Download Preclinical Testing Considerations:

Preclinical Testing Considerations:
Device Development and Validation
From Bench to Bedside to Market
John W. Karanian, Ph.D.
USFDA
„
Laboratory of Cardiovascular and Interventional Therapeutics
Office of Science and Engineering Laboratories
Center for Devices and Radiological Health
The opinions expressed are those of the authors and do not necessarily reflect those of CDRH or FDA
Session Overview
„
This session will review the device development process
from bench to bedside. The concepts underlying preclinical pre-market device regulation will be
presented. Regulatory aspects of the conduct of preclinical studies of the safety and effectiveness of medical
devices will be reviewed. The types of pre-clinical data
that may be needed to enter into a clinical trial or for a
successful marketing application will be discussed with
case examples, including laboratory-based experience in
the evaluation of failure modes for devices and
combination products to treat vascular and oncologic
disease.
Safety
Ethics
Trust
Innovation
Regulatory Science 100
Total Product Life Cycle
Cross-generations
The Pipeline
Science Cycle
Regulatory Cycle
Safe Therapeutic Products
„Drugs
– Pure molecules
– Toxicology
– Short half-life
– Long market life
– Drug interactions
– Wrong Drug / Dose
– Clinically studied
– Good Manufacturing
Practices
„
Devices
–
–
–
–
–
–
–
–
Complex components
Biocompatibility
Durable Equipment
Rapid product cycles
Malfunction
User Error
Bench studied
Quality Systems
(ISO 9000)
Device...
Any thing which is ….
"intended for use in the diagnosis of disease … or in the cure,
mitigation, treatment, or prevention of disease …, or
intended to affect the structure or any function of the body of
man…, and
which does not achieve its primary intended purposes through
chemical action … and which is not dependent upon being
metabolized for the achievement of its primary intended
purposes"
Devices
„
“Device” refers to
– the physical device, and
– its indication for use
Devices
„
“Device” refers to
– the physical device, and
– its indication for use
„
Example: Biliary stents
– Indication for use: treatment of biliary strictures
– Use for peripheral arterial disease represents a
new device (same physical item, new indication
for use)
Combination Product Jurisdiction
Drug Eluting Stent
Drug Eluting Disk
Combination Product Jurisdiction
Drug Eluting Stent
„
Primary Mode of Action:
– Stent opens artery
Drug Eluting Disk
„
Primary Mode of Action:
– Cancer Chemotherapy for
brain tumor
Combination Product Jurisdiction
Drug Eluting Stent
„
Primary Mode of Action:
– Stent opens artery
„
Secondary Actions
– Drug prevents inflammation
and restenosis of artery
Drug Eluting Disk
„
Primary Mode of Action:
– Cancer Chemotherapy for
brain tumor
„
Secondary Actions
– Local drug delivery of drug
by device
Combination Product Jurisdiction
Drug Eluting Stent
Drug Eluting Disk
„
Primary Mode of Action:
– Stent opens artery
„
Primary Mode of Action:
– Cancer Chemotherapy for
brain tumor
„
Secondary Actions
– Drug prevents inflammation
and restenosis of artery
„
Secondary Actions
– Local drug delivery of drug
by device
„
Regulated as a Device (PMA)
„
Regulated as a Drug (NDA)
Safe and Effective
„
FD&C Act grants explicit authority to
ensure that devices are safe and effective
before marketed rather than limited to
reacting to hazardous devices after
marketing
Safety
...that the probable benefits to health...for its
intended use...when accompanied by
adequate directions and warnings against
unsafe use, outweigh any probable risks
„ absence of unreasonable risk of illness or
injury
„ May require
„
– in vitro studies
– in vivo studies
– clinical investigations
Effectiveness
...that in a significant portion of the target
population, the use of the device for its
intended uses and conditions of use...will
provide clinically significant results
„ shown principally through well-controlled
clinical investigations (typically not
preclinical studies)
„
Device Classification
Medical devices vary widely in complexity
and potential risk
„ Classification determined on the basis of the
