Physiologically Based Pharmacokinetic Analyses — Format and Content Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Physiologically Based Pharmacokinetic Analyses – Format and Content
09/03/18
Physiologically Based
Pharmacokinetic
Analyses — Format and
Content
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2018
Clinical Pharmacology

Physiologically Based Pharmacokinetic Analyses – Format and Content
09/03/18
Physiologically Based
Pharmacokinetic
Analyses — Format and
Content
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4 th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2018
Clinical Pharmacology

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Physiologically Based Pharmacokinetic Analyses – Format and Content
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TABLE OF CONTENTS
I. 	INTRODUCTION...................................................................................................... 1
II. 	BACKGROUND ........................................................................................................ 1
III. 	FORMAT AND CONTENT....................................................................................... 2
A. 	Executive Summary ...................................................................................................... 2
B. 	Introduction ................................................................................................................. 2
C. 	Materials and Methods.................................................................................................. 2
1. Overview of Modeling Strategy......................................................................................... 2
2. Modeling Parameters ...................................................................................................... 3
3. Simulation Design .......................................................................................................... 3
4. Electronic Files and Other Documentation......................................................................... 3
5. Software........................................................................................................................ 4
D. 	Results ......................................................................................................................... 5
1. Model Verification and Modification ................................................................................. 5
2. Model Application .......................................................................................................... 5
E. 	Discussion .................................................................................................................... 5
F. 	Appendices ................................................................................................................... 6
1. List of Tables ................................................................................................................. 6
2. List of Figures................................................................................................................ 6
3. Table of Acronyms and Abbreviations................................................................................ 6
4. References ..................................................................................................................... 6

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Physiologically Based Pharmacokinetic Analyses —
Format and Content
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. 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.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
This guidance outlines the recommended format and content for a sponsor or applicant to submit
physiologically based pharmacokinetic (PBPK) analyses to the FDA to support 	applications
including, but not limited to, investigational new drug applications (INDs), new drug
applications (NDAs), biologics license applications (BLAs), or abbreviated new drug
applications (ANDAs). To enable efficient and consistent review, the FDA recommends
including the following six sections in a PBPK study report: (A) Executive Summary; (B)
Introduction; (C) Materials and Methods; (D) Results; (E) Discussion; and (F) Appendices. The
content of each section is described in detail below. This guidance does not address
methodological considerations and best practices for the conduct of PBPK modeling and
simulation or the appropriateness of PBPK analyses for a particular drug or a drug product. The
decision to accept results from PBPK analyses in lieu of clinical pharmacokinetic (PK) data is
made on a case-by-case basis, considering the intended uses, as well as the quality, relevance,
and reliability of the results from the PBPK analyses.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
A PBPK analysis uses models and simulations that combine physiology, population, and drug
characteristics to mechanistically describe the PK and/or pharmacodynamic (PD) behaviors of a
drug. Throughout a drug’s life cycle, PBPK model predictions can be used to support decisions
1 This guidance has been prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, in the
Center for Drug Evaluation and Research at the Food and Drug Administration.

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on whether, when, and how to conduct certain clinical pharmacology studies, and to support
dosing recommendations in product labeling. 	Because of the lack of regulatory guidance, the
format and content of PBPK analysis reports that are submitted to the FDA vary significantly.
The goal of this guidance is to standardize the content and format of these reports to facilitate the
FDA’s efficient assessment, consistent application, and timely decision making during regulatory
review.
III. 	FORMAT AND CONTENT
The FDA suggests including the following sections in the PBPK study report for all PBPK
analyses.
A. 	Executive Summary
The executive summary should include the objectives and rationale for conducting the PBPK
analyses, provide a succinct overview of model development and simulation scenarios, and
summarize the key conclusions of the report. This section should clearly convey how the
analyses address a specific scientific question in a clinical setting in support of a regulatory
decision.
B. 	Introduction
This section should provide the following components, if available: 	(1) a high-level synopsis of
the drug’s physicochemical, PK, and PD properties; (2) the exposure-response relationships for
the efficacy and safety of the drug to the extent that they are known; (3) a brief PBPK-related
regulatory history (i.e., prior interactions with the FDA and other regulatory agencies) to provide
context for the PBPK analyses; (4) cross-referencing to PBPK study reports previously submitted
to the FDA for different intended uses at different stages of the development of the same drug
substance or the same drug product.
C. 	Materials and Methods
This section should include sufficient information to allow FDA reviewers to duplicate and
evaluate the submitted modeling and simulation results and to conduct supplemental analyses
when necessary. Suggested components of the materials and methods section include the
following:
1. 	Overview of Modeling Strategy
This section should detail the modeling procedures, including model development, model
verification/modification, and model application. 	The procedures should be outlined in a step-
wise manner using a workflow, decision-tree, table, or other representation. The sponsor should
appropriately reference the data and studies used in each step of the modeling process.

