[Federal Register Volume 79, Number 28 (Tuesday, February 11, 2014)]
[Pages 8192-8194]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-02883]



Food and Drug Administration

[Docket No. FDA-2014-N-0129]

Application of Physiologically-Based Pharmacokinetic Modeling To 
Support Dose Selection; Notice of Public Workshop; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public workshop; request for comments.


SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
announcing a public workshop entitled ``Application of Physiologically-
Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection.'' The 
purpose of the workshop is to obtain input on scientific approaches for 
the conduct and assessment of physiologically-based pharmacokinetic 
(PBPK) modeling within the framework of drug development and regulatory 
decisionmaking. The input from the workshop may be used to refine FDA's 
thinking on the various applications of PBPK. Preliminary elements of a 
draft concept paper will be presented to facilitate discussion at this 
public workshop.

DATES: The workshop will be held on March 10, 2014, from 8:30 a.m. to 
4:30 p.m. Individuals who wish to attend the

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workshop must register by February 24, 2014. Please submit either 
electronic or written comments by April 10, 2014, to receive 

ADDRESSES: The public workshop will be held at FDA's White Oak Campus, 
10903 New Hampshire Ave., Bldg. 2, Rm. 2047, Silver Spring, MD 20993. 
Participants must enter through Building 1 and undergo security 
screening. For parking and security information, please visit http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
    Please submit electronic comments to http://www.regulations.gov. 
Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD 20852. Identify all comments with the corresponding 
docket number found in brackets in the heading of this notice. A 
transcript of the workshop will be available for review at the Division 
of Dockets Management and at http://www.regulations.gov approximately 
30 days after the public workshop (see section VI of SUPPLEMENTARY 

FOR FURTHER INFORMATION CONTACT: Ping Zhao, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Rm. 3182, Silver Spring, MD 20993, 301-796-3774, FAX: 301-
847-8720, email: [email protected].


I. Background

    On July 9, 2012, the President signed into law the Food and Drug 
Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144). 
Title I of FDASIA reauthorizes the Prescription Drug User Fee Act 
(PDUFA) and provides FDA with the user fee resources necessary to 
maintain an efficient review process for human drug and biological 
products. The reauthorization of PDUFA includes performance goals and 
procedures for the Agency that represent FDA's commitments during 
fiscal years 2013-2017. These commitments are fully described in the 
document entitled ``PDUFA Reauthorization Performance Goals and 
Procedures Fiscal Years 2013 through 2017'' (``PDUFA Goals Letter''), 
which is available at http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf. Section IX of the PDUFA 
Goals Letter, entitled ``Enhancing Regulatory Science and Expediting 
Drug Development,'' includes provisions to promote innovation through 
enhanced communication between FDA and sponsors during drug 
development. As part of this enhanced communication, FDA made a 
commitment to hold a public workshop to: (1) Engage stakeholders in a 
discussion of current and emerging scientific approaches and 
applications for the conduct of PBPK modeling and simulations and (2) 
to facilitate stakeholder input regarding the utility of PBPK during 
drug development and regulatory review. The public workshop announced 
by this document will fulfill this commitment.
    PBPK modeling is a mathematical modeling technique for predicting 
drug behavior in humans. A PBPK model takes information about a drug's 
physical, chemical, and other properties, as well as information about 
processes in the body, and turns them into mathematical equations to 
predict what will happen when a patient takes the medication. 
Consequently, PBPK models may be a useful platform in risk assessment 
during drug development.

