Preclinical Testing Considerations - Biomedical …bme.virginia.edu/FDA/John Karanian MD-TIP UVA...

Preclinical Testing Considerations:Preclinical Testing Considerations:Device Development and ValidationDevice Development and ValidationFrom Bench to Bedside to MarketFrom Bench to Bedside to Market

John W. Karanian, Ph.D.John W. Karanian, Ph.D.

Laboratory of Cardiovascular and Interventional TherapeuticsLaboratory of Cardiovascular and Interventional TherapeuticsOffice of Science and Engineering LaboratoriesOffice of Science and Engineering Laboratories

Center for Devices and Radiological HealthCenter for Devices and Radiological Health

The opinions expressed are those of the authors and do not necesThe opinions expressed are those of the authors and do not necessarily reflect those of CDRH or FDAsarily reflect those of CDRH or FDA

USFDAUSFDAUSFDA

Session OverviewSession Overview

This session will review the device development process This session will review the device development process from bench to bedside. The concepts underlying prefrom bench to bedside. The concepts underlying pre--clinical preclinical pre--market device regulation will be market device regulation will be presented.presented. Regulatory aspects of the conduct of preRegulatory aspects of the conduct of pre--clinical studies of the safety and effectiveness of medical clinical studies of the safety and effectiveness of medical devices will be reviewed.devices will be reviewed. The types of preThe types of pre--clinical data clinical data that may be needed to enter into a clinical trial or for a that may be needed to enter into a clinical trial or for a successful marketing application will be discussed with successful marketing application will be discussed with case examples, including laboratorycase examples, including laboratory--based experience in based experience in the evaluation of failure modes for devices and the evaluation of failure modes for devices and combination products to treat vascular and oncologic combination products to treat vascular and oncologic disease.disease.

SafetySafety Innovation Innovation

Ethics Ethics TrustTrust

Regulatory Science 100Regulatory Science 100

Total Product Life CycleTotal Product Life Cycle

CrossCross--generationsgenerations

The PipelineThe Pipeline

Science CycleScience Cycle

Regulatory CycleRegulatory Cycle

Safe Therapeutic ProductsSafe Therapeutic ProductsDrugsDrugs

–– Pure moleculesPure molecules–– ToxicologyToxicology–– Short halfShort half--lifelife–– Long market lifeLong market life–– Drug interactionsDrug interactions–– Wrong Drug / DoseWrong Drug / Dose–– Clinically studiedClinically studied–– Good Manufacturing Good Manufacturing

PracticesPractices

DevicesDevices–– Complex componentsComplex components–– BiocompatibilityBiocompatibility–– Durable EquipmentDurable Equipment–– Rapid product cyclesRapid product cycles–– MalfunctionMalfunction–– User ErrorUser Error–– Bench studiedBench studied–– Quality Systems Quality Systems

(ISO 9000)(ISO 9000)

Device...Device...Any thing which is Any thing which is ……. .

"intended for use in the diagnosis of disease "intended for use in the diagnosis of disease …… or in the cure, or in the cure, mitigation, treatment, or prevention of disease mitigation, treatment, or prevention of disease ……, or, or

intended to affect the structure or any function of the body of intended to affect the structure or any function of the body of manman……, and , and

which does not achieve its primary intended purposes through which does not achieve its primary intended purposes through chemical action chemical action …… and which is not dependent upon being and which is not dependent upon being metabolized for the achievement of its primary intended metabolized for the achievement of its primary intended purposes" purposes"

DevicesDevices

““DeviceDevice”” refers to refers to –– the physical device, and the physical device, and –– its indication for useits indication for use

DevicesDevices

““DeviceDevice”” refers to refers to –– the physical device, and the physical device, and –– its indication for useits indication for use

Example: Biliary stentsExample: Biliary stents–– Indication for use: treatment of biliary strictures Indication for use: treatment of biliary strictures –– Use for peripheral arterial disease represents a Use for peripheral arterial disease represents a

new device (same physical item, new indication new device (same physical item, new indication for use)for use)

Combination Product JurisdictionCombination Product Jurisdiction

Drug Eluting StentDrug Eluting Stent Drug Eluting DiskDrug Eluting Disk


Drug Eluting StentDrug Eluting Stent

Primary Mode of Action:Primary Mode of Action:–– Stent opens arteryStent opens artery

