83_FR_23787 83 FR 23688 - Framework for Assessing pH-Dependent Drug-Drug Interactions; Establishment of a Public Docket; Request for Comments

83 FR 23688 - Framework for Assessing pH-Dependent Drug-Drug Interactions; Establishment of a Public Docket; Request for Comments

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 83, Issue 99 (May 22, 2018)

Page Range23688-23689
FR Document2018-10927

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 In October 2017, FDA published two draft guidance documents on DDIs entitled ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies'' (In Vitro Studies Draft Guidance) and ``Clinical Drug Interaction Studies--Study Design, Data Analysis, and Clinical Implications'' (Clinical Drug Interaction Studies Draft Guidance).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.

Federal Register, Volume 83 Issue 99 (Tuesday, May 22, 2018) 
[Federal Register Volume 83, Number 99 (Tuesday, May 22, 2018)]
[Notices]
[Pages 23688-23689]
From the Federal Register Online  [www.thefederalregister.org]
[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 In October 2017, FDA published two draft guidance documents on 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Interaction Studies'' (In Vitro Studies Draft Guidance) and ``Clinical 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Implications'' (Clinical Drug Interaction Studies Draft Guidance).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.thefederalregister.org/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

23688 Federal Register / Vol. 83, No. 99 / Tuesday, May 22, 2018 / Notices TABLE 1—LIST OF SAFETY AND EFFECTIVENESS SUMMARIES FOR APPROVED PMAS MADE AVAILABLE FROM JULY 1, 2017, THROUGH DECEMBER 31, 2017—Continued PMA No., Docket No. Applicant Trade name Approval date P150031, FDA–2017–M–6800 Boston Scientific Corporation Vercise Deep Brain Stimulation (DBS) System ....................... 12/8/2017 P170012, FDA–2017–M–6896 Biom’Up SA ............................ HEMOBLASTTM Bellows ......................................................... 12/15/2017 II. Electronic Access be submitted on or before July 23, 2018. Instructions: All submissions received Persons with access to the internet The https://www.regulations.gov must include the Docket No. FDA– may obtain the documents at http:// electronic filing system will accept 2018–N–1820 for ‘‘Framework for www.fda.gov/MedicalDevices/ comments until midnight Eastern Time Assessing pH-dependent Drug-Drug ProductsandMedicalProcedures/ at the end of July 23, 2018. Comments Interactions; Establishment of Public DeviceApprovalsandClearances/ received by mail/hand delivery/courier Docket; Request for Comments.’’ PMAApprovals/default.htm. (for written/paper submissions) will be Received comments, those filed in a considered timely if they are timely manner (see ADDRESSES), will be Dated: May 17, 2018. postmarked or the delivery service placed in the docket and, except for Leslie Kux, acceptance receipt is on or before that those submitted as ‘‘Confidential Associate Commissioner for Policy. date. Submissions,’’ publicly viewable at [FR Doc. 2018–10924 Filed 5–21–18; 8:45 am] https://www.regulations.gov or at the Electronic Submissions BILLING CODE 4164–01–P Dockets Management Staff between 9 Submit electronic comments in the a.m. and 4 p.m., Monday through following way: Friday. DEPARTMENT OF HEALTH AND • Federal eRulemaking Portal: • Confidential Submissions—To HUMAN SERVICES https://www.regulations.gov. Follow the submit a comment with confidential Food and Drug Administration instructions for submitting comments. information that you do not wish to be Comments submitted electronically, made publicly available, submit your [Docket No. FDA–2018–N–1820] including attachments, to https:// comments only as a written/paper www.regulations.gov will be posted to submission. You should submit two Framework for Assessing pH- the docket unchanged. Because your copies total. One copy will include the Dependent Drug-Drug Interactions; comment will be made public, you are information you claim to be confidential Establishment of a Public Docket; solely responsible for ensuring that your with a heading or cover note that states Request for Comments comment does not include any ‘‘THIS DOCUMENT CONTAINS AGENCY: Food and Drug Administration, confidential information that you or a CONFIDENTIAL INFORMATION.’’ The HHS. third party may not wish to be posted, Agency will review this copy, including ACTION: Notice; establishment of a such as medical information, your or the claimed confidential information, in public docket; request for comments. anyone else’s Social Security number, or its consideration of comments. The confidential business information, such second copy, which will have the SUMMARY: The Food and Drug as a manufacturing process. Please note claimed confidential information Administration (FDA) is establishing a that if you include your name, contact redacted/blacked out, will be available public docket to assist with the information, or other information that for public viewing and posted on development of a policy or guidance identifies you in the body of your https://www.regulations.gov. Submit document on the assessment of pH- comments, that information will be both copies to the Dockets Management dependent drug-drug interactions posted on https://www.regulations.gov. Staff. If you do not wish your name and (DDIs). In October 2017, FDA published • If you want to submit a comment contact information to be made publicly two draft guidance documents on DDIs with confidential information that you available, you can provide this entitled ‘‘In Vitro Metabolism- and do not wish to be made available to the information on the cover sheet and not Transporter-Mediated Drug-Drug public, submit the comment as a in the body of your comments and you Interaction Studies’’ (In Vitro Studies written/paper submission and in the must identify this information as Draft Guidance) and ‘‘Clinical Drug manner detailed (see ‘‘Written/Paper ‘‘confidential.’’ Any information marked Interaction Studies—Study Design, Data Submissions’’ and ‘‘Instructions’’). as ‘‘confidential’’ will not be disclosed Analysis, and Clinical Implications’’ except in accordance with 21 CFR 10.20 (Clinical Drug Interaction Studies Draft Written/Paper Submissions and other applicable disclosure law. For Guidance). These two draft guidances Submit written/paper submissions as more information about FDA’s posting focus on enzyme- and transporter-based follows: of comments to public dockets, see 80 DDIs and do not include a framework to • Mail/Hand delivery/Courier (for FR 56469, September 18, 2015, or access assess pH-dependent DDIs. FDA is written/paper submissions): Dockets the information at: https://www.gpo.gov/ seeking public input on best practices in Management Staff (HFA–305), Food and fdsys/pkg/FR-2015-09-18/pdf/2015- the planning and evaluation of pH- Drug Administration, 5630 Fishers 23389.pdf. dependent DDIs. Lane, Rm. 1061, Rockville, MD 20852. Docket: For access to the docket to amozie on DSK3GDR082PROD with NOTICES1 DATES: Submit either electronic or • For written/paper comments read background documents or the written comments on this notice by July submitted to the Dockets Management electronic and written/paper comments 23, 2018. Staff, FDA will post your comment, as received, go to https:// ADDRESSES: You may submit comments well as any attachments, except for www.regulations.gov and insert the as follows. Please note that late, information submitted, marked and docket number, found in brackets in the untimely filed comments will not be identified, as confidential, if submitted heading of this document, into the considered. Electronic comments must as detailed in ‘‘Instructions.’’ ‘‘Search’’ box and follow the prompts VerDate Sep<11>2014 16:47 May 21, 2018 Jkt 241001 PO 00000 Frm 00064 Fmt 4703 Sfmt 4703 E:\FR\FM\22MYN1.SGM 22MYN1

