[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

[[Page 38635]]

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

[[Page 38636]]

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]
BILLING CODE 4164-01-P