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FDA/NIH/DARPA Microphysiological
Systems Program and Qualification of
Drug Development Tools
Suzanne Fitzpatrick, PhD, DABT
US Food and Drug Administration
Challenges to FDA
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Recent breakthroughs in science and technology have the potential to
transform our ability to prevent, diagnose and treat disease.
However, major investments in basic and translational research are not
efficiently yielding new products needed to benefit patients/populations
Product development is increasingly costly, success rates remain low, many
uncertainties exist, including, as a major component, failures in predicting
toxicity despite extensive animal testing
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STRATEGIC PLAN: Vision
“FDA will advance regulatory science to speed
innovation, improve regulatory decision-making, and
get safe and effective products to people in need.
21st Century regulatory science will be a driving
force as FDA works with diverse partners to protect
and promote the health of our nation and the global
community”
What is Regulatory Science?
The application of
science to the
development and
utilization of new tools,
standards, and
approaches for the
assessment of product
efficacy, safety, and quality
 Critical to effectively
translate cutting-edge
developments in science
and technology into
promising products and
therapies.

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1. Modernize Toxicology to
Enhance Product Safety
Develop better models of human
adverse response
 Identify and evaluate biomarkers and
endpoints that can be used in nonclinical and clinical evaluations
 Use and develop computational
methods and in silico modeling

Advancing Regulatory Science
• FDA-NIH Joint Leadership Council formed in 2010
• Issued RFA for Advancing Regulatory Science through Novel Research & ScienceBased Technologies Program ($7M, 4 awards):
o
Accelerating Drug & Device Evaluation through Innovative Clinical Trial Design
o
Replacement Ocular Battery
o
Heart-Lung Micromachine for Safety and Efficacy Testing
o
Characterization/Bioinformatics-modeling of Nanoparticle: Complement Interactions
Microphysiological Systems
DARPA –BAA-11-73
Reconfigurable platform
 Ten or more in vitro physiological systems
 Able to monitor resident tissues for up to 4weeks
 Uses human cells
 Commercial availability
 Includes plan for validating integrated platform
performance
 70 million over 5 years
 Applications jointly reviewed by DARPA, FDA, and NIH
 Contracts were awarded to Wyss and MIT
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DARPA-FDA-NIH Microphysiological
Systems Program
• Started in 2011 to support the development of human
microsystems, or organ “chips,” to screen for safe and effective
drugs swiftly and efficiently (before human testing)
• Collaboration through coordination of independent programs
Engineering platforms and biological proof-of-concept (DARPA-BAA-11-73:
Microphysiological Systems)
Underlying biology/pathology and mechanistic understanding
(RFA-RM-12-001 and RFA RM-11-022)
Advise on regulatory requirements, validation and qualification
Integrated Microphysiological Systems for Drug Efficacy
and Toxicity Testing (UH2/UH3)
• GOAL: Develop in vitro microphysiological systems representative of major
organs/tissues in the human body, that will facilitate the assessment of
biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to
clinical trials.
• SCOPE/ACTIVITIES:
o Multicellular architecture representative of the tissue of origin
o Functional representation of normal human biology
o Reproducible and viable operation under physiological conditions
maintained up to 4 weeks in culture
o Capacity for representation of normal and disease phenotypes,
o Capacity for representation of population diversity
o Amenable to high content screening for repeated dose efficacy testing, and
for toxicology, and safety screening
Stem/Progenitor Cell-Derived Human Micro-organs
and -tissues (U18)
• GOAL: Develop stem- and progenitor-derived cell resources to
seed circulatory, endocrine, gastrointestinal, immune, integumentary,
musculoskeletal, nervous (including eye), reproductive, respiratory
and urinary microsystems.
• SCOPE/ACTIVITIES:
o Improvements
in differentiation efficiencies
towards cell-type diversity, genetic complexity,
population diversity, and disease modeling
o Development of 3D culturing approaches to
enhance cellular microenvironments
24 months
UH3 phase:
- Incorporation of differentiated
stem- and progenitor-derived cells
- Integration of various organ systems
Integration &
validation
U18 generated cell resources
UH2 generated organ systems
Base period
Period 1
Period 2
DARPA bioengineering
Platform + 2 systems
4 systems
7 systems
10 systems
• Multicellular architecture
• Vascularization, innervation,
hormonal, humoral and
immunological signaling
• Genetic diversity and
pharmacogenomic capacity
• Representation of normal
and disease phenotypes
60 months
• Cell viability for 4 weeks
• Integrated system predicts
human in vivo efficacy,
toxicity, and
pharmacokinetics:
o
o
o
o
safe and effective
safe and ineffective
unsafe, but effective
unsafe and ineffective
Period 3
The Challenges in Predicting
Human Response: System
Complexity
Chemical
Tissue Dose
Tissues
Molecular
Targets
Cellular Systems
Cell
Cellular
Changes
Networks
Toxicity
Molecular
Pathways
Predict
Health Outcomes
Of Interest
The Challenges in Predicting
Human Response: Outcome
Modifiers
Chemical
External Factors
Acute/Chronic?
Metabolism
(including disease, interacting
systems)
Tissue Dose
Tissues
Molecular
Targets
Cellular Systems
Cell
Cellular
Changes
Networks
Toxicity
Molecular
Pathways
Predict
Metabolism
Individual Variability
Response
Health Outcomes
Of Interest
The Challenges in Predicting
Human Response: Assay
Considerations
Source?
External Factors
Chemical
S9(?)
QC?
(including disease,
interacting systems)
Metabolites?
Tissue Dose
Acute/Chronic?
ASSAY
Molecular
Targets
Cellular Systems
Cell
Cellular
Changes
Networks
Toxicity
Molecular
Pathways
•
•
•
•
Predict
Solubility?
Concentration?
Health Outcomes
Protein binding?
Of Interest
Relationship to plasma levels? Exposure?
A Chemical Testing Paradigm for MPS
Cells
Cellular Systems
Cell
Changes
Molecular
Targets
Cellular
Networks
Molecular
Pathways
Function
Test Compounds # 1
Evaluate and optimize
cell response
Test Compounds # 2
3D organ structure
assemblies
Linked multiple
organ systems
Evaluate and optimize
organ response
Test Compounds # 3
Evaluate and optimize
system response
Criteria for Selecting Test
Compounds
Do individual organ models respond to test
compounds with the expected organ-specific
effects?
 Do linked organ system models respond to test
compounds with the expected systemic effects?
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Selection of test compounds should consider:
◦ Individual organ function  linked organ functions
◦ Direct organ toxicities  dependent organ toxicities
◦ Study read-outs?  health outcomes of interest?
Limitations of Current Validation
Strategies
Clear that a “one size fits all” approach no
longer viable
 Clear that in vivo animal studies cannot be the
gold standard that new toxicology methods
are against.
 Clear need to determine the relevance of in
vitro results to what occurs in humans rather
than what occurs in rodents and other test
animals.
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Drug Development Tool
Qualification
FDA program that provides a mechanism for
formal review by CDER to qualify new tools that
would benefit drug development
 Currently, 3 programs have been implemented:
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◦ Biomarkers
◦ Clinical outcome assessments
◦ Animal models
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But the concept should be applicable to any tool
proposed for use in regulatory decision making
Can the concept of “qualification” help to position
MPS assays for eventual regulatory use?
What is a Biomarker?