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2. 	Modeling Parameters
All system-specific and drug-specific components, as well as the sources of parameter values,
should be clearly specified and justified (e.g., appropriate references). If there are several
sources of one parameter, the selection should be described. If a parameter value has been
estimated, the data source and estimation method should be described or appropriately
referenced. The use of clinical PK data to optimize model parameters should be described and
justified. 	Key model assumptions that may impact the model application, including biological
and/or pharmacological rationales, patient/disease-related assumptions, or mathematical
representations of the biological system, should be clearly stated. The sponsor should present the
modeling parameters using a table or other visual representation. For example, drug-dependent
parameters for the investigational drug of interest, including names, values, units, and sources of
the parameters, prediction algorithms, and assumptions should be summarized in table format.
Procedures for assessing uncertainty (e.g., using sensitivity analysis) of the PBPK model
parameters should be provided.
When library drug and system models (e.g., a virtual population) within a specific software
platform are used, the sponsor should justify the use of these models and clearly identify and
justify modifications made to the library models.
3. 	Simulation Design
The description of simulation conditions should include the following information for the model
development, verification, and application:
• 	Route, dose, formulation of the drug product (either substrate or modulator), time of
administration, and fasting or fed conditions
• 	Dosing regimen of the drug product
• 	Duration of the simulated trials
• 	Demographics of the virtual population and distribution of demographic information
• 	Number of simulation studies for a specific scenario (simulated trials)
• 	Number of virtual subjects in each simulated trial
• 	Settings for differential equation integrators, when applicable
4. 	Electronic Files and Other Documentation
Submitting electronic files streamlines the review process and allows for effective
communication between the FDA and the sponsor. Examples of permissible file types can be

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found in the Specifications for File Format Types Using eCTD Specifications document.2 This
includes permissible file types/extensions and the modules in which they are permissible. 	In
addition, the Technical Rejection Criteria for Study Data document denotes what modules’ study
data validation rules will not be applicable.3
Electronic files related to modeling software and simulations should be submitted along with the
PBPK study report. Supporting information such as clinical PK or PK/PD data used in PBPK
analyses, a scientific publication, or an orientation document for submitted simulation data and
model files can also be included. 	Cross-references to other parts of the report and other parts of
the application should be provided with hyperlinks or locations of the modules of an IND, NDA,
BLA, or ANDA submission, if applicable. 	If necessary, consult the FDA regarding the
feasibility of submitting certain types of electronic files.
5. 	Software
The FDA does not recommend the use of any particular software for PBPK modeling. 	As PBPK
models are highly complex in nature, sponsors anticipating the application of PBPK modeling in
their drug development program should communicate early with the FDA. Additional technical
and instructional information beyond the minimum data listed below may be needed to ensure
that the FDA has sufficient working knowledge of the specific PBPK model and software to
facilitate a timely review.
The following information should be included in the submission to facilitate a timely review:
• 	Name and version of the software4
• 	Schematic view of the model structure and mathematical equations (or relevant
references) based on established theoretical or biological knowledge
• 	Parameterization of system information and sources of parameter values, such as
databases used to describe the population variability and correlation between parameters
• 	User’s manual (i.e., instructions on how to run the code)
2 The Specifications for File Format Types Using eCTD Specifications can be found at:
https://www.fda.gov/downloads/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmis
sions/ucm347471.pdf
3 The Technical Rejection Criteria for Study Data can be found at:
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSu
bmissions/UCM523539.pdf
4 The sponsor should provide sufficient documentation regarding any changes made by the software vendor to the
version of the software over the period of PBPK model development and describe how these changes may impact
the performance of the submitted model.

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D. 	Results
The sponsor should both demonstrate that the PBPK model is appropriate for the intended uses
and describe the results of model application. 	Descriptive statistics or other appropriate analysis
on the results of model-generated simulations should be presented, and when applicable,
compared to observed data. In addition, a summary of supplementary materials should be
included. 	Often, supplementary tables and figures are needed to facilitate the assessment of a
PBPK analysis. Details on suggested components of model verification and model application
are provided below.
1. 	Model Verification and Modification
This section of the report should provide sufficient information to clearly demonstrate that the
proposed PBPK model is appropriate for the modeling purpose or question asked for the
particular drug product and study population and is robust enough to respond to perturbations in
uncertain parameters. To allow the FDA to evaluate the robustness of the models, the sponsor
should clearly present results from the methods used to verify the model, confirm model results,
and conduct sensitivity analyses. The sponsor should include and discuss the procedures used
for model verification (both the drug and system models). Results of sensitivity analyses for
uncertain parameters should be discussed in the context of the simulation conditions and
potential clinical relevance.
In some instances, model parameters may be refined during model verification. 	Such
modifications are important aspects of model refinement and should be described and justified.
If the assumptions of the model parameters cannot be confirmed during modification, further
verification to predict clinical scenarios that were not previously evaluated should also be
submitted.
2. 	Model Application
The sponsor should present the results of using the verified PBPK model to address the study
question using tables, graphs, and text where appropriate.
E. 	Discussion
In this section, the sponsor should discuss how the PBPK modeling and simulation analyses
adequately address the proposed scientific, regulatory, or clinical questions. The basis for any
requests to waive the conduct of clinical studies should be discussed and well substantiated. If
simulations are used to support specific dosing recommendations to be tested in future clinical
trials or to be incorporated in prescription drug labeling, the proposed dosing recommendations
should be discussed and justified within the totality of evidence, including the context of known
exposure-response relationships and the level of confidence in the PBPK model for its intended
uses. See the FDA’s guidance for industry entitled Clinical Pharmacology Section of Labeling
for Human Prescription Drug and Biological Products — Format and Content for more details

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on specific language to include in the labeling.5 	The sponsor should also note the limitations of
its modeling approach in this section of the report and assess the potential impact of these
limitations on the PBPK study results and interpretation.
F. 	Appendices
The following information should be included in the appendices.
1. 	List of Tables
Provide a list of all tables used throughout the document.
2. 	List of Figures
Provide a list of all figures used throughout the document.
3. 	Table of Acronyms and Abbreviations
Spell out all acronyms and abbreviations used in the document.
4. 	References
Include a list of all references.
5 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.