[Federal Register Volume 89, Number 42 (Friday, March 1, 2024)]
[Notices]
[Pages 15208-15210]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-04375]
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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; 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 ``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) for ADCs with a cytotoxic small-molecule drug
or payload. Currently, there are no final FDA guidances outlining the
clinical pharmacology considerations for ADCs. This guidance finalizes
the draft guidance of the same title issued on February 8, 2022.
DATES: The announcement of the guidance is published in the Federal
Register on March 1, 2024.
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
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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 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 to the 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 guidance document.
FOR FURTHER INFORMATION CONTACT: Rajanikanth Madabushi, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD 20903, 301-796-1537,
[email protected]; or James Myers, 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 final 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 component and an antibody component
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 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.
This guidance finalizes the draft guidance of the same title issued
on February 8, 2022 (87 FR 7184). FDA considered comments received on
the draft guidance as the guidance was finalized. Changes from the
draft to the final guidance include: (1) updates to guidance
terminology to provide clarity, (2) additional FDA guidance references
included in support of existing guidance text, and (3) additional
considerations provided for ADC dosing strategies. 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 ``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 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 for submission of investigational new drug
applications have been approved under OMB control number 0910-0014. The
collections of information in 21 CFR part 314 for submission of new
drug applications have been approved under OMB control number 0910-
0001. The collections of information in 21 CFR part 601 for submission
of biologic license applications have been approved under OMB control
number 0910-0338. The collections of information in 21 CFR 201.56 and
201.57 pertaining to the content and format requirements of labeling
for prescription drug products and biological products have been
approved under OMB control number 0910-0572. The collections of
information in 21 CFR part 211
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pertaining to current good manufacturing practice requirements have
been approved under OMB control number 0910-0139. The collections of
information in 21 CFR part 58 pertaining to good laboratory practice
for nonclinical laboratory studies have been approved under OMB control
number 0910-0119.
III. Electronic Access
Persons with access to the internet may obtain the guidance at
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, or https://www.regulations.gov.
Dated: February 26, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-04375 Filed 2-29-24; 8:45 am]
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