II. Purpose and Scope of the Workshop

    The objectives of the workshop are to:
    1. Share and discuss best practices in the use of PBPK to inform 
dose selection in specific patient populations, such as patients with 
renal or hepatic impairment, pediatric patients, elderly patients, and 
patients with genetic variation,
    2. Discuss the current state of knowledge and share current FDA 
experience regarding important criteria for evaluating the adequacy of 
PBPK models for intended uses, as well as criteria for considering 
modeling results when making regulatory decisions,
    3. Obtain input on specific issues identified by FDA on the conduct 
of PBPK analysis.
    Since the 1970s PBPK modeling and simulation has been routinely 
used in toxicology to assess the risk of environmental toxins that 
cannot be safely studied in humans. In the past decade, PBPK models 
have increasingly been applied to complex drug development issues that 
cannot be evaluated in a clinical trial or to issues that can be 
reliably assessed in silico, thereby minimizing the need for costly 
clinical trials. These types of applications of PBPK are submitted to 
FDA for regulatory review. As a result, FDA is looking to adopt a 
rigorous approach to the review of PBPK submissions and the conduct of 
de novo PBPK analysis to support regulatory review. FDA also wishes to 
be transparent regarding its evidentiary standards and how it weighs 
the evidence of a PBPK simulation in arriving at a decision or 
regulatory action.
    The public workshop will focus on the use of PBPK models for 
assessing the effect of various intrinsic and extrinsic factors in 
order to inform dose optimization. FDA acknowledges, however, that PBPK 
can be used to support decision making through the entire life cycle of 
drug development, including preclinical and clinical evaluations.
    The input from the workshop may be used to refine FDA's thinking on 
use of PBPK in determining proper dosage and may lead to the 
development of a draft guidance for industry. There is currently no FDA 
guidance on this topic. Specifically, this guidance would describe 
FDA's view of criteria considered important when evaluating the 
strength and quality of evidence provided by a PBPK analysis.
    FDA will also be preparing a concept paper that will propose best 
practices and principles for the use of PBPK modeling in drug 
development and regulatory review. Preliminary elements of this 
document will be presented at the public workshop by FDA to elicit 
comments and facilitate discussion. The paper will incorporate the 
workshop outcomes, then the public will be invited to comment through a 
public docket.

III. Scope of Public Input Requested

    FDA seeks input on a range of topics related to the conduct of PBPK 
modeling and simulation by pharmaceutical industries and by FDA and on 
the interpretation and use of simulations when evaluating risk in the 
regulation of pharmaceutical products. These include:
    1. Predictive performance of PBPK models for a specific aim
    2. Identification of knowledge gaps in the specific application of 
PBPK simulation to replace a clinical trial:

a. Criteria for the adequacy of a PBPK model for a specific aim
b. Biological plausibility and predictive performance
c. Model validation and statistical considerations

    3. Presentation of simulations in approved product labeling 
    a. When should PBPK simulations be included in drug labeling?
    b. What is the best format for presenting PBPK simulations in 
different sections of the labeling?
    c. How should uncertainty in simulations be presented in the 

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IV. Attendance and Registration

    The FDA Conference Center at the White Oak Campus is a Federal 
facility with security screening and limited seating. Individuals who 
wish to attend the public workshop must register on or before February 
24, 2014, by visiting https://www.surveymonkey.com/s/MW5WZDW and 
contacting Ping Zhao (see FOR FURTHER INFORMATION CONTACT). Early 
registration is recommended. Registration is free and will be on a 
first-come, first-served basis. However, FDA may limit the number of 
participants from each organization based on space limitations. Onsite 
registration on the day of the workshop will be based on space 
    During the workshop, time will be designated for questions and 
answers throughout the day and for general comments and questions from 
the audience following the panel discussions.
    In this Federal Register document, FDA has included specific issues 
that will be addressed by the panel. If you wish to address one or more 
of these issues in your presentation, please indicate this at the time 
you register so that FDA can consider that in organizing the 
presentations. FDA will do its best to accommodate requests to speak 
and will determine the amount of time allotted to each presenter and 
the approximate time that each oral presentation is scheduled to begin. 
An agenda will be available approximately 2 weeks before the workshop 
at http://www.fda.gov/Drugs/NewsEvents/ucm132703.htm (select this 
workshop meeting from the events list).
    If you need special accommodations because of a disability, please 
contact Ping Zhao (see FOR FURTHER INFORMATION CONTACT) at least 7 days 
before the workshop.
    A live webcast of this workshop will be viewable at https://collaboration.fda.gov/pbpk/ on the day of the workshop. A video record 
of the workshop will be available at the same web address for 1 year.

V. Comments

    Regardless of attendance at the public workshop, interested persons 
may submit written or electronic comments to the Division of Dockets 
Management (see ADDRESSES). It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this notice. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at http://www.regulations.gov.

VI. Transcripts

    Transcripts of the workshop will be available for review at the 
Division of Dockets Management (see ADDRESSES) and at http://www.regulations.gov approximately 30 days after the workshop. A 
transcript will also be made available in either hard copy or on CD-ROM 
upon submission of a Freedom of Information request. Send requests to 
Division of Freedom of Information (ELEM-1029), Food and Drug 
Administration, 12420 Parklawn Dr., Element Bldg., Rockville, MD 20857.

    Dated: February 5, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-02883 Filed 2-10-14; 8:45 am]