliminary evidence suggesting 
effectiveness of the drug has been obtained, and are intended to 
gather the additional information about effectiveness and safety 
that is needed to evaluate the overall benefit-risk relationship of 
the drug and to provide an adequate basis for physician labeling'' 
(21 CFR 312.21(c)).
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    On July 8, 1997, a new dietary ingredient notification \3\ for 
vinpocetine was submitted to FDA (see FDA's Table of New Dietary 
Ingredient Notifications

[[Page 61702]]

(available on the Web at http://www.fda.gov/food/dietarysupplements/newdietaryingredientsnotificationprocess/ucm109764.htm#new_din)). Four 
additional new dietary ingredient notifications for vinpocetine were 
later submitted to FDA.\4\
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    \3\ As defined in section 413(d) of the FD&C Act (21 U.S.C. 
350b(d)), the term ``new dietary ingredient'' means a dietary 
ingredient that was not marketed in the United States before October 
15, 1994. Section 413(a) of the FD&C Act (21 U.S.C. 350b(a)) 
requires manufacturers and distributors who wish to market dietary 
supplements that contain ``new dietary ingredients'' to submit a 
notification containing safety information to FDA before they begin 
marketing, unless the new dietary ingredient and all other dietary 
ingredients in the dietary supplement have been present in the food 
supply, without chemical alteration, as articles used for food.
    \4\ We acknowledged receipt of each of those new dietary 
ingredient notifications without objection.
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C. Vinpocetine and Section 201(ff)(1) of the FD&C Act

    We first consider whether vinpocetine is a dietary ingredient under 
section 201(ff)(1) of the FD&C Act--specifically, whether it is a 
vitamin, mineral, herb or other botanical, amino acid, dietary 
substance for use by man to supplement the diet by increasing the total 
dietary intake, or a concentrate, metabolite, constituent, extract, or 
combination of dietary ingredients from the preceding categories. We 
are not aware of any argument that vinpocetine is a vitamin, a mineral, 
or an amino acid. Thus, vinpocetine does not appear to qualify as a 
dietary ingredient under section 201(ff)(1)(A), (B), or (D) of the FD&C 
Act.
    Vinpocetine is not an herb or other botanical, nor is it a 
constituent of any botanical. Rather, vinpocetine is a synthetic 
compound, derived from vincamine, an alkaloid found in the Vinca minor 
plant, or tabersonine, an alkaloid found in Voacanga seeds (Ref. 5). 
Vinpocetine can be formed synthetically from vincamine, including via a 
``one-pot'' synthesis, through transesterification and/or dehydration 
of vincamine in ethanol using Lewis acids and catalyzed by ferric 
chloride (Refs. 5 and 6). The process to prepare vinpocetine from 
tabersonine involves first converting to vincamine via hydrogenation, 
oxidation, reduction and, finally, isolation of vincamine (Ref. 7). The 
previously discussed method of producing vinpocetine from vincamine can 
then be used. As a synthetic compound, vinpocetine is not an herb or 
other botanical. Thus, vinpocetine does not appear to qualify as a 
dietary ingredient under section 201(ff)(1)(C) of the FD&C Act.
    Vinpocetine is not a dietary substance for use by man to supplement 
the diet by increasing the total dietary intake. Extensive database and 
literature searches did not identify any food use of vinpocetine. Thus, 
vinpocetine does not appear to qualify as a dietary ingredient under 
section 201(ff)(1)(E) of the FD&C Act.
    Finally, vinpocetine is not a concentrate, metabolite, constituent, 
extract, or combination of any ingredient described in section 
201(ff)(1)(A), (B), (C), (D), or (E) of the FD&C Act. We are not aware 
of any factual basis to conclude that vinpocetine is a concentrate, 
metabolite, constituent, extract, or combination of a vitamin, mineral, 
amino acid, or dietary substance. As described earlier, vinpocetine is 
not found in V. minor, Voacanga, or any other botanical, but rather is 
a synthetic derivative of vincamine or tabersonine. Therefore, 
vinpocetine cannot be a concentrate, constituent, or extract of a 
botanical. After extensive literature and database searches, we have 
been unable to find any evidence that vinpocetine is a concentrate, 
metabolite, constituent, extract, or combination of another dietary 
ingredient or dietary ingredients. Therefore, vinpocetine does not 
appear to qualify as a dietary ingredient under section 201(ff)(1)(F) 
of the FD&C Act.
    We therefore tentatively conclude that vinpocetine is not a dietary 
ingredient under section 201(ff)(1) of the FD&C Act because it does not 
fit any of the dietary ingredient categories.