nature of the device and the extent of FDA
control to ensure safety and effectiveness
„ Class I, II, and III in order of increasing risk
„
– Class III
Class I: General Controls
„
General Controls
– Prohibit adulterated or misbranded devices
– Good Manufacturing Practices
– Registration by manufacturers
Lead shields, radiographic film, CPR boards
„ Most Class I devices are exempted
„
Class II: General and Special
Controls
General Controls as for Class I
„ Special Controls-established by regulation
„
– Performance standards
– Patient registries
– Postmarket surveillance
– Guidance documents for testing
„
Imaging systems (CT, US, MR), diagnostic
catheters
Class III: General Controls and
Premarket Clearance
General and special controls cannot provide
reasonable assurance of safety and
effectiveness
„ Typical characteristics
„
– Support or sustain human life
– Present a potentially unreasonable risk of
illness or injury
„
Ventricular assist devices, heart valves,
endovascular grafts, Stents
Class III: General Controls and
Premarket Clearance
Subject to general controls
„ Require an approved premarket approval
(PMA) application before commercial
distribution
„
Approval for marketing (Class III):
PMA Application
Required of all new Class III devices
„ PMA application: demonstrate safety and
effectiveness through:
„
– Design validation
– Manufacturing control
– Performance testing
– Animal studies
– Clinical trials
Label: Scientific Justification
„
Drug
– Description (Chemical info)
– Pharmacology
» Mechanism of action
» PK, metabolism
– Clinical studies
– Indications and usage
– Contraindications
– Precautions
– Warnings
– Adverse reactions
– Overdosage
– Dosage and Administration
– How supplied
„
Device
–
–
–
–
–
–
–
–
–
–
–
Device description
Indications for use
Contraindications
Warnings
Precautions
Summary of clinical studies
Adverse events, potential
complications
Individualization of
treatment (patient selection)
How supplied
Operator instructions
Imaging, post-op F/U,
patient tracking
HOW?
Investigational Device Exemptions
(IDE)
„
Purpose:
– Promoting the public health: encourage
discovery and development of devices useful
for human use
– Protecting the public health
„
IDE review: think in terms of a failure
modes and effects analysis
Investigational Device
Exemptions (IDE)
Discovery and development of new devices
requires exemption from the requirements
that apply to devices in commercial
distribution
„ IDE regulation:
„
– Encourages discovery and development of
devices consistent with protection of public
health and safety and with ethical standards
Investigational Device
Exemptions (IDE)
Conduct of a clinical investigation of a
medical device requires approval under the
IDE regulation
„ Investigation: a clinical investigation or
research, which involves one or more
subjects, to determine the safety or
effectiveness of a device
„
Investigational Device
Exemptions (IDE)
IRB: responsible for determination of SR/NSR
„ Non-significant risk study: IRB approval
„ Significant risk study:
– IRB approval and approved IDE application
are required before study may begin
„ References/requirements
„
– http://www.fda.gov/cdrh/
– Device advice
Development and Validation of Devices
to Treat Vascular Disease
Regulatory Science 400
Device/Drug Development Process
Pre-IDE
IDE
Conception
Clinical
Feasibility
Pre-clinical
Feasibility
Clinical
Trial
Pre-PMA
IND
Final
Labeling
Data
Compilation/
Formatting
Market
Post-Market
Pre-clinical
Testing
Pre-IND
PMA
Pre-NDA
IDE: Investigational Device Exemption
PMA: Pre-Market Approval
IND: Investigational New Drug
NDA: New Drug Application
NDA
Pre-Market Development and Testing
Requirements: Bench to Bedside
„
Preclinical bench
– Design criteria
– Performance criteria
– Safety/failure modes
»
»
»
»
„
Biocompatibility
Toxicology
Biomaterials
Durability
Preclinical animal
-Safety
- Failure modes
- Predictive value
„
Clinical investigation-feasibility
– Safety
– Performance
„
Clinical investigation-pivotal
– Final product configuration
– Safety
– Effectiveness
Post-market studies
– Safety
– Effectiveness
New and Emerging Technology
e.g., Drug eluting implant
„
What is new ?
