[Federal Register Volume 86, Number 90 (Wednesday, May 12, 2021)]
[Notices]
[Pages 26054-26056]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-09962]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-D-3614]


M9 Biopharmaceutics Classification System-Based Biowaivers; 
International Council for Harmonisation; 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 ``M9 
Biopharmaceutics Classification System-Based Biowaivers.'' The guidance 
was prepared under the auspices of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH), formerly the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use. The guidance provides recommendations to support the 
biopharmaceutics classification of drug substances and the 
Biopharmaceutics Classification System (BCS)-based waiver of the in 
vivo bioequivalence (BE) study requirement for certain drug products. 
The guidance is intended to avoid or reduce the need for human BE 
trials based on extensive in vitro characterization of the drug 
substance and drug product properties. The guidance replaces the 
existing FDA guidance issued December 26, 2017, entitled ``Waiver of In 
Vivo Bioavailability and Bioequivalence Studies for Immediate-Release 
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification 
System.'' The guidance also finalizes the draft ICH guidance, ``M9 
Biopharmaceutics Classification System-Based Biowaivers,'' issued on 
October 26, 2018.

DATES: The announcement of the guidance is published in the Federal 
Register on May 12, 2021.

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:
     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-2018-D-3614 for ``M9 Biopharmaceutics Classification System-Based 
Biowaivers.'' 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

[[Page 26055]]

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 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 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, or the Office of 
Communication, Outreach and Development, Center for Biologics 
Evaluation and Research (CBER), Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. The guidance may also be obtained by mail by calling 
CBER at 1-800-835-4709 or 240-402-8010. See the SUPPLEMENTARY 
INFORMATION section for electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Regarding the guidance: Mehul Mehta, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
10903 New Hampshire Ave., Bldg. 51, Rm. 2178, Silver Spring, MD 20993-
0002, 301-796-1573; or Stephen Ripley, Center for Biologics Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.
    Regarding the ICH: Jill Adleberg, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 6364, Silver Spring, MD 20993-0002, 301-796-5259.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``M9 Biopharmaceutics Classification System-Based 
Biowaivers.'' The guidance was prepared under the auspices of ICH. ICH 
has the mission of achieving greater regulatory harmonization worldwide 
to ensure that safe, effective, high-quality medicines are developed, 
registered, and maintained in the most resource-efficient manner.
    By harmonizing the regulatory requirements in regions around the 
world, ICH guidelines have substantially reduced duplicative clinical 
studies, prevented unnecessary animal studies, standardized the 
reporting of important safety information, standardized marketing 
application submissions, and made many other improvements in the 
quality of global drug development and manufacturing and the products 
available to patients.
    The six Founding Members of the ICH are FDA; the Pharmaceutical 
Research and Manufacturers of America; the European Commission; the 
European Federation of Pharmaceutical Industries Associations; the 
Japanese Ministry of Health, Labour, and Welfare; and the Japanese 
Pharmaceutical Manufacturers Association. The Standing Members of the 
ICH Association include Health Canada and Swissmedic. Additionally, the 
Membership of ICH has expanded to include other regulatory authorities 
and industry associations from around the world (refer to https://www.ich.org/).
    ICH works by involving technical experts from both regulators and 
industry parties in detailed technical harmonization work and the 
application of a science-based approach to harmonization through a 
consensus-driven process that results in the development of ICH 
guidelines. The regulators around the world are committed to 
consistently adopting these consensus-based guidelines, realizing the 
benefits for patients and for industry.
    As a Founding Regulatory Member of ICH, FDA plays a major role in 
the development of each of the ICH guidelines, which FDA then adopts 
and issues as guidance for industry. FDA's guidance documents do not 
establish legally enforceable responsibilities. Instead, they describe 
the Agency's current thinking on a topic and should be viewed only as 
recommendations, unless specific regulatory or statutory requirements 
are cited.
    In the Federal Register of October 26, 2018 (83 FR 54107), FDA 
published a notice announcing the availability of a draft guidance 
entitled ``M9 Biopharmaceutics Classification System-Based 
Biowaivers.'' The notice gave interested persons an opportunity to 
submit comments by January 24, 2019.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Assembly and endorsed by the regulatory agency members in November 
2019.
    The guidance provides recommendations to support the 
biopharmaceutics classification of drug substances and the BCS-based 
waiver of the in vivo BE study requirement for drug products. The BCS-
based biowaiver approach is intended to reduce the need for in vivo 
bioequivalence studies. In vivo bioequivalence studies may be waived if 
an assumption of equivalence in in vivo performance can be justified by 
satisfactory in vitro data. The BCS is a scientific approach based on 
the aqueous solubility and intestinal permeability characteristics of 
the drug substance or substances. The BCS categorizes drug substances 
into one of four BCS classes as follows:
     Class I: High solubility, high permeability
     Class II: Low solubility, high permeability
     Class III: High solubility, low permeability
     Class IV: Low solubility, low permeability
    In vivo BE studies are needed to demonstrate lack of impact of 
significant formulation changes on a drug's bioavailability during its 
development, for post approval line extensions, and when developing a 
generic product. Utilizing the critical properties of the drug 
substance and the drug product, and applying the BCS framework, 
extensive in vitro studies

[[Page 26056]]

can support the waiver of the in vivo BE requirement for certain drug 
products.
    Following the public consultation period, clarifications were made 
to the guidance based on the comments received.
    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 ``M9 Biopharmaceutics Classification System-
Based Biowaivers.'' 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.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
refer to previously approved FDA collections of information. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not 
required. However, this final guidance refers to previously approved 
FDA collections of information. The previously approved collections of 
information are subject to review by OMB under the PRA. The following 
collections of information have been approved under OMB control number 
0910-0001:
     Submitting under 21 CFR 314.50 content and format of new 
drug applications, including the pharmacokinetics and bioavailability 
sections.
     Submitting under 21 CFR 314.70 postapproval changes.
     Submitting under 21 CFR 314.94 content and format of 
abbreviated new drug applications.
    The collections of information for submitting under 21 CFR 312.23 
information about pharmacokinetics and biological disposition of the 
drug has been approved under OMB control number 0910-0014.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.regulations.gov, https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

    Dated: May 6, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-09962 Filed 5-11-21; 8:45 am]
BILLING CODE 4164-01-P