[Federal Register Volume 87, Number 26 (Tuesday, February 8, 2022)]
[Notices]
[Pages 7184-7186]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-02604]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2021-D-1051]


Clinical Pharmacology Considerations for Antibody-Drug 
Conjugates; Draft Guidance for Industry; Availability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 or Agency) is announcing 
the availability of a draft guidance for industry entitled ``Clinical 
Pharmacology Considerations for Antibody-Drug Conjugates,'' which 
provides recommendations for the development of antibody-drug 
conjugates (ADCs). Specifically, this guidance addresses the FDA's 
current thinking regarding clinical pharmacology considerations and 
recommendations for ADC development programs, including bioanalytical 
methods, dose selection and adjustment, dose- and exposure-response 
analysis, intrinsic factors, QTc assessments, immunogenicity, and drug-
drug interactions (DDIs). Currently, there are

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no FDA guidances outlining the clinical pharmacology considerations for 
antibody-drug conjugates. This draft guidance is not final nor is it in 
effect at this time.

DATES: Submit either electronic or written comments on the draft 
guidance by May 9, 2022 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 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-2021-D-1051 for ``Clinical Pharmacology Considerations for 
Antibody-Drug Conjugates.'' 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 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; or to 
Office of Communication, Outreach and Development, Center for Biologics 
Evaluation and Research, 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. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Kimberly Maxfield, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 209903, 301-348-1978, 
[email protected]; 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.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Clinical Pharmacology Considerations for Antibody-Drug 
Conjugates.'' An ADC is a type of therapeutic biologic product that is 
composed of a small-molecule moiety and an antibody moiety conjugated 
together by a chemical linker. An antibody or antibody fragment carrier 
is selected or engineered against a specific antigen of interest 
present on the target, which is ideally unique to the disease state 
being treated (e.g., a tumor-specific antigen). In general, when the 
antibody or antibody fragment binds to its target antigen, the ADC is 
internalized through physiological mechanisms (e.g., endocytosis), at 
which point the small-molecule drug or payload moiety is released 
either upon exposure to the low pH of the lysosome or by degradation of 
the antibody/linker by lysosomal enzymes. The released small-molecule 
drug then exerts its effect in the targeted cell (e.g., the cells 
expressing the specific antigen of interest) while, ideally, minimizing 
the effect on healthy cells (e.g., cells that do not express the 
specific antigen of interest).
    ADCs combine the selectivity of an antibody or antibody fragment 
with the potency of a small molecule. Therefore, development of ADCs 
requires careful consideration of the differences between the clinical 
pharmacology of the antibody or antibody fragment and the small 
molecule. This draft guidance addresses FDA's current thinking 
regarding clinical pharmacology considerations and recommendations for 
ADC development programs, including bioanalytical methods, dose 
selection and adjustment, dose- and exposure-response analysis, 
intrinsic factors, QTc assessments, immunogenicity, and DDIs. Although

[[Page 7186]]

this draft guidance is primarily based on FDA's experience with ADCs 
for oncology indications, the principles discussed in this guidance are 
also generally applicable to the development of ADCs for other 
indications.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on ``Clinical 
Pharmacology Considerations for Antibody-Drug Conjugates.'' 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 draft 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 for this guidance. The previously approved collections of 
information are subject to review by OMB under the PRA. The collections 
of information for submissions of investigational new drug 
applications, new drug applications, and biologic license applications 
in 21 CFR parts 312, 314, and 601 have been approved under OMB control 
numbers 0910-0014, 0910-0001, and 0910-0338, respectively. In addition, 
the submission of prescription drug labeling under 21 CFR 201.56 and 
201.57 has been approved under OMB control number 0910-0572. The 
collections of information in 21 CFR part 211 have been approved under 
OMB control number 0910-0139; and the collections of information 
regarding good laboratory practice in 21 CFR part 58 have been approved 
under OMB control number 0910-0119.

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/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: February 1, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-02604 Filed 2-7-22; 8:45 am]
BILLING CODE 4164-01-P