The technology itself
b) A component or biomaterial or coating
c) A combination of new technology with old
technology
d) The benefit or risk
e) All of the above
a)
Total Product Life Cycle Vision
e.g., Drug-eluting implant
Early Product Life Cycle
ƒ How does the material perform
in the device? (e.g., stent wear
characteristics)
ƒ Can failure modes be anticipated
from the design? (e.g., coating
biocompatibility )
ƒ Failure modes analysis
ƒ Are there criticial performance
specifications? (e.g., coating
thickness and elution profile)
Early Product Life Cycle
ƒ Toxicology
ƒ
/Immunogenicity/
Pharmacokinetics
- What is already known ?
- Drug amount and elution
profile?
- Standards: ISO, CDER,
CBER, CDRH
- Limitations of preclinical
models
Mid Product Life Cycle
ƒ Clinical Evaluation
– With final manufactured
product or prototype ?
– Least burdensome
source of clinical
evidence ?
° Controls
° Questions to be left
for postmarketing
period ?
Mid Product Life Cycle
ƒ Full Scale Manufacturing
– Know your supplier
° Can you detect
changes in
components
– Liability
Late Product Life Cycle
ƒ End-of-Life Problems
–
–
–
Customer complaints
User Errors
Product Failures
° Post-market failure
modes analysis
Product Life Cycle
Premarket
Postmarket
Regulatory Cycle
Science Cycle
Developing Technologies for the
Treatment of Cardiovascular Disease
Lesion
Muscle
Pre-Market
Preclinical Trials
Clinical Trials
Lumen
Purpose of Preclinical Trials
„
„
Provision of reasonable evidence of safety
(effectiveness) prior to human clinical trial
Model selection is critical
- in vivo feasibility (define or refine a
model…refine the technology)
- in vivo safety and effectiveness (S&E) (refine
technology, S&E study)
Predictive Models
Failure Modes/Signals
Regulatory-Based
Translational
Research
Atheroma
Coronary
Restenosis
Coronary
Ischemia
Evaluative Tools
Methods Development
Cardiovascular Interventional Device
L
Performance and Failure Mode s
Sample Study Endpoints
Hemodynamic Changes
Vasospasm
Hemorrhage
Thrombosis (early and late)
Inflammatory Response
Progression of Underlying Disease
Healing: Vascular Remodeling
Patency: Stenosis/Restenosis
Preclinical Evaluation Tools
Imaging
„ Histology
„ Morphometry
„ Immunohistochemistry
„ ……………..and beyond
„
Landscape: Catheter-Based Interventional
Devices for the Treatment of Vascular Disease
1977
Angioplasty Balloons
2010
Stents
Pre-Intervention: Swine Coronary
The Standard Approach
Intervention
Coronary Stent Placement
Evaluation
Stent
Explant: Gross and Radiographic Follow-Up
Stent
Failure Modes/Signals
Smooth Luminal Surface
Marked Restenosis
Thrombosis
Inflammation
Morphometric & Morphologic Evaluation
Explant Histology
Internal elastic lamina
Media
Normal
Lumen
Lumen
Area
Area
Vessel
Area
No measurable Intimal Area
Restenosis
Lumen
Area
Vessel
Area
Media
Stenosis
( Intimal Area = Intimal Hyperplasia)
Human Failure Mode: Restenosis
Catheter-Based Interventional Devices for the
Treatment of Vascular Disease: LDD
1977
Angioplasty Balloons
2010
Stents
DES
Combination Products
Multiple Component Approach to Drug-Device Design
Material
Drug + Carrier
Treatment Approaches
Stenosis and Restenosis
Anti-Inflammatory
Immunomodulators
Anti-Proliferative
Migration Inhibitors
ECM-Modulators
Promote Healing &
Re-Endothelialization
Dexamethasone
Taxols
Batimastat
BCP671
M-prednisolone
Actinomycin
VEGF
Interferon γ-1b
Methothrexate
Prolyl hydroxyls
inhibitors
Angiopeptin
Halofuginone
Vincristine
Mitomycine
C-proteinase
inhibitors
Statins
Probucol
Leflunomide
Sirolimus
Tacrolimus
Everolimus
C MYC antisense
Mycophenolic acid
Abbott ABT- 578
Mizoribine
RestenASE
Cyclosporine
2-chlorodeoxyadenosine
Drug
PCNA Ribozyme
Carrier
Tranilast
Estradiols
NO donors
EPC antibodies
Biorest
Advanced coatings
Stent
Drug Eluting Stent
A Post-Market Signal
with Drug Eluting Stents
Delayed Healing
Inflammation
Thrombosis
Courtesy of Renu Virmani, CVPath
LESSON
The Science of Evaluating Combination Products
The combination of a biologic or drug with a
medical device for the therapeutic treatment of
disease raises new scientific and technical issues
such as the potential for complex tissue interactions
which may result in unanticipated hazards
Do Preclinical Failure Modes & Signals
Predict Human Adverse Events?
