[Federal Register Volume 86, Number 90 (Wednesday, May 12, 2021)]
[Notices]
[Pages 26048-26050]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-10017]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2017-D-5138]


S5(R3) Detection of Reproductive and Developmental Toxicity for 
Human Pharmaceuticals; International Council for Harmonisation; 
Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a final guidance for industry entitled ``S5(R3) 
Detection of Reproductive and Developmental Toxicity for Human 
Pharmaceuticals.'' 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 key 
considerations for developing a testing strategy to identify hazard and 
characterize reproductive risk for human pharmaceuticals. The guidance 
is intended to align with other ICH guidances, elaborate on concepts to

[[Page 26049]]

consider when designing studies, and identify potential circumstances 
in which a risk assessment can be made based on preliminary studies. It 
also clarifies the qualification and potential use of alternative 
assays. This guidance finalizes the draft guidance issued on November 
13, 2017.

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-2017-D-5138 for ``S5(R3) Detection of Reproductive and 
Developmental Toxicity for Human Pharmaceuticals.'' 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 
``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: Ronald Wange, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
10903 New Hampshire Ave., Bldg. 22, Rm. 3342, Silver Spring, MD 20993-
0002, 301-796-1304; 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, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``S5(R3) Detection of Reproductive and Developmental Toxicity 
for Human Pharmaceuticals.'' 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

[[Page 26050]]

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 November 13, 2017 (82 FR 52306), FDA 
published a notice announcing the availability of a draft guidance 
entitled ``S5(R3) Detection of Toxicity to Reproduction for Human 
Pharmaceuticals.'' The notice gave interested persons an opportunity to 
submit comments by February 12, 2018.
    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 January 2020.
    The guidance finalizes the guidance issued on November 13, 2017. 
The guidance has undergone revisions to align with other ICH guidances, 
elaborate on concepts to consider when designing studies, and identify 
potential circumstances in which a risk assessment can be made based on 
preliminary studies. It also clarifies the qualification and potential 
use of alternative assays.
    The purpose of this guidance is to provide key considerations for 
developing a testing strategy to identify hazard and characterize 
reproductive risk for human pharmaceuticals. The guidance informs on 
the use of existing data and identifies potential study designs to 
supplement available data to identify, assess, and convey risk. General 
concepts and recommendations are provided that should be considered 
when interpreting study data and assessing reproductive risk in support 
of clinical development and marketing approval.
    This guidance applies to pharmaceuticals, including biotechnology-
derived pharmaceuticals; vaccines (and their novel constitutive 
ingredients) for infectious diseases; and novel excipients that are 
part of the final pharmaceutical product. It does not apply to cellular 
therapies, gene therapies, and tissue-engineered products. The 
methodological principles (e.g., study design, dose selection, and 
species selection) outlined in this guidance can also apply to all 
compounds for which the conduct of reproductive and/or developmental 
toxicity studies is appropriate, including vaccines for other 
indications (e.g., cancer). (see ICH guidance for industry ``S9 
Nonclinical Evaluation for Anticancer Pharmaceuticals'' (March 2010), 
available at https://www.fda.gov/media/73161/download).
    The guidance reflects revisions made in response to comments 
received on the draft guidance. These include reorganization of the 
guidance to improve readability and clarity, to introduce discussion of 
conventional assessment strategies earlier in the document, and to 
clarify which elements of the guidance are more appropriate for 
biotechnology-derived therapies. To accommodate the rapidly evolving 
nature of alternative assay development, the discussion of alternative 
assays was placed in an Annex, subject to a maintenance procedure, to 
allow for more frequent updating of this material.
    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 ``S5(R3) Detection of Reproductive and 
Developmental Toxicity for Human Pharmaceuticals.'' 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

    This guidance contains no collection 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 guidance refers to previously approved FDA 
collections of information. These collections of information are 
subject to review by OMB under the PRA. The collections of information 
in 21 CFR part 58 have been approved under OMB control number 0910-
0119; the collections of information in 21 CFR part 314 have been 
approved under OMB control number 0910-0001; the collections of 
information in 21 CFR part 312 have been approved under OMB control 
number 0910-0014; and the content and format requirements for pregnancy 
and lactation labeling of human prescription drug and biological 
products have been approved under OMB control number 0910-0624.

III. Electronic Access

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

    Dated: May 6, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-10017 Filed 5-11-21; 8:45 am]
BILLING CODE 4164-01-P