A characteristic that is objectively measured
and evaluated as an indicator of normal
biologic processes, pathogenic processes
(abnormal biologic processes), or biological
responses to a therapeutic intervention
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A measurable characteristic that is not a
clinical assessment of the patient
◦ Clinical measures are those evaluating or closely relating
to how a patient feels or functions, or survival
Biomarker Qualification

A conclusion that within a carefully and
specifically stated “context of use” the
biomarker has been demonstrated to reliably
support a specified manner of interpretation
and application in drug development
◦ Utility in drug development, particularly regulatory
decisions, is central to purpose of qualification
◦ Particularly for biomarkers expected to have application
in multiple different drug development programs
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Context of Use
Key concept in the qualification process
 Refers to a clearly articulated description
delineating the manner and purpose of use for
the tool (when and how will it be used?)
 Also defines the boundaries the available data
adequately justify the use of the tool
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Models and assays are inevitably associated with
limitations: important to define:
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The context in which results are intended to be used
The specific human outcomes that will be predicted
Context of Use
How the biomarker is used in drug
development
 What decision is made based on the data
 What action, and how, drug development is
altered by the biomarker results
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Adequately specifying the CoU is often a
difficult first step towards qualification
◦ Determines what kind of data are needed
Types of Biomarkers
(1)
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Categorize by how it is used in drug
development
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Prognostic biomarker
◦ Indicates future clinical course of the patient
with respect to some specified clinical outcome,
in the absence of any additional Tx intervention
◦ No connection to any particular new Tx
Types of Biomarkers (2)
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Predictive biomarker
◦ Measured prior to an intervention
◦ Identifies patients who are relatively susceptible
to a particular drug effect versus less
susceptible patients
 Benefit or harm
 Exists only for a Tx with some effect
Types of Biomarkers (3)
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Pharmacodynamic biomarker (PD)
◦ Response-indicator biomarker
◦ Post Tx measurement
◦ Marker that reveals whether, or how large, a
biological response has occurred in that
particular patient
◦ May or may not be Tx-specific
 Development occurs in a Tx by Tx manner
Types of Biomarkers (4)
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Efficacy-response biomarker
 Efficacy-surrogate biomarker, Surrogate endpoint
◦ Small subset of general pharmacodynamic
biomarkers
◦ Predicts the clinical outcome of the patient at
some later time
◦ Developed Tx by Tx
Qualification of a Drug
Development Tool (DDT)
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The qualification of DDT begins with a meeting of
CDER personnel and the biomarker sponsors
Consultation on information need to compile a
comprehensive evidence to support the
application for qualification of a DDT
CDER and other appropriate FDA scientists
undertake a multi-disciplinary formal review of
the DDT submission from the sponsor
Decision reached regarding qualification of DDT
If positive, decision is publically communicated in
form of a guidance
Qualification of a Drug
Development Tool (DDT)
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Once qualification is granted, any drug sponsor
can submit data obtained with the qualified DDT
without being asked for further evidence in
support of its suitability
◦ FDA Draft Guidance on Qualification of Drug
Development Toolshttp://www.fda.gov/downloads/Drugs/GuidanceComplian
ceRegulatoryInformation/Guidances/UCM230597.pdf
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DDT Qualification is a complex process that
requires significant time and resources
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Qualifying DDTs for regulatory purposes more feasible
in collaborative approach with representatives from
government, industry, academics
Summary
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Selection of the appropriate test chemicals and
endpoints of interest will be important in
developing and externally validating MPS assays
◦ Organ  System level
◦ Adverse Function  Toxicity
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Would a common library of positive/negative
controls be useful in comparing assay performance
and determining predictivity?
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What specific (human) outcome data will be used
to anchor assay performance?
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Can a specific context of use be defined?
Thanks to the Following People
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FDA Partners in this Project
◦ NIH/NCATS- Dan Tagle
◦ DARPA-Barry Pallotta
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For Use of Their Slides
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Dan Tagle
Abby Jacobs
Tom Colatsky
Marc Walton
Jesse Goodman