Laboratory for Image-Guided Studies
Devices
Database Subsets
Animal – Human
In vivo imaging
Explant imaging
Analysis Drugs
Target Vessel
Intra‐ Extra‐Cranial
Carotid
Subclavian and Foreleg
Valves
Thoracic Aorta
Coronary
Celiac
Mesenteric
Renal
Abdominal Aorta
Iliac
Femoral
Popliteal
Tibial
Case Study: Stent Fracture and Wear
Failure modes
Restenosis
Malapposition
Fracture
Inflammation
Modeling Implant Environment
Failure Mode: Loss of Stent Integrity
Fracture
Corrosion
Chowdhurdy and Renato, N Engl J Med, (3478, August 22, 2002
Brita et al, ACC 2008
Treatment of Human SFA disease
USUHS, MedPix
Clinical Lesson: SIROCCO Trial
courtesy of Dr. C. Bonsignore
The Problem…
„
„
„
Human explant data suggests evidence of mechanical &
chemical corrosion in vivo
Limited data for
– Prevalence of fracture in vivo
– Fracture mode
– Design, configuration and site specificity
Objective: To investigate the mechanisms by which
stents fracture
– Effects of single vs overlapping dissimilar stents
– Associations with site and arterial deformations
Longitudinal Imaging of Stent Integrity
Delivery
Implant*
90 days
0 days
30 days
30 days 60 days
180 days
Explant
Nitinol (NiTi
(NiTi))
Stainless Steel (SS)
*OL - NiTi implanted first and SS stent implanted proximally with target overlap length of 6mm
Stent Fracture Rate Across Implant Site
• No stent fractures in NiTi stents
SS Stents
75%
Coronary
Femoral
50%
100%
Overlapping Single
75%
0%
LAD
Overlapping
Single
100%
100%
RFCA
Vascular Geometry and Implant Performance:
Animal vs. Human
Vascular Motion and Deformation
Stent Design, Implant Configuration and Implant Site
„
„
Image-Based Interventional Studies
Improved Modeling
– Bedside: animal to human
– Computational
Vascular Deformation
Animal
Head
Forces
Measures
Toe
Human
Coronary vs Femoral Motion
Angiograms in Swine
„
Evaluation of vascular motion and geometric deformation
Human Model: Bending the Stented Leg
courtesy Dr. Jean-Paul Beregi
Human Femoral Arteries: Deformation
„
Supine
courtesy of Chris Cheng
vs. Swine Femoral Arteries
„
Fetal Position
Image-Based Modeling of Vascular Characteristics
Animal-Human: Aorto-Iliac
Image
Acquisition
Image
Image
Enhancement & Segmentation of
Vasculature
Processing
2D
Bedside
3D
Geometric
Model
Construction
Solid Model
Quantification and Modeling
Geometric &
Kinematic
Analysis
Computational
Modeling
Data
Simulation
Geometric model and vascular deformation of aorto-iliac-fem-pop
vessel in extended and flexed position
Extended
Flexed
Arterial
Segment
Axial
length, cm
(% change)
Curvature
Change, cm-1
(% change)
Axial Twist°
Twist°
1. Abdominal
Aorta
-6.5 ± 1.1
97.4 ± 12.3
27.5 ± 4.8
2. Iliac
-11.8 ± 2.3
87.5 ± 36.0
27.5 ± 4.8
3. Proximal
Femoral
-33.2 ± 0.8
66.4 ± 5.4
-4.9 ± 2.5
4. Middle
Femoral
-26.2 ± 3.0
67.7 ± 2.2
+68.3 ± 8.0
5. Distal
Femoral
-31.9 ± 1.0
58.0 ± 7.8
+26.0 ± 3.0
6. Proximal
Popliteal
-10.1 ± 0.7
0.17 ± 0.03
+13.0 ± 13.8
IlioIlio-FemFemPop (1(1-5)
-5.37 ± 0.21
(-25.8 ± 0.8)
0.46 ± 0.06
+112.2 ± 4.9
Geometric Model of Aorto-Iliac Artery Curvature
1
Renal branch points
Iliac
