[Federal Register Volume 83, Number 91 (Thursday, May 10, 2018)]
[Notices]
[Pages 21781-21782]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-09931]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-1415]


Framework for Assessment of Drug-Drug Interactions for 
Therapeutic Proteins; Establishment of a Public Docket; Request for 
Information and Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for 
information and comments.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is 
establishing a public docket to assist with its development of a 
policy/guidance document on the assessment of drug-drug interactions 
(DDIs) for therapeutic proteins (TPs). The Agency split the 2012 DDI 
draft guidance into two draft guidance documents published in October 
2017: ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug 
Interaction Studies'' and ``Clinical Drug Interaction Studies--Study 
Design, Data Analysis, and Clinical Implications.'' The two guidance 
documents focus on enzyme- and transporter-based DDIs and do not 
include a discussion on TPs, which was originally included in the 2012 
guidance. The Agency is currently revisiting the framework for 
assessment of DDIs for TPs outlined in the draft 2012 DDI guidance to 
offer timely and actionable information pertaining to DDIs for TPs and 
is seeking public input to assist in updating or creating a new 
framework.

DATES: Although you can comment at any time, to ensure that the Agency 
considers your comment in our development of recommendations, submit 
either electronic or written information and comments by July 9, 2018.

ADDRESSES: You may submit comments 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-2018-N-1415 for ``Framework for Assessment of Drug-Drug 
Interactions for Therapeutic Proteins.'' 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.

FOR FURTHER INFORMATION CONTACT: 
    Regarding human prescription drugs: Julie Chronis, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 3203, Silver Spring, MD 20993-0002, 301-
796-1200.
    Regarding human prescription biological products: Stephen Ripley, 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver 
Spring, MD 20993-0002, 240-402-7911.

SUPPLEMENTARY INFORMATION: 

I. Background

    Concurrent use of more than one prescription drug is common. A 
Centers for Disease Control and Prevention survey reports that about 20 
percent of U.S. adults take three or more prescription drugs; and among 
adults age 65 and older, 40 percent take five or more medications.\1\ 
Taking more than one drug at a time can result in DDIs which can result 
in toxicities or loss of efficacy. It is impractical to evaluate the 
impact of every possible drug combination. Therefore, the FDA

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follows a systematic risk-based approach for DDI assessment.
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    \1\ Centers for Disease Control and Prevention's National Health 
and Nutrition Examination Survey: https://www.cdc.gov/nchs/data/hus/hus16.pdf#079.
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    Two draft guidance documents, when finalized, which are intended to 
assist drug developers in the planning and evaluation of the DDI 
potential of their drug during development were published in October 
2017 entitled ``Clinical Drug Interaction Studies--Study Design, Data 
Analysis, and Clinical Implications,'' and ``In Vitro Metabolism- and 
Transporter-Mediated Drug-Drug Interaction Studies.'' \2\ These two 
draft guidances replaced the 2012 draft guidance entitled ``Drug 
Interaction Studies--Study Design, Data Analysis, Implications for 
Dosing, and Labeling Recommendations.'' The 2017 draft guidance 
documents focus on enzyme- and transporter-based DDIs; however, they do 
not discuss TPs.
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    \2\ ``Clinical Drug Interaction Studies--Study Design, Data 
Analysis, and Clinical Implications'' can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf; provide comments to this guidance using 
docket number FDA-2017-D-596.
    ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug 
Interaction Studies'' can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581965.pdf; provide comments to this guidance using docket number 
FDA-2017-D-5961.
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    The 2012 guidance recommended DDI assessment for TPs in three 
scenarios: (1) For cytokine or cytokine modulators, (2) for a known or 
suspected mechanism of DDI not related to effects on Cytochrome P450 
enzymes or transporters, and (3) for when a TP is used in combination 
with another drug. The Agency now plans to revisit the previous 
framework for the assessment of DDIs for TPs that was included in the 
2012 draft guidance. We are seeking public input on the revision and 
development of a framework to address DDIs for TPs with the goal of 
publishing this framework in a short policy/guidance document.

II. Additional Issues for Consideration and Request for Information

    Interested persons are invited to provide detailed information and 
comments on the approach to the DDI assessment of TPs. Please read the 
information above regarding the submission of comments and confidential 
information. FDA is particularly interested in responses to the 
following overarching questions:
    1. In what scenarios/circumstances and for which classes of TPs 
should DDI assessment be performed? Please provide rationale for your 
suggestions including available data and scientific principles to 
inform the considerations.
    2. For circumstances when DDI assessments are necessary:
    a. What types of assessments can be useful (e.g., in vitro studies, 
dedicated clinical studies, population pharmacokinetic analyses, 
physiologically based pharmacokinetic analyses)? Please discuss the 
challenges and limitations with each type of assessment, and, as 
necessary, organize any discussions by the class of TP.
    b. What are the study design considerations (e.g., population, 
analytes) for the types of assessments discussed in bullet 2a. above? 
Please describe the rationale for any design considerations proposed.
    FDA will consider all information and comments submitted.

    Dated: May 4, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-09931 Filed 5-9-18; 8:45 am]
 BILLING CODE 4164-01-P


