[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 In October 2017, FDA published two draft guidance documents on 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Interaction Studies'' (In Vitro Studies Draft Guidance) and ``Clinical 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Implications'' (Clinical Drug Interaction Studies Draft Guidance).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