[Federal Register Volume 83, Number 99 (Tuesday, May 22, 2018)]
[Notices]
[Pages 23688-23689]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-10927]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2018-N-1820]
Framework for Assessing pH-Dependent Drug-Drug Interactions;
Establishment of a Public Docket; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; establishment of a public docket; request for comments.
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SUMMARY: The Food and Drug Administration (FDA) is establishing a
public docket to assist with the development of a policy or guidance
document on the assessment of pH-dependent drug-drug interactions
(DDIs). In October 2017, FDA published two draft guidance documents on
DDIs entitled ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug
Interaction Studies'' (In Vitro Studies Draft Guidance) and ``Clinical
Drug Interaction Studies--Study Design, Data Analysis, and Clinical
Implications'' (Clinical Drug Interaction Studies Draft Guidance).
These two draft guidances focus on enzyme- and transporter-based DDIs
and do not include a framework to assess pH-dependent DDIs. FDA is
seeking public input on best practices in the planning and evaluation
of pH-dependent DDIs.
DATES: Submit either electronic or written comments on this notice by
July 23, 2018.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before July 23, 2018. The https://www.regulations.gov electronic filing system will accept comments until
midnight Eastern Time at the end of July 23, 2018. Comments received by
mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.
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-2018-N-1820 for ``Framework for Assessing pH-dependent Drug-Drug
Interactions; Establishment of Public Docket; Request for Comments.''
Received comments, those filed in a timely manner (see ADDRESSES), 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
[[Page 23689]]
and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Xinning Yang, Office of Clinical
Pharmacology, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002,
301-796-7412, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
FDA is establishing a public docket to assist with the development
of a policy or guidance document on the assessment of pH-dependent
DDIs. In October 2017, FDA published the In Vitro Studies draft
guidance and the Clinical Drug Interaction Studies draft guidance
(Refs. 1 and 2). These draft guidance documents assist drug developers
in the planning and evaluation of DDI studies during drug development.
These draft guidance documents also focus on enzyme- and transporter-
based DDIs but do not include a framework for assessing DDIs caused by
drug-induced changes in gastric pH.
Acid-reducing agents (ARAs) such as antacids, histamine
H2-receptor antagonists (H2 blockers), and proton
pump inhibitors (PPIs) are widely used, and many of these products are
available over the counter (Refs. 3 and 4). For a drug whose solubility
is pH-dependent, concomitant administration with an ARA may affect its
absorption and systemic exposure, potentially resulting in loss of
efficacy or, in some cases, increased toxicity. Therefore, it is
important to assess a drug's susceptibility to pH-dependent DDIs during
drug development, characterize the DDI effect with clinical studies
when needed, and communicate study results in the drug labeling (Ref.
4). FDA is seeking public input to inform a framework to assess pH-
dependent DDIs.
II. Request for Information and Comments
Interested persons are invited to provide detailed information and
comments on approaches to assess pH-dependent DDIs. You may also submit
information and comments in a confidential manner (see Instructions in
the ADDRESSES section). FDA is particularly interested in responses to
the following overarching questions:
1. What are the characteristics of drugs that are susceptible to
pH-dependent DDIs? Can a stepwise approach be applied to evaluate the
interaction potential? Please provide the rationale for your
suggestions.
2. When conducting pH-dependent DDI assessments:
a. What are the utilities and limitations of different approaches
to evaluating DDIs (e.g., in silico, in vitro, and dedicated clinical
studies, as well as population pharmacokinetic analyses)?
b. What are the study design considerations (e.g., study
population, choice of ARAs, dosing regimen and administration, and
pharmacokinetic sampling) for the in vivo assessments discussed in 2a
above? Please describe the rationale for any design considerations
proposed.
c. Can we extrapolate the findings from a clinical DDI study with
one ARA drug (a PPI, H2 blocker, or antacid) to anticipate
the DDI potential for other ARAs in the same class or in a different
class? Please provide the rationale for your proposal.
FDA will consider all information and comments submitted in a
timely manner (see ADDRESSES).
III. References
The following references are on display in the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.
1. FDA Draft Guidance for Industry, ``In Vitro Metabolism- and
Transporter-Mediated Drug-Drug Interaction Studies,'' October 2017.
Available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581965.pdf.
2. FDA Draft Guidance for Industry, ``Clinical Drug Interaction
Studies--Study Design, Data Analysis, and Clinical Implications,''
October 2017. Available at https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf.
3. Centers for Disease Control and Prevention's (CDC's) National
Health and Nutrition Examination Survey. Available at https://www.cdc.gov/nchs/data/hus/hus16.pdf#079 (accessed May 16, 2018).
4. Zhang, L., F. Wu, S.C. Lee, et al., ``pH-Dependent Drug-Drug
Interactions for Weak Base Drugs: Potential Implications for New
Drug Development,'' Clinical Pharmacology and Therapeutics,
96(2):266-277, 2014.
Dated: May 17, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-10927 Filed 5-21-18; 8:45 am]
BILLING CODE 4164-01-P