Flexed
Normalized Curvature
Aorta
Extended
0
90% increase in peak curvature
from extension to flexion
Changes in Elevation and Separation Angle Between Iliacs
from Extension to Flexed&Torqued Position
(Cartesian plots)
Elevation Angle (+81%)
Separation Angle (-17%)
90
90
1
120
60
0.6
0.6
150
30
0.2
30
0.4
0.4
0.2
Extended
180
60
0.8
0.8
150
1
120
180
0
0
Torqued
330
210
300
240
270
210
330
240
300
270
Geometric Model of Right Iliac-Femoral Artery Curvature
2
2
Flexed
4
High Curvature
5
Extended
Normalized
Curvature
Normalized
Curvature
3
Image-Based Modeling of Vascular Characteristics
Animal-Human: Coronary
Image
Acquisition
Image
Image
Enhancement & Segmentation of
Vasculature
Processing
2D
Bedside
3D
Geometric
Model
Construction
Solid Model
Quantification and Modeling
Geometric &
Kinematic
Analysis
Computational
Modeling
Data
Simulation
Coronary (LAD) Geometric Deformation
Swine: Systole vs. Diastole
Segment
Axial length, cm
(% change)
Curvature Change, cm-1
(% change)
Axial Twist°
Twist°
1
2.7%
-145%
17 °
2
2.7%
NS
-43 °
3
-5.7%
-72%
34 °
6
-2%
-145%
25 °
1
2
6
3
Coronary line paths
Solid model curvagram - End diastole
Coronary CTA and Geometric Model
Human: Systole vs. Diastole
Systole
Diastole
Segmentation of coronary vessels
Line paths
Coronary (LAD) Geometric Deformation
Human: Systole vs. Diastole
Segment
Axial length, cm
(% change)
1
-19.3%
2
Curvature Change, cm-1
(% change)
Tortuosity
(% change)
Axial Twist°
Twist°
-
ns
ns
12.1%
-
100.0%
-49 °
3
-10.7%
-
18.2%
14°
14°
6
-7.4%
-79.6%
238.5%
2°
Coronary line paths
x
LC
D
LA
A
RC
LC
x
LA
RC D
A
Solid model curvagram
Coronary (LAD) Model
Swine vs. Human at Systole and Diastole
Swine
Curvature
Human
Proximal end
*Normalized to maximum curvature = highest human curvature at systole
Normalized Curvature
Diastole
Impact of Vascular Motion and Deformation
Implant Design
Implant Configuration
Implant Site
Stented Swine Femoral Motion Angiogram
Cohort
Axial length, cm
(% change)
Curvature Change, cm-1
(% change)
Axial Twist°
Twist°
Native
-39.7 ± 2.3
+166.9 ± 18.1
125.6 ± 10.7
Stented
-15.4 ± 4.4
+55.5 ± 6
147.4 ± 18.1
Geometric Model Of Native And Stented
Swine Femoral Curvature In Flexed Position
X Represent high flexion points
Translational Modeling and Testing
Recommendations for Implant Studies…
Bench
Computational
Bedside
courtesy Dr. Christopher Cheng
35 °
88 °
Supine position
Bent position
AortoAorto-iliac
courtesy Dr. Christopher Cheng
. Human
Human
Coronary (LAD)
Swine
Swine
1
Femoral
Coronary
0
A. Swine
Catheter-Based Interventional Devices for the
Treatment of Vascular Disease: LDD
1977
Angioplasty Balloons
2010
Stents
DES
Infusion Catheters
Drug-Eluting Balloons
MIC
DEB
DIB
SFIC
Catheter-Based Local Drug Delivery
The Devices
ƒ Drug Eluting Stents (DES)
ƒ Catheter-Based (ie, non-implant based)
Drug Infusion Balloons (DIB)
Micro Infusion Catheters (MIC)
Stop Flow Infusion Catheters (SFIC)
Drug Eluting Balloons (DEB)
ƒ Vascular Wraps
ƒ Drugs may be delivered
Systemic
Luminal
Intimal
Adventitial
Is safety and efficacy delivery mode- and site-dependent?
