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###### Department of Health and Human Services

###### Food and Drug Administration

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

# 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 This guidance finalizes the draft guidance of the same title issued on February 8, 2022.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       ( print 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,                         *Rajanikanth.Madabushi@fda.hhs.gov;*                         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      ( print 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