2024-28033. Use of Circulating Tumor Deoxyribonucleic Acid for Curative-Intent Solid Tumor Drug Development; Guidance for Industry; Availability

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Department of Health and Human Services

Food and Drug Administration

1. [Docket No. FDA-2022-D-0084]

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 “Use of Circulating Tumor DNA for Curative-Intent Solid Tumor Drug Development.” This guidance is intended to help sponsors planning to use circulating cell-free plasma derived tumor DNA (ctDNA) as a biomarker in cancer clinical trials conducted under an investigational new drug application (IND) and/or to support marketing approval of drugs and biological products for treating solid tumor malignancies in the early-stage (curative-intent) setting. This guidance finalizes the draft guidance entitled “Use of Circulating Tumor DNA for Early-Stage Solid Tumor Drug Development” issued on May 2, 2022.

DATES:

The announcement of the guidance is published in the Federal Register on November 29, 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 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-2022-D-0084 for “Use of Circulating ( print page 94739) Tumor Deoxyribonucleic Acid for Curative-Intent Solid Tumor Drug Development.” 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 onhttps://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; 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; or Office of Policy, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 5431, 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:

Paz Vellanki, Center for Drug Evaluation and Research (HFD-150), Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, 301-796-9366; James Myers, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993, 240-402-7911; or Center for Devices and Radiological Health, [e-mail].

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of a guidance for industry entitled “Use of Circulating Tumor DNA for Curative-Intent Solid Tumor Drug Development.” This guidance is intended to help sponsors planning to use circulating cell-free plasma derived tumor DNA (ctDNA) as a biomarker in cancer clinical trials conducted under an IND and/or to support marketing approval of drugs and biological products for treating solid tumor malignancies in the early-stage (curative-intent) setting.

Certain patients with early-stage solid tumors can be cured with local therapy alone ( e.g., surgery, radiation, or chemoradiation), other patients require (neo)adjuvant systemic therapy in order to be cured, and others may progress to metastatic disease despite surgery and/or systemic therapy. ctDNA is tumor-derived fragmented DNA shed into a patient's bloodstream that is not associated with cells. ctDNA quantity can vary among individuals and depends on the type of tumor, location, stage, tumor burden, and response to therapy. ctDNA as a biomarker has a number of potential regulatory and clinical uses in the early-stage setting that may assist and expedite drug development. In the early-stage cancer setting, ctDNA may be used to detect a certain targetable alteration, to enrich a high- or low-risk population for study in a trial, to reflect a patient's response to treatment, or, potentially, as an early marker of efficacy.

This guidance finalizes the draft guidance entitled, “Use of Circulating Tumor DNA for Early-Stage Solid Tumor Drug Development,” issued on May 2, 2022 (87 FR 26207). FDA considered comments received on the draft guidance as the guidance was finalized. Changes from the draft to the final guidance include edits to further explain the rationale for writing a guidance on use of ctDNA for solid tumor drug development specific to the early-stage, curative-intent disease setting. The part of the guidance that discusses assay considerations was also clarified to indicate that while a major focus of this section pertains to assessment of molecular residual disease (MRD), there may be other uses of ctDNA in the early-stage disease setting. 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 “Use of Circulating Tumor DNA for Curative-Intent Solid Tumor Drug Development.” 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 parts 50 and 56 have been approved under OMB control number 0910-0130; 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; the collections of information in 21 CFR part 601 have been approved under OMB control number 0910-0338; the collections of information in 21 CFR part 800 have been approved under OMB control number 0910-0625; and the collections of information pertaining to submission of a biologics license application under section 351(k) of the Public Health Service Act (42 U.S.C. 262(k)) have been approved under OMB control number 0910-0718. ( print page 94740)

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/​vaccines-blood-biologics/​guidance-compliance-regulatory-information-biologics/​biologics-guidances, https://www.fda.gov/​medical-devices/​device-advice-comprehensive-regulatory-assistance/​guidance-documents-medical-devices-and-radiation-emitting-products, https://www.fda.gov/​regulatory-information/​search-fda-guidance-documents, or https://www.regulations.gov.

Dated: November 19, 2024.

P. Ritu Nalubola,

Associate Commissioner for Policy.