4164-01-P
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2022-D-0235]
Clinical Pharmacology Considerations for the Development of Oligonucleotide
Therapeutics; 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
the Development of Oligonucleotide Therapeutics,” which provides recommendations for the
development of oligonucleotide therapeutics. Specifically, this guidance addresses FDA’s
current thinking regarding clinical pharmacology considerations and recommendations for
oligonucleotide therapeutic development programs, including characterizing the potential for QT
interval prolongation, performing immunogenicity risk assessment, characterizing the impact of
hepatic and renal impairment, and assessing the potential for drug-drug interactions. This
guidance finalizes the draft guidance of the same name issued on June 27, 2022.
DATES: The announcement of the guidance is published in the Federal Register on [INSERT
DATE OF PUBLICATION IN THE FEDERAL REGISTER].
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-0235

for “Clinical Pharmacology Considerations for the Development of Oligonucleotide
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.
•

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. 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: Anuradha Ramamoorthy, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver
Spring, MD, 20903, 240-402-6426, Anuradha.Ramamoorthy@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry entitled “Clinical
Pharmacology Considerations for the Development of Oligonucleotide Therapeutics.”
Oligonucleotide therapeutics are an emerging therapeutic modality with increasing numbers of
drugs in development. While antisense and siRNA oligonucleotide therapeutics have been
approved in recent years to treat rare diseases, many oligonucleotide therapeutics are in
development to treat common chronic diseases. This guidance provides recommendations to
assist industry in the development of oligonucleotide therapeutics. Specifically, this guidance
represents FDA’s recommendations for certain pharmacokinetic and pharmacodynamic
investigations including characterizing QT interval prolongation potential, performing
immunogenicity risk assessment, characterizing the impact of hepatic and renal impairment, and
assessing the potential for drug-drug interactions during oligonucleotide therapeutic
development. This guidance provides recommendations on when these assessments may be
appropriate and what types of assessments can help address these issues.
This guidance finalizes the draft guidance of the same name issued on June 27, 2022 (87
FR 38161). 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 terms used in the
guidance to provide clarity, (2) additional references to FDA guidance that have been published
since publication of the draft guidance, and (3) editorial changes 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 the Development of Oligonucleotide 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
part 312 for investigational new drug applications have been approved under OMB control
number 0910-0014. The collections of information in 21 CFR part 314 for new drug
applications have been approved under OMB control number 0910-0001. The collections of
information in 21 CFR part 601 for biologics license applications have been approved under
OMB control number 0910-0338.
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, or
https://www.regulations.gov.

Dated: June 12, 2024.

Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-13271 Filed: 6/14/2024 8:45 am; Publication Date: 6/17/2024]