Catheter-Based Local Drug Delivery
Determinants of Safety and Efficacy
iliz
e
te n
os
is
Efficacy
es
Sta
b
tR
• Geometry
Safety
• Existing pathology
•
&
De
C
D
Chha evvicD
ararac icee ev
ice
cteteri
risstic
tic s
s
sio
ns
en
Le
v
Pre
rugg tcicss
ug Dru rsisti
Dr D teri
raccte
haara
CCh
Vessel
Vessel
Vessel
Physicochemical properties
Characteristics
•
Characteristics
in specific tissues
• Diffusivity
Therapeutic index
efficiency
• Dose
• Delivery
(formulation, IC50)
of administration
• Administration
• Site
(number, location)
Ease of use
•
•Anatomic
structure (→ PK)
Disease Regression
Case Study: Drug Infusion Catheters
Modeling Catheter-Based Local Drug Delivery
PK and Drug-Induced Vascular/Tissue Injury (DIVI/DITI)
Karanian et al, JVIR 2010;
Karanian et al Cardiovasc Revasc Med 11(4), 2010
Evaluation of Local Drug Delivery
Comparison of delivery technologies
„ Comparison of vascular beds
„ Safety (PK, device safety/failure modes)
„ Reliability
„ Effectiveness
„ Toward more predictive animal models
„
Karanian et al, J Vasc Interv Radiol, 21(9), 2010
Modes of Delivery: Infusion Catheters
SFIC
„
„
„
Drug Infusion Balloons (DIB)
Micro Infusion Catheters (MIC)
Stop Flow Infusion Catheters (SFIC)
DIB
MIC
Artery
Drug
The Pharmacokinetics of Anti-Proliferative Drugs
From Catheter-Based Local Drug Delivery Systems
What are the determinants of safety and efficacy?
Efficiency of Drug Delivery to the Coronary Arteries in Swine
is Dependent on the Route of Administration
Assessment of luminal, intimal and adventitial coronary artery delivery methods
100.000%
Luminal (MIC‐NA)
Intimal (DIB)
10.000%
Adventitial (MIC‐A)
1.000%
0.100%
0.010%
0.001%
P3
P2
P1 Inj slice
D1
D2
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
D3
D4
Coronary (LAD) marker distribution (log
scale) showing the disparity (> 2 orders of
magnitude) between the adventitial
(black) and the intimal (gray)
and
luminal delivery (white). A bell-shaped
distribution pattern is more apparent for
the adventitial than for the intimal or
luminal delivery method (p<0.001).
Luminal (MIC-NA)
Intimal (DIB)
Adventitial (MIC-A)
P3
P2
P1 Inj slice
D1
D2
D3
D4
Karanian et al, J Vasc Interv Radiol, 21(9), 2010
Coronary marker distribution following
luminal, intimal and adventitial delivery.
All values were normalized to total DPM
detected in each coronary (LAD) section to
allow for comparison of the longitudinal
distribution pattern along the blood vessel.
