Federal Register, Volume 90 Issue 233 (Monday, December 8, 2025)

[Federal Register Volume 90, Number 233 (Monday, December 8, 2025)]
[Notices]
[Pages 56772-56773]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-22249]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2007-D-0369]


Product-Specific Guidance on Estradiol; Draft Guidance for 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, Agency, or we) is 
announcing the availability of a new draft guidance for industry 
entitled ``Draft Guidance on Estradiol'' and a revised draft guidance 
for industry entitled ``Draft Guidance on Estradiol.'' The new draft 
guidance and the revised draft guidance, when finalized, will provide 
product-specific recommendations on, among other things, the design of 
bioequivalence (BE) studies to support abbreviated new drug 
applications (ANDAs) for estradiol vaginal inserts and estradiol 
vaginal tablets.

DATES: Submit either electronic or written comments on the draft 
guidance by February 6, 2026 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://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 https://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): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, 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-2007-D-0369 for ``Draft Guidance on Estradiol.'' Received comments 
will be placed in the docket and, except for those submitted as 
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     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

[[Page 56773]]

``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 https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. 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: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://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 Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the draft guidance to 
the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10001 New Hampshire Ave., 
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002. 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 document.

FOR FURTHER INFORMATION CONTACT: Joseph Kotsybar, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 75, Rm. 3623A, Silver Spring, MD 20993-0002, 240-
402-1062, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of June 11, 2010 (75 FR 33311), FDA 
announced the availability of a guidance for industry entitled 
``Bioequivalence Recommendations for Specific Products'' that explained 
the process that would be used to make product-specific guidances 
available to the public on FDA's website at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.
    As described in that guidance, FDA adopted this process as a means 
to develop and disseminate product-specific guidances and provide a 
meaningful opportunity for the public to consider and comment on those 
guidances. This notice announces the availability of a new draft 
product-specific guidance on generic estradiol vaginal inserts and a 
revised draft product-specific guidance on generic estradiol vaginal 
tablets.
    FDA initially approved new drug application (NDA) 208564 IMVEXXY 
(estradiol) in May 2018. We are now issuing a draft guidance for 
industry on, among other things, BE recommendations for generic 
estradiol vaginal inserts that use IMVEXXY as the reference listed drug 
(RLD) (``Draft Guidance on Estradiol'' (vaginal inserts)). FDA 
initially approved NDA 020908 VAGIFEM (estradiol) in March 1999. We are 
also now issuing a revised draft guidance for industry on, among other 
things, BE recommendations for generic estradiol vaginal tablets that 
use VAGIFEM as the RLD (``Draft Guidance on Estradiol'' (vaginal 
tablets)).
    In December 2018 and May 2020, TherapeuticsMD, Inc. submitted 
citizen petitions requesting, among other things, that FDA not approve 
any ANDA referencing IMVEXXY (estradiol vaginal inserts) unless certain 
criteria are met and that FDA issue a product-specific guidance for 
generic estradiol vaginal inserts that recommends studies consistent 
with those requested in the petitions and includes certain BE 
recommendations for generic estradiol vaginal inserts that are 
consistent with the then-current version of ``Draft Guidance on 
Estradiol'' (vaginal tablets) (Docket No. FDA-2018-P-4714 and Docket 
No. FDA-2020-P-1334, available at https://www.regulations.gov). FDA is 
separately responding to TherapeuticsMD, Inc.'s citizen petitions.
    These draft guidances are being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidances, 
when finalized, will represent the current thinking of FDA on ``Draft 
Guidance on Estradiol'' (vaginal inserts; vaginal tablets). They do not 
establish any rights for any person and are not binding on FDA or the 
public. You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.
    As we develop any final guidance on this topic, FDA will consider 
comments on costs or cost savings the guidance may generate, relevant 
for Executive Order 14192.

II. Paperwork Reduction Act of 1995

    While these guidances contain no collection of information, they do 
refer to previously approved FDA collections of information. The 
previously approved collections of information are subject to review by 
the Office of Management and Budget (OMB) under the Paperwork Reduction 
Act of 1995 (44 U.S.C. 3501-3521). The collections of information in 21 
CFR part 312 for investigational new drugs have been approved under OMB 
control number 0910-0014. The collections of information in 21 CFR part 
314 for applications for FDA approval to market a new drug and in 21 
CFR part 320 for bioavailability and bioequivalence requirements have 
been approved under OMB control number 0910-0001.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

Lowell M. Zeta,
Acting Deputy Commissioner for Policy, Legislation, and International 
Affairs.
[FR Doc. 2025-22249 Filed 12-5-25; 8:45 am]
BILLING CODE 4164-01-P