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4 Οκτ 2013 (πριν από 3 χρόνια και 9 μήνες)

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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


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




2

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.
21
st

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


C
ritical to effectively
translate cutting
-
edge
developments in science
and technology into
promising products and
therapies.





4

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 non
-
clinical 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 & Science
-
Based 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

7

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
M
ulticellular architecture representative of the tissue of origin

o
F
unctional
representation of normal human
biology

o
R
eproducible
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


Base period

DARPA bioengineering

Platform + 2 systems

24 months

60 months

Integration &

validation

Period 1

4 systems

7 systems

10 systems

Period 3



Cell viability for 4 weeks



Integrated system predicts


human in vivo efficacy,


toxicity, and


pharmacokinetics:

o

safe and effective

o

safe and ineffective

o

unsafe, but effective

o

unsafe and ineffective

U18 generated cell resources

UH2 generated organ systems

UH3 phase:

-

Incorporation of differentiated


stem
-

and progenitor
-
derived cells

-

Integration of various organ systems



Multicellular architecture



Vascularization
,
innervation
,


hormonal,
humoral

and


immunological signaling



Genetic diversity and


pharmacogenomic

capacity



Representation of normal


and disease phenotypes


Period 2

Tissues

Cell

Changes

Cellular

Networks

Cellular Systems

Molecular

Pathways

Molecular

Targets

Tissue Dose

Toxicity

Health Outcomes

Of Interest

Chemical

The Challenges in Predicting
Human Response:
System
Complexity

Predict

Tissues

Cell

Changes

Cellular

Networks

Cellular Systems

Molecular

Pathways

Molecular

Targets

Tissue Dose

Toxicity

Health Outcomes

Of Interest

Chemical

The Challenges in Predicting
Human Response:
Outcome
Modifiers

External Factors

(including disease, interacting
systems)

Individual Variability

Metabolism

Response

Predict

Acute/Chronic?

Metabolism

ASSAY

Cell

Changes

Cellular

Networks

Cellular Systems

Molecular

Pathways

Molecular

Targets

Tissue Dose

Toxicity

Health Outcomes

Of Interest

Chemical

The Challenges in Predicting
Human Response:
Assay
Considerations

External Factors

(including disease,
interacting systems)

Metabolites?


Solubility?


Concentration?


Protein binding?


Relationship to plasma levels? Exposure?

S9(?)

Predict

Source?

QC?

Acute/Chronic?

A Chemical Testing Paradigm for MPS

Cell

Changes

Cellular

Networks

Cellular Systems

Molecular

Pathways

Molecular

Targets

Function

3D organ structure

assemblies

Linked multiple

organ systems

Cells

Test Compounds # 1

Test Compounds # 2

Test Compounds # 3

Evaluate and optimize

cell response

Evaluate and optimize

organ response

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?



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.


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:


Biomarkers


Clinical outcome assessments


Animal models


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



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

20

Context of Use


Key concept in the qualification process


R
efers
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


Models and assays are inevitably associated with
limitations: important to define:


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



Adequately specifying the CoU is often a
difficult first step towards qualification


Determines what kind of data are needed


Types of Biomarkers
(1)


Categorize by
how it is used

in drug
development



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)


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)


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)


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)


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)


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 Tools
-
http://www.fda.gov/downloads/Drugs/GuidanceComplian
ceRegulatoryInformation/Guidances/UCM230597.pdf


DDT Qualification is a complex process that
requires significant time and resources


Qualifying DDTs for regulatory purposes more feasible
in collaborative approach with representatives from
government, industry, academics


Summary


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


Would a common library of positive/negative
controls be useful in comparing assay performance
and determining predictivity?


What specific (human) outcome data will be used
to anchor assay performance?


Can a specific context of use be defined?

Thanks to the Following People


FDA Partners in this Project


NIH/NCATS
-

Dan Tagle


DARPA
-
Barry
Pallotta


For Use of Their Slides


Dan Tagle


Abby Jacobs


Tom Colatsky


Marc Walton


Jesse Goodman