[Federal Register Volume 82, Number 205 (Wednesday, October 25, 2017)]
[Notices]
[Pages 49371-49373]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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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[[Page 49372]]

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replace the revised draft guidance for industry entitled ``Drug 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draft guidance).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

[[Page 49373]]

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