D. Vinpocetine and Section 201(ff)(3) of the FD&C Act

    As noted above, the statutory definition of ``dietary supplement'' 
excludes an article authorized for investigation as a new drug for 
which substantial clinical investigations have been instituted and made 
public, unless the article was marketed as a dietary supplement or as a 
food before such authorization (see section 201(ff)(3)(B)(ii) of the 
FD&C Act).
    Based on FDA's IND records and articles published between 1985 and 
1988 that mention or report on phase 3 clinical trials for vinpocetine 
(Refs. 1 to 4), it appears that: (1) Vinpocetine was authorized for 
investigation as a new drug in 1981, long before the first new dietary 
ingredient notification for vinpocetine was filed in 1997 and, 
therefore, also long before vinpocetine was marketed as a dietary 
supplement; (2) substantial clinical investigations of vinpocetine have 
been instituted, and (3) the existence of such investigations has been 
made public.
    We therefore tentatively conclude that vinpocetine is excluded from 
the dietary supplement definition under section 201(ff)(3)(B) of the 
FD&C Act.

E. Tentative Conclusion

    Based on the evidence available to us to date, we tentatively 
conclude that vinpocetine is not a dietary ingredient as defined in 
section 201(ff)(1) of the FD&C Act. We further tentatively conclude 
that vinpocetine is excluded from the dietary supplement definition 
under section 201(ff)(3)(B) of the FD&C Act and therefore may not be 
marketed as or in a dietary supplement. We are interested in receiving 
information that would inform our final decision on the regulatory 
status of vinpocetine, such as information about any food uses of 
vinpocetine and information on the date vinpocetine was first marketed 
as a food or as a dietary supplement.
    To afford all interested parties an adequate opportunity to 
participate in this matter, we request comments and other supporting 
information related to this matter. Interested persons may submit to 
the Division of Dockets Management (see ADDRESSES) written or 
electronic comments regarding this document.

II. References

    The following references are on display in FDA's 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. The Pink Sheet, ``Ayerst Planning on First Quarter 1986 NDA 
Submission for Alredase (Tolrestat) in Diabetic Neuropathy; Firm is 
Shooting for Early 1987 Market Launch,'' June 17, 1985. Retrieved 
from: https://pink.pharmamedtechbi.com/PS008480/AYERST-PLANNING-ON-FIRST-QUARTER-1986-NDA-SUBMISSION-FOR-ALREDASE-TOLRESTAT-IN-DIABETIC-NEUROPATHY-F.
2. Maugh II, T. H., ``Firm Hopes to Market New `Memory' Drug,'' The 
Los Angeles Times, April 15, 1986. Retrieved from: http://articles.latimes.com/1986-04-15/news/mn-4847_1_vinpocetine.
3. Manconi, E., F. Binaghi, and F. Pitzus, ``A Double-Blind Clinical 
Trial of Vinpocetine in the Treatment of Cerebral Insufficiency of 
Vascular and Degenerative Origin,'' Current Therapeutic Research, 
Vol. 40, No. 4, 1986.
    4. The Pink Sheet, ``American Home Products' `Third Generation' 
TPA Entering Clinicals,'' March 21, 1988. Retrieved from: https://pink.pharmamedtechbi.com/PS013359/AMERICAN-HOME-PRODUCTS-THIRD-GENERATION-TPA-ENTERING-CLINICALS.
5. National Toxicology Program, U.S. Dept. of Health and Human 
Services, ``Chemical Information Review Document for Vinpocetine 
[CAS No. 42971-09-5].'' Retrieved from: http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/vinpocetine091613_508.pdf.
6. Y. Kuge, H. Nakazawa, T. Kometani, et al., ``A Facile One-Pot 
Synthesis of Vinpocetine,'' Synthetic Communications:

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An Internal Journal for Rapid Communication of Synthetic Organic 
Chemistry, vol. 24, no. 6, 1994.
7. U.S. Patent and Trademark Office, ``Process of Preparation of 
Vincamine from Tabersonine.'' Retrieved from: http://www.google.com/patents/US3892755.


    Dated: August 31, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-21350 Filed 9-6-16; 8:45 am]
 BILLING CODE 4164-01-P