Evaluation of Local Drug Delivery
Comparison of delivery technologies
„ Comparison of vascular beds
„ Safety (PK, device safety/failure modes)
„ Reliability
„ Effectiveness
„ Toward more predictive animal models
„
Pharmaco-Image of Surrogate Drug Marker Across Coronary
and Peripheral Arteries Following Adventitial Delivery (MIC)
Coronary (LAD)
ARenal A.
Femoral A.
Carotid A.
Representative 3D CT reconstructions of the surrogate drug marker contrast plume around the
coronary, renal, femoral and carotid arteries 4 minutes following delivery via MIC.
Comparison of Surrogate Drug Marker Retention Across
Arteries Following Adventitial Delivery (MIC)
Sample Detected Across Four Major Arteries
(Percent of Respective Controls)
Percent Dose Detected ± SEM
100%
80%
60%
40%
20%
0%
Coronary (LAD)
Renal
Femoral
Carotid
All values were determined as a percentage of the control sample from each delivery
Evaluation of Local Drug Delivery
Comparison of delivery technologies
„ Comparison of vascular beds
„ Safety (PK, device safety/failure modes)
„ Reliability
„ Effectiveness
„ Toward more predictive animal models
„
Reported Anti-Restenotics: Safety & Efficacy
Anti-Inflammatory
Immunomodulators
Anti-Proliferative
Migration Inhibitors
ECM-Modulators
Promote Healing &
Re-endothelialization
Dexamethasone
QP-2
Batimastat
BCP671
M-prednisolone
Paclitaxel (PTX)
VEGF
Interferon γ-1b
Prolyl hydroxyls
inhibitors
Actinomycin
Leflunomide
Methothrexate
Halofuginone
Sirolimus
Angiopeptin
C-proteinase
inhibitors
Tacrolimus
Vincristine
Probucol
Everolimus
Mitomycine
Mycophenolic acid
Statins
Mizoribine
C MYC antisense
Cyclosporine
Abbott ABT- 578
Tranilast
RestenASE
2-chlorodeoxyadenosine
PCNA Ribozyme
Estradiol
NO donors
EPC antibodies
Biorest
Advanced coatings
Safety: DIVI/DITI
Paclitaxel (PTX) Across Delivery Method and Vessel
PTX
Doses
Delivery
Method
Coronary
(0.3 ml)
Peripheral
(1.5 ml)
Low Dose
MIC
10 μg in 0.3 ml
50 μg in 1.5 ml
High Dose
MIC
SFIC
100 μg in 0.3 ml
500 μg in 1.5 ml
Systemic
Dose
IV
50 mg
50 mg
MIC: Micro-infusion catherer
SFIC: Stop flow infusion catheter
IV: Intra-venous
1Hr Coronary PTX Levels
(vessel segment: cm, negative=proximal, 0=center, positive=distal)
Adventitial (MIC)
10ug
Adventitial (MIC)
100ug
Paclitaxel concentration in coronary arteries
(logM) after delivery of 0.3 ml to coronary
arteries or systemic IV dose
Delivery:
Dose:
Karanian et al, Cardiovasc Revasc Med 11(4), 2010
Intimal (SFIC)
100ug
IV
50mg
3D Coronary PTX Levels
(vessel segment: cm, negative=proximal, 0=center, positive=distal)
Adventitial (MIC)
10ug
Adventitial (MIC)
100ug
(after delivery of 1.5 ml to artery)
after the delivery of 1.5ml to artery
))
Paclitaxelconcentration
Concentrationin
incoronary
coronary arteries
arteries ((logM
Paclitaxel
(logM)
logM
Delivery:
Dose:
Karanian et al, Cardiovasc Revasc Med 11(4), 2010
Intimal (SFIC)
100ug
PTX Retention in Coronary and Femoral
1Hr to 3D
Coronary
Femoral
Retention in Femoral Artery
(% of drug delivered)
Retention in Coronary Artery
(% of drug delivered)
100.0000%
100.0000%
10.0000%
10.0000%
1.0000%
Dose: Delivery Mode
10ug Adventitial (MIC)
0.1000%
50ug Adventitial (MIC)
0.0100%
1.0000%
Dose: Delivery Mode
50ug Adventitial (MIC)
0.1000%
