[Federal Register Volume 88, Number 48 (Monday, March 13, 2023)]
[Notices]
[Pages 15422-15423]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-05067]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-D-1794]


Evaluation of Gastric pH-Dependent Drug Interactions With Acid-
Reducing Agents: Study Design, Data Analysis, and Clinical 
Implications; Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a final guidance for industry entitled ``Evaluation 
of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: 
Study Design, Data Analysis, and Clinical Implications.'' This guidance 
focuses on specific recommendations pertinent to pH-dependent drug-drug 
interaction (DDI) assessment and describes the current recommendations 
of FDA regarding when clinical DDI studies with acid-reducing agents 
(ARAs) are needed, design of the clinical studies, interpretation of 
study results, and options for managing pH-dependent DDIs in patients. 
This guidance finalizes the draft guidance of the same title issued on 
December 1, 2020.

DATES: The announcement of the guidance is published in the Federal 
Register on March 13, 2023.

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-2020-D-1794 for ``Evaluation of Gastric pH-Dependent Drug 
Interactions With Acid-Reducing Agents: Study Design, Data Analysis, 
and Clinical Implications.'' 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

[[Page 15423]]

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., Bldg. 51, Rm. 3118, Silver Spring, MD 20993, 240-402-
6426, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``Evaluation of Gastric pH-Dependent Drug Interactions With 
Acid-Reducing Agents: Study Design, Data Analysis, and Clinical 
Implications.'' ARAs such as antacids, histamine H2-receptor 
antagonists, and proton pump inhibitors (PPIs) are widely used, and 
many of these drugs are available over-the-counter. Because ARAs can 
elevate the gastric pH, concomitant administration of a drug with an 
ARA could alter the solubility, dissolution, and bioavailability of the 
drug, potentially resulting in a loss of efficacy for weak-base drugs 
or increased toxicity for weak-acid drugs. Therefore, it is important 
to assess the susceptibility of an investigational drug to gastric pH 
change-mediated DDIs early in drug development, characterize the DDI 
effect with clinical studies when needed, and communicate the relevant 
findings in the drug product labeling. This guidance addresses when 
clinical DDI studies with ARAs should be conducted, the design and 
conduct of clinical pH-dependent DDI studies, alternative approaches 
for evaluating pH-dependent DDIs, and extrapolating clinical DDI study 
results among drug classes of ARAs.
    This guidance finalizes the draft guidance entitled ``Evaluation of 
Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: Study 
Design, Data Analysis, and Clinical Implications'' issued on December 
1, 2020 (85 FR 77222). FDA considered comments received on the draft 
guidance as the guidance was finalized. Changes from the draft to the 
final guidance include: (1) adding footnotes to update the framework to 
evaluate the pH-DDI liability of an investigational drug based on 
solubility and dissolution of a drug product, (2) additional literature 
and FDA guidance references included to provide additional clarity, (3) 
modified examples of PPIs and their doses for clinical DDI studies, and 
(4) 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 ``Evaluation of Gastric pH-Dependent Drug 
Interactions With Acid-Reducing Agents: Study Design, Data Analysis, 
and Clinical Implications.'' 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. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not 
required for this guidance. The previously approved collections of 
information are subject to review by OMB under the PRA. The collections 
of information for submissions of investigational new drug 
applications, new drug applications, and biologic license applications 
in 21 CFR parts 312, 314, and 601 have been approved under OMB control 
numbers 0910-0014, 0910-0001, and 0910-0338, respectively. The 
collections of information in 21 CFR 201.56 and 201.57 pertaining to 
the submission of prescription drug labeling have been approved under 
OMB control number 0910-0572.

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: March 7, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-05067 Filed 3-10-23; 8:45 am]
BILLING CODE 4164-01-P


