Notice2023-05067
Evaluation of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications; Guidance for Industry; Availability
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Published
March 13, 2023
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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 This guidance finalizes the draft guidance of the same title issued on December 1, 2020.
Full Text
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<title>Federal Register, Volume 88 Issue 48 (Monday, March 13, 2023)</title>
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[Federal Register Volume 88, Number 48 (Monday, March 13, 2023)]
[Notices]
[Pages 15422-15423]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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:
<a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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, <a href="/cdn-cgi/l/email-protection#83c2edf6f1e2e7ebe2add1e2eee2eeececf1f7ebfac3e5e7e2adebebf0ade4ecf5"><span class="__cf_email__" data-cfemail="f9b8978c8b989d9198d7ab9894989496968b8d9180b99f9d98d791918ad79e968f">[email protected]</span></a>.
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
<a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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
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