2024-26682. Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics; Draft Guidance for Industry; Availability

Document Headings

Document headings vary by document type but may contain the following:

1. the agency or agencies that issued and signed a document
2. the number of the CFR title and the number of each part the document amends, proposes to amend, or is directly related to
3. the agency docket number / agency internal file number
4. the RIN which identifies each regulatory action listed in the Unified Agenda of Federal Regulatory and Deregulatory Actions

See the Document Drafting Handbook for more details.

Department of Health and Human Services

Food and Drug Administration

1. [Docket No. FDA-2024-D-4624]

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The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics.” FDA is publishing this draft guidance which, when finalized, will provide recommendations on approaches for the nonclinical safety evaluation of oligonucleotide-based therapeutics (ONTs) to support clinical development and marketing of these products. ONTs present unique challenges and opportunities in the nonclinical evaluation of safety that differ in many regards from those appropriate for small molecule drugs or therapeutic proteins.

DATES:

Submit either electronic or written comments on the draft guidance by January 14, 2025 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.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-2024-D-4624 for “Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics.” 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. ( print page 90297)

• 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 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. 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:

Ronald Wange, Center for Drug Evaluation and Research (HFD-510), Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 3342, Silver Spring, MD 20903, 301-796-1304.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of a draft guidance for industry entitled “Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics.” ONTs represent a rapidly evolving therapeutic modality, which is seeing application to a broad range of indications, including rare diseases, and have the potential to act on therapeutic targets that are not amenable to the action of small molecule drugs or therapeutic proteins. To further support the development of ONTs, FDA is publishing this draft guidance which, when finalized, will assist sponsors in optimizing the design of their nonclinical development package for ONTs.

The scope of the draft guidance includes single-stranded or double-stranded ONTs created synthetically or derived naturally, with native or modified backbone or nucleoside structures that increase or decrease expression and/or function of proteins. Examples of included oligonucleotides are antisense, small interfering RNA, microRNA, transfer RNAs, decoys, and aptamers. Immune stimulatory oligonucleotides ( e.g., CpG motifs acting via Toll-like receptors) are excluded, as are Center for Biologics Evaluation and Research-regulated ONTs ( e.g., DNA/RNA vaccines, messenger RNA, virally delivered ONTs, and RNA used for gene editing).

ONTs present unique opportunities and challenges in the nonclinical evaluation of safety that differ in many regards from that appropriate for small molecule drugs or therapeutic proteins. This draft guidance provides specific recommendations on approaches for the nonclinical safety evaluation of ONTs to support clinical development and marketing of these products. The draft guidance, when finalized, will provide recommendations on the nonclinical evaluation of oligonucleotides in multiple areas, including genotoxicity, safety pharmacology, general toxicity, carcinogenicity, and reproductive and developmental toxicity. These recommendations have been developed based on industry best practices and Agency experience to date with this category of drug products.

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 “Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics.” 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 pertaining to protection of human subjects have been approved under OMB control number 0910-0130. 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. The collections of information in 21 CFR 201.56 and 201.57 pertaining to content and format of labeling for human prescription drug and biological products have been approved under OMB control numbers 0910-0572. The collections of information in 21 CFR parts 210 and 211 pertaining to current good manufacturing practice have been approved under OMB control number 0910-0139. The collections of information in 21 CFR part 312 relating to the content and format of investigational new drug applications have been approved under OMB control number 0910-0014. The collections of information in 21 CFR part 314 relating to the content and format of new drug applications have been approved under OMB control number 0910-0001. The collections of information in 21 CFR part 601 relating to the content and format of biologics license applications are approved under OMB control number 0910-0338. The collections of information for MEDWATCH Adverse Event and Product Experience Reporting system have been approved under OMB control number 0910-0291.

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/​regulatory-information/​search-fda-guidance-documents, or https://www.regulations.gov.

( print page 90298)

Dated: November 6, 2024.

Kimberlee Trzeciak,

Deputy Commissioner for Policy, Legislation, and International Affairs.