Federal Register / Vol. 83, No. 99 / Tuesday, May 22, 2018 / Notices 23689 and/or go to the Dockets Management interaction potential? Please provide the Dated: May 17, 2018. Staff, 5630 Fishers Lane, Rm. 1061, rationale for your suggestions. Leslie Kux, Rockville, MD 20852. 2. When conducting pH-dependent Associate Commissioner for Policy. FOR FURTHER INFORMATION CONTACT: DDI assessments: [FR Doc. 2018–10927 Filed 5–21–18; 8:45 am] Xinning Yang, Office of Clinical BILLING CODE 4164–01–P a. What are the utilities and Pharmacology, Center for Drug limitations of different approaches to Evaluation and Research, Food and evaluating DDIs (e.g., in silico, in vitro, DEPARTMENT OF HEALTH AND Drug Administration, 10903 New and dedicated clinical studies, as well HUMAN SERVICES Hampshire Ave., Silver Spring, MD as population pharmacokinetic 20993–0002, 301–796–7412, Xinning.Yang@fda.hhs.gov. analyses)? Food and Drug Administration SUPPLEMENTARY INFORMATION: b. What are the study design [Docket No. FDA–2005–D–0461] considerations (e.g., study population, I. Background choice of ARAs, dosing regimen and Acne Vulgaris: Establishing FDA is establishing a public docket to administration, and pharmacokinetic Effectiveness of Drugs Intended for assist with the development of a policy sampling) for the in vivo assessments Treatment; Guidance for Industry; or guidance document on the discussed in 2a above? Please describe Availability assessment of pH-dependent DDIs. In the rationale for any design October 2017, FDA published the In considerations proposed. AGENCY: Food and Drug Administration, Vitro Studies draft guidance and the HHS. c. Can we extrapolate the findings Clinical Drug Interaction Studies draft from a clinical DDI study with one ARA ACTION: Notice of availability. guidance (Refs. 1 and 2). These draft drug (a PPI, H2 blocker, or antacid) to guidance documents assist drug SUMMARY: The Food and Drug anticipate the DDI potential for other Administration (FDA or Agency) is developers in the planning and ARAs in the same class or in a different evaluation of DDI studies during drug announcing the availability of a class? Please provide the rationale for guidance for industry entitled ‘‘Acne development. These draft guidance your proposal. documents also focus on enzyme- and Vulgaris: Establishing Effectiveness of transporter-based DDIs but do not FDA will consider all information and Drugs Intended for Treatment.’’ This include a framework for assessing DDIs comments submitted in a timely manner guidance provides recommendations to caused by drug-induced changes in (see ADDRESSES). industry for establishing the clinical gastric pH. effectiveness of drugs for the treatment III. References of acne vulgaris (acne). This guidance Acid-reducing agents (ARAs) such as antacids, histamine H2-receptor The following references are on finalizes the draft guidance for industry antagonists (H2 blockers), and proton display in the Dockets Management entitled ‘‘Acne Vulgaris: Developing pump inhibitors (PPIs) are widely used, Staff (see ADDRESSES) and are available Drugs for Treatment,’’ issued September and many of these products are for viewing by interested persons 19, 2005. available over the counter (Refs. 3 and between 9 a.m. and 4 p.m., Monday DATES: The announcement of the 4). For a drug whose solubility is pH- through Friday; they are also available guidance is published in the Federal dependent, concomitant administration electronically at https:// Register on May 22, 2018. with an ARA may affect its absorption www.regulations.gov. FDA has verified ADDRESSES: You may submit either and systemic exposure, potentially the website addresses, as of the date this electronic or written comments on resulting in loss of efficacy or, in some document publishes in the Federal Agency guidances at any time as cases, increased toxicity. Therefore, it is Register, but websites are subject to follows: important to assess a drug’s change over time. Electronic Submissions susceptibility to pH-dependent DDIs 1. FDA Draft Guidance for Industry, ‘‘In Vitro during drug development, characterize Metabolism- and Transporter-Mediated Submit electronic comments in the the DDI effect with clinical studies Drug-Drug Interaction Studies,’’ October following way: when needed, and communicate study 2017. Available at https://www.fda.gov/ • Federal eRulemaking Portal: results in the drug labeling (Ref. 4). FDA downloads/Drugs/Guidance https://www.regulations.gov. Follow the is seeking public input to inform a ComplianceRegulatoryInformation/ instructions for submitting comments. framework to assess pH-dependent Guidances/UCM581965.pdf. Comments submitted electronically, DDIs. 2. FDA Draft Guidance for Industry, ‘‘Clinical including attachments, to https:// Drug Interaction Studies—Study Design, www.regulations.gov will be posted to II. Request for Information and the docket unchanged. Because your Comments Data Analysis, and Clinical Implications,’’ October 2017. Available comment will be made public, you are Interested persons are invited to at https://www.fda.gov/downloads/drugs solely responsible for ensuring that your provide detailed information and /guidances/ucm292362.pdf. comment does not include any comments on approaches to assess pH- 3. Centers for Disease Control and confidential information that you or a dependent DDIs. You may also submit Prevention’s (CDC’s) National Health and third party may not wish to be posted, information and comments in a Nutrition Examination Survey. Available such as medical information, your or confidential manner (see Instructions in at https://www.cdc.gov/nchs/data/hus/ anyone else’s Social Security number, or amozie on DSK3GDR082PROD with NOTICES1 the ADDRESSES section). FDA is hus16.pdf#079 (accessed May 16, 2018). confidential business information, such particularly interested in responses to 4. Zhang, L., F. Wu, S.C. Lee, et al., ‘‘pH- as a manufacturing process. Please note the following overarching questions: Dependent Drug-Drug Interactions for that if you include your name, contact 1. What are the characteristics of Weak Base Drugs: Potential Implications information, or other information that drugs that are susceptible to pH- for New Drug Development,’’ Clinical identifies you in the body of your dependent DDIs? Can a stepwise Pharmacology and Therapeutics, comments, that information will be approach be applied to evaluate the 96(2):266–277, 2014. posted on https://www.regulations.gov. VerDate Sep<11>2014 16:47 May 21, 2018 Jkt 241001 PO 00000 Frm 00065 Fmt 4703 Sfmt 4703 E:\FR\FM\22MYN1.SGM 22MYN1


Document Created: 2018-11-02 11:09:57
Document Modified: 2018-11-02 11:09:57
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionNotices
ActionNotice; establishment of a public docket; request for comments.
DatesSubmit either electronic or written comments on this notice by July 23, 2018.
ContactXinning 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]
FR Citation83 FR 23688 
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