Notice2026-10705
Statistical Approaches To Establishing Bioequivalence; Guidance for Industry; Availability
Primary source
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Published
May 29, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled "Statistical Approaches to Establishing Bioequivalence." This guidance provides recommendations to sponsors and applicants planning to use equivalence criteria in analyzing bioequivalence (BE) studies for investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and amendments and supplements to these applications. The guidance discusses statistical approaches for BE comparisons and focuses on how to use these approaches both generally and in specific situations. This guidance finalizes the draft guidance of the same title issued on December 5, 2022, and replaces the guidance of the same title issued on February 2, 2001.
Full Text
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<title>Federal Register, Volume 91 Issue 103 (Friday, May 29, 2026)</title>
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[Federal Register Volume 91, Number 103 (Friday, May 29, 2026)]
[Notices]
[Pages 32056-32057]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-10705]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2001-D-0197]
Statistical Approaches To Establishing Bioequivalence; 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 Agency) is announcing
the availability of a final guidance for industry entitled
``Statistical Approaches to Establishing Bioequivalence.'' This
guidance provides recommendations to sponsors and applicants planning
to use equivalence criteria in analyzing bioequivalence (BE) studies
for investigational new drug applications (INDs), new drug applications
(NDAs), abbreviated new drug applications (ANDAs), and amendments and
supplements to these applications. The guidance discusses statistical
approaches for BE comparisons and focuses on how to use these
approaches both generally and in specific situations. This guidance
finalizes the draft guidance of the same title issued on December 5,
2022, and replaces the guidance of the same title issued on February 2,
2001.
DATES: The announcement of the guidance is published in the Federal
Register on May 29, 2026.
ADDRESSES: You may submit either electronic or written comments on
Agency guidances at any time as follows:
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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-2001-D-0197 for ``Statistical Approaches to Establishing
Bioequivalence.'' Received comments will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 this 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 guidance document.
FOR FURTHER INFORMATION CONTACT: David Coppersmith, Center for Drug
Evaluation and Research, Food and
[[Page 32057]]
Drug Administration, 10903 New Hampshire Ave., Bldg. 75, Rm. 1666,
Silver Spring, MD 20993-0002, 301-796-9193,
<a href="/cdn-cgi/l/email-protection#6c280d1a0508422f031c1c091e1f010518042c0a080d4204041f420b031a"><span class="__cf_email__" data-cfemail="a7e3c6d1cec389e4c8d7d7c2d5d4caced3cfe7c1c3c689cfcfd489c0c8d1">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``Statistical Approaches to Establishing Bioequivalence.''
This guidance provides recommendations to sponsors and applicants
planning to use equivalence criteria in analyzing in vivo or in vitro
BE studies for INDs, NDAs, ANDAs, and amendments and supplements to
these applications. The guidance discusses statistical approaches for
BE comparisons and focuses on how to use these approaches both
generally and in specific situations.
These specific situations include statistical methods for narrow
therapeutic index drugs and highly variable drugs; recommendations for
missing data and outlier detection; and a discussion of statistical
methods regarding assessment of in vitro BE, including population BE
and statistical approaches for in vitro release tests, in vitro
permeation tests, and in vitro abuse-deterrent formulation comparative
studies.
This guidance finalizes the draft guidance entitled ``Statistical
Approaches to Establishing Bioequivalence'' issued on December 5, 2022
(87 FR 74426) and replaces the guidance entitled ``Statistical
Approaches to Establishing Bioequivalence'' issued on February 2, 2001
(66 FR 8805). FDA considered comments received on the draft guidance as
the guidance was finalized. Changes from the draft to the final
guidance include updates to provide clarifying information on estimands
and intercurrent events, sample size determinations, and outlier data.
The final guidance incorporates additional information on statistical
analysis using population BE and statistical analysis using modified
population BE, which was previously included in product-specific
guidances. The final guidance also incorporates additional information
on the statistical analysis for the reference scaled average BE for
narrow therapeutic index drugs and highly variable drugs, which was
previously included in the draft guidance for industry entitled
``Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs
Submitted Under an ANDA'' issued on August 23, 2021 (FDA issued a final
guidance for industry of the same title concurrently with this
guidance). In addition, editorial changes were made to improve clarity.
This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on ``Statistical Approaches to Establishing
Bioequivalence.'' It does not establish any rights for any person and
is not binding on FDA or the public. You can use an alternative
approach if it satisfies the requirements of the applicable statutes
and regulations.
FDA considered the applicability of Executive Order 14192, per OMB
guidance in M-25-20, and finds this action to be neither regulatory nor
deregulatory.
II. Paperwork Reduction Act of 1995
While this guidance contains no collection of information, it does
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 (PRA) (44 U.S.C. 3501-3521). The collections of information
in 21 CFR part 312 relating to the submission of INDs and
bioavailability/BE (BA/BE) studies or pharmacogenomic data and the
collections of information in part 320 for ``Investigational New Drug
Safety Reporting Requirements for Human Drug and Biological Products
and Safety Reporting Requirements for Bioavailability and
Bioequivalence Studies in Humans'' have been approved under OMB control
numbers 0910-0014 and 0910-0291. The collections of information in 21
CFR part 314 relating to the submission of NDAs, ANDAs, and
supplemental applications and applicable BA/BE requirements have been
approved under OMB control number 0910-0001. The collections of
information that support Good Laboratory Practice for Non-Clinical
Laboratory Studies have been approved under OMB control number 0910-
0119. The recordkeeping requirement for current good manufacturing
practices sample retention in 21 CFR 211.170 has been approved under
OMB control number 0910-0139. The collections of information under the
administrative practices and procedures for petitions, hearings, and
other administrative proceedings and activities conducted by the FDA
under 21 CFR part 10 and 12 are approved under OMB control number 0910-
0191. The collections of information for the submission of controlled
correspondence, and for meetings pertaining to ANDA approval are
approved under OMB control number 0910-0727. The collections of
information relating to good clinical practice have been approved under
OMB control number 0910-0014.
III. Electronic Access
Persons with access to the internet may obtain the guidance at
<a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-10705 Filed 5-28-26; 8:45 am]
BILLING CODE 4164-01-P
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