[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]


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

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.

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

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the draft guidance of the same title issued on February 8, 2022.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

[[Page 15209]]

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

[[Page 15210]]

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]
BILLING CODE 4164-01-P