[Federal Register Volume 82, Number 205 (Wednesday, October 25, 2017)]
[Notices]
[Pages 49371-49373]
[FR Doc No: 2017-23102]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2017-D-5961]

In Vitro Metabolism- and Transporter-Mediated Drug-Drug
Interaction Studies, and Clinical Drug Interaction Studies--Study
Design, Data Analysis, and Clinical Implications; Draft Guidances 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 two draft guidances for industry entitled ``In
Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction
Studies'' (in vitro DDI guidance) and ``Clinical Drug Interaction
Studies--Study Design, Data Analysis, and Clinical Implications''
(clinical DDI guidance). These two draft guidances will update and
replace the revised draft guidance for industry entitled ``Drug
Interaction Studies--Study Design, Data Analysis, Implications for
Dosing, and Labeling Recommendations'' issued February 21, 2012 (2012
draft guidance). These draft guidances are intended to assist drug
developers in the planning and evaluation of drug-drug interaction
(DDI) potential during drug development. In particular, the in vitro
DDI guidance focuses on in vitro experimental approaches for evaluating
metabolizing enzyme- and transporter-based drug interaction potential
and how to extrapolate in vitro data to decide on the need for clinical
DDI studies. The clinical DDI guidance focuses on clinical studies that
evaluate the potential for DDIs, which alter a drug's pharmacokinetics
by modulating the effects of drug metabolizing enzymes and
transporters, and advises sponsors on the timing and design of the
clinical studies, interpretation of the results, and options for
managing DDIs in patients. Together, these two draft guidances describe
a systematic, risk-based approach to the assessment of DDIs.

DATES: Submit either electronic or written comments on these draft
guidances by January 23, 2018 to ensure that the Agency considers your
comment on these two draft guidances before it begins work on the final
versions of these guidances.

ADDRESSES: You may submit comments on any guidance 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-2017-D-5961 for ``In Vitro Metabolism- and Transporter-Mediated
Drug-Drug Interaction Studies, and Clinical Drug Interaction Studies--
Study Design, Data Analysis, and Clinical Implications; Draft Guidances
for Industry; Availability.'' 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.
     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 and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
    You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
    Submit written requests for single copies of the draft guidances 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 draft guidance documents.

FOR FURTHER INFORMATION CONTACT: Lauren Brum, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 3188, Silver Spring, MD 20903-0002, 301-
796-5008, or [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of two draft guidances for
industry entitled ``In Vitro Metabolism- and Transporter-Mediated Drug-
Drug Interaction Studies'' and ``Clinical Drug Interaction Studies--
Study Design, Data Analysis, and Clinical Implications.'' The
concomitant use of more than one medication in a patient is common.
Unanticipated, unrecognized, or mismanaged DDIs are an important cause
of morbidity and mortality associated with prescription drug use and
has occasionally been the basis for withdrawal of approved drugs from
the market. In some instances, understanding how to safely manage a DDI
can allow approval of a drug that would otherwise have an unacceptable

level of risk. Clinically relevant DDIs between an investigational drug
and other drugs should therefore: (1) Be defined during drug
development as part of an adequate assessment of the drug's overall
benefit/risk profile; (2) be known at the time of the drug's approval;
and (3) be communicated in labeling. These two draft guidances are
intended to assist drug developers in the planning and evaluation of
DDI potential during drug development. In particular, the in vitro DDI
guidance focuses on in vitro experimental approaches for evaluating
metabolizing enzyme- and transporter-based drug interaction potential,
and how to extrapolate in vitro data to decide on the need for clinical
DDI studies. The appendix of the in vitro DDI guidance includes
considerations in the choice of in vitro experimental systems, key
issues regarding in vitro experimental conditions, and a more detailed
explanation of model-based DDI prediction strategies. If in vitro
assessments indicate the need to conduct clinical DDI studies, sponsors
should consult the related clinical DDI guidance. The clinical DDI
guidance focuses on clinical studies that evaluate DDIs that alter a
drug's pharmacokinetics by modulating the effects of drug metabolizing
enzymes and/or transporters and advises sponsors on the timing and
design of the clinical studies, interpretation of the results, and
options for DDI management in patients. Together, the two draft
guidances describe a systematic, risk-based approach to evaluation and
communication of DDIs.
    In the Federal Register of February 21, 2012 (77 FR 9946), FDA
announced the availability of a revised draft guidance entitled ``Drug
Interaction Studies--Study Design, Data Analysis, Implications for
Dosing, and Labeling Recommendations.'' We received comments on the
2012 draft guidance and have considered these comments while updating
the information in the two draft guidances. In addition, new
developments in the field have been incorporated to reflect the
Agency's current thinking.
    The Agency decided to divide the 2012 draft guidance into two
guidances with one focusing on in vitro DDI evaluation and the other
focusing on clinical DDI evaluation. We are publishing the two draft
guidances to collect additional public comments. These new draft
guidances focus on metabolism- and transporter-based drug interactions.
Other types of interactions, e.g., drug-therapeutic protein
interactions and pH-dependent drug interactions, are not included.
Separate guidances will be developed to cover other types of DDIs. In
addition, a draft guidance specific to Section 7 (Drug Interactions)
labeling will be developed to delineate the communication of DDI
information in labeling.
    These two draft guidances are being issued consistent with FDA's
good guidance practices regulation (21 CFR 10.115). These draft
guidances, when finalized, will represent the Agency's current thinking
on ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug
Interaction Studies'' and ``Clinical Drug Interaction Studies--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. These
guidances are not subject to Executive Order 12866.

II. Paperwork Reduction Act of 1995

    These draft guidances refer to previously approved collections of
information found in FDA regulations. These collections of information
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The
collections of information in 21 CFR 314.50(d) have been approved under
OMB control number 0910-0001.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance
at either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or
https://www.regulations.gov.

    Dated: October 19, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-23102 Filed 10-24-17; 8:45 am]
 BILLING CODE 4164-01-P