500ug Adventitial (MIC)
0.0100%
50ug Intimal (SFIC)
0.0010%
IV DOSE
0.0001%
500ug Intimal (SFIC)
0.0010%
IV DOSE
0.0001%
1 hour
3 days
1 hour
3 days
PK Summary*
Micro Infusion Catheter
(MIC: Mercator MedSystems)
Paclitaxel
Concentration
( µ M) in Artery
Wall at 1 hour
Paclitaxel
Concentration
( µ M) in Artery
Wall at 3 days
Stop Flow
Infusion Catheter
(SFIC:Accrotek )
Systemic IV
Delivery
Systemic Dose
Low Dose
High Dose
High Dose
Coronary
1.11 ± 0.21
13.2 ± 4.8
1.65 ± 0.46
0.46 ± 0.07
Peripheral
10.3 ± 1.7
46.0 ± 15.3
1.43 ± 0.31
0.19 ± 0.02
Coronary
0.12 ± 0.03
0.19 ± 0.03
0.20 ± 0.05
Peripheral
0.97 ± 0.18
1.49 ± 0.68
0.34 ± 0.08
* Average ±SEM of all segments in 5cm range. Color coding based on literature interpretation.
Therapeutic Values
Karanian et al, Cardiovasc Revasc Med 11(4), 2010
Representative 3-Day Histological Results
Following Adventitial PTX Delivery
Control
Low Dose
(10ug)
High Dose
(50ug)
Low Dose
(50ug)
High Dose
(500ug)
Coronary
Focal features included
• Minor Inflammation
• Minor fibrin deposition
• Moderate hemorrhage
Femoral
Control
Study Conclusion
PTX Local Drug Delivery
„
Markedly more efficient and localized drug
retention along the femoral and coronary
artery
following
adventitial
delivery
compared to intimal delivery methods.
„
Minimal histologic changes 3 days after low
and high dose delivery.
Local Drug Delivery (Infusion Model): S&E
Safety & Efficacy
- Delivery method dependent
- Site specific?
- Drug specific?
Efficiency
- Agents delivered to outside of artery diffuse
circumferentially, longitudinally, transmurally
- Lower loading dose and greater retention
possible with infusion
of lipophilic drugs
Drug
Artery
Impact and Beyond
The R&D Perspective
„
Reproducible in vivo model of highly localized
surrogate/drug delivery for PK/PD studies.
„
Evaluation of drug, device and combination therapy
safety for key anti-restenotic drug.
„
Demonstration of highly localized administration and
reduced systemic exposure associated with adventitial
delivery that should minimize toxicity and provide
controlled dosing with increased therapeutic value.
„
Development of a delivery method with potential
impact on revascularization rates.
Summary
The Challenge for All Stakeholders
Development Process
Pre-market pre-clinical work that leads to technology changes
„
S&E testing (bench and animal)
– Predictive tests
– Predictive biomarkers
– Translation to humans
„
Identify and qualify S&E biomarkers for
regulatory decision making
„
Preclinical Goals
– Match or outperform gold standards
– Succeed at predicting failure
– Enable technology development
You are here in Charlottesville, Va
We are here in Laurel, MD
Thank
You!
USFDA, CDRH, OSEl, Laboratory of Cardiovascular and Interventional Therapeutics
[email protected]
William Pritchard, MD,PhD
Alberto Chiesa, DVM,PhD
Brad Wood, MD (NIH)
Juan Esparza
Srinidhi Nagaraja, PhD
Orlando Lopez, PhD
Mark Kreitz, PhD
Maureen Dreher, PhD
Renu Virmani, MD (CVPath)
JafarVossoughi, PhD
Peter Davies, PhD (UPENN)
Dena Rad
Nadine Abi Jaudeh, MD (NIH)
Briana McDowell
Mathew Dreher, PhD (NIH)
Ryan Haughey
Karun Sharma, MD (NIH)
David Woods
John W Karanian, PhD
[email protected]
Laboratory of Cardiovascular and Interventional Therapeutics