[Federal Register Volume 84, Number 152 (Wednesday, August 7, 2019)]
[Notices]
[Pages 38634-38636]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-16880]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2019-N-3369]
Evaluating the Clinical Pharmacology of Oligonucleotide
Therapeutics; Establishment of a Public Docket; Request for Information
and Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; establishment of a public docket; request for
information and comments.
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SUMMARY: The Food and Drug Administration (FDA or Agency) is
establishing a public docket to collect comments on evaluating the
clinical pharmacology of oligonucleotide therapeutics. There are many
unique clinical pharmacology considerations concerning the development
of oligonucleotide therapeutics; however, for the purposes of this
request, the Agency is specifically interested in
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comments regarding the characterization of the effects of hepatic and
renal impairment, drug-drug interactions, and immunogenicity on the
pharmacokinetics of oligonucleotide therapeutics as well as the effects
of oligonucleotide therapeutics on cardiac electrophysiology. Public
comments will help the Agency develop recommendations for the design
and conduct of studies important to the safe and effective use of
oligonucleotide therapeutics and facilitate the regulatory assessment
of such studies.
DATES: Although you can comment at any time, to ensure that the Agency
considers your comment in our development of recommendations, submit
either electronic or written information and comments by October 7,
2019.
ADDRESSES: You may submit comments 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-2019-N-3369 for ``Evaluating the Clinical Pharmacology of
Oligonucleotide Therapeutics; Request for Comments.'' 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.
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.gpo.gov/fdsys/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.
FOR FURTHER INFORMATION CONTACT: Hobart Rogers, Office of Clinical
Pharmacology, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002,
301-796-2213, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Oligonucleotide therapeutics typically are synthetically modified
single- or double-stranded ribonucleic acid (RNA) or deoxyribonucleic
acid (DNA) that exert pharmacologic effects through a variety of
mechanisms (e.g., altered splicing, RNA interference, immunomodulation,
microRNA modulation). Compared to small molecule or biological
products, oligonucleotide therapeutics have unique characteristics
regarding their chemistry, pharmacology, sites of action,
pharmacokinetic disposition, and pharmacodynamics. As a result, there
may be special considerations for the design and conduct of clinical
pharmacology studies to assess oligonucleotide therapeutics, such as
those designed to evaluate the effects of organ impairment or drug
interactions. Currently, none of FDA's currently published guidance
documents on clinical pharmacology assessments contain specific
recommendations for oligonucleotide therapeutics.
II. Request for Information and Comments
Interested persons are invited to provide detailed information and
comments on certain aspects of evaluating the clinical pharmacology of
oligonucleotide therapeutics. This request focuses on oligonucleotide
therapeutics designed to hybridize to a cognate RNA to elicit a
pharmacologic effect. For all questions, organize any discussion by the
type of oligonucleotide therapeutics (e.g., by chemistry or
modification type). Please provide the rationale for your suggestions
and include supporting data if available. FDA is particularly
interested in responses to the following overarching questions:
(1) Evaluating Drug-Drug Interactions (DDIs)
(a) Under what circumstances should clinical DDI assessment be
warranted or not warranted for oligonucleotide therapeutics?
(b) In circumstances where DDI assessments are warranted:
(i) What types of DDI assessments are suitable and why (e.g., in
vitro studies, dedicated clinical studies, cocktail studies, population
pharmacokinetic analyses)? Please discuss the advantages, challenges,
and limitations with each type of assessment.
(ii) What are the study design considerations (e.g., in vitro test
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systems, population, analytes) for the types of assessments discussed
in item (1)(b)(i) above? Please describe the rationale for any design
considerations proposed.
(2) Evaluating the Pharmacokinetics in Organ Impairment
(a) Under what circumstances are organ impairment assessments for
oligonucleotide therapeutics warranted or not warranted for:
(i) Renal function
(ii) hepatic function
(b) In circumstances where organ impairment assessments are
warranted:
(i) What types of assessments are suitable for renal and/or hepatic
impairment and why (e.g., dedicated clinical studies, population
pharmacokinetic analyses)? Please discuss the advantages, challenges,
and limitations with each type of assessment.
(ii) What are the study design considerations (e.g., study
population) for the types of assessments discussed in item (2)(b)(i)
above for renal and/or hepatic impairment? Please describe the
rationale for any design considerations proposed.
(3) Evaluating Immunogenicity
(a) Under what circumstances are immunogenicity assessments of
oligonucleotide therapeutics warranted or not warranted?
(b) In circumstances where immunogenicity assessments are
warranted:
What types of assessments are suitable and why (e.g., antibodies
against other components of the formulation, antibodies against a newly
created ``splice-altered'' protein, neutralizing titers, cytokine
measurements)? Please discuss the advantages, challenges, and
limitations with each type of assessment.
(4) Evaluating QT Prolongation
(a) Under what circumstances are cardiac electrophysiology
assessments warranted or not warranted in the evaluation of
oligonucleotide therapeutics?
(b) In circumstances where cardiac electrophysiology assessments
are warranted:
What types of assessments are suitable and why (e.g., hERG
inhibition assay, thorough QT assessment) in nonclinical or clinical
studies? Please discuss the advantages, challenges, and limitations
with each type of assessment.
(5) With regard to the four questions above, when a sponsor seeks
to rely on previously generated data and information that it owns or to
which it has a right of reference, what scientific findings may be
applied across the sponsor's oligonucleotide therapeutics with shared
characteristics (e.g., similar backbone modifications)?
FDA will consider all information and comments submitted.
III. Electronic Access
Persons with access to the internet may obtain relevant clinical
pharmacology guidances at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
Dated: August 2, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-16880 Filed 8-6-19; 8:45 am]
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