Drug Eluting DiskDrug Eluting Disk

Primary Mode of Action:Primary Mode of Action:–– Cancer Chemotherapy for Cancer Chemotherapy for

brain tumorbrain tumor




Secondary ActionsSecondary Actions–– Drug prevents inflammation Drug prevents inflammation

and restenosis of arteryand restenosis of artery




Secondary ActionsSecondary Actions–– Local drug delivery of drug Local drug delivery of drug

by deviceby device




Secondary ActionsSecondary Actions–– Drug prevents inflammation Drug prevents inflammation

and restenosis of arteryand restenosis of artery

Regulated as a Device (PMA)Regulated as a Device (PMA)




Secondary ActionsSecondary Actions–– Local drug delivery of drug Local drug delivery of drug

by deviceby device

Regulated as a Drug (NDA)Regulated as a Drug (NDA)

Safe and EffectiveSafe and Effective

FD&C Act grants explicit authority to FD&C Act grants explicit authority to ensure that devices are safe and effective ensure that devices are safe and effective before marketed rather than limited to before marketed rather than limited to reacting to hazardous devices after reacting to hazardous devices after marketingmarketing

SafetySafety...that the probable benefits to health...for its ...that the probable benefits to health...for its intended use...when accompanied by intended use...when accompanied by adequate directions and warnings against adequate directions and warnings against unsafe use, outweigh any probable risksunsafe use, outweigh any probable risksabsence of unreasonable risk of illness or absence of unreasonable risk of illness or injuryinjuryMay requireMay require–– in vitro studiesin vitro studies–– in vivo studiesin vivo studies–– clinical investigations clinical investigations

EffectivenessEffectiveness

...that in a significant portion of the target ...that in a significant portion of the target population, the use of the device for its population, the use of the device for its intended uses and conditions of use...will intended uses and conditions of use...will provide clinically significant resultsprovide clinically significant resultsshown principally through wellshown principally through well--controlled controlled clinical investigations (typically not clinical investigations (typically not preclinical studies)preclinical studies)

Device ClassificationDevice Classification

Medical devices vary widely in complexity Medical devices vary widely in complexity and potential riskand potential riskClassification determined on the basis of the Classification determined on the basis of the nature of the device and the extent of FDA nature of the device and the extent of FDA control to ensure safety and effectivenesscontrol to ensure safety and effectivenessClass I, II, and III in order of increasing riskClass I, II, and III in order of increasing risk–– Class IIIClass III

Class I: General ControlsClass I: General Controls

General ControlsGeneral Controls–– Prohibit adulterated or misbranded devicesProhibit adulterated or misbranded devices–– Good Manufacturing PracticesGood Manufacturing Practices–– Registration by manufacturersRegistration by manufacturers

Lead shields, radiographic film, CPR boardsLead shields, radiographic film, CPR boardsMost Class I devices are exempted Most Class I devices are exempted

Class II: General and Special Class II: General and Special ControlsControls

General Controls as for Class IGeneral Controls as for Class ISpecial ControlsSpecial Controls--established by regulationestablished by regulation–– Performance standardsPerformance standards–– Patient registriesPatient registries–– Postmarket surveillancePostmarket surveillance–– Guidance documents for testingGuidance documents for testing

Imaging systems (CT, US, MR), diagnostic Imaging systems (CT, US, MR), diagnostic catheterscatheters

Class III: General Controls and Class III: General Controls and Premarket ClearancePremarket Clearance

General and special controls cannot provide General and special controls cannot provide reasonable assurance of safety and reasonable assurance of safety and effectivenesseffectivenessTypical characteristicsTypical characteristics–– Support or sustain human lifeSupport or sustain human life–– Present a potentially unreasonable risk of Present a potentially unreasonable risk of

illness or injuryillness or injury

Ventricular assist devices, heart valves, Ventricular assist devices, heart valves, endovascular grafts, Stentsendovascular grafts, Stents

Class III: General Controls and Class III: General Controls and Premarket ClearancePremarket Clearance

Subject to general controlsSubject to general controlsRequire an approved premarket approval Require an approved premarket approval (PMA) application before commercial (PMA) application before commercial distributiondistribution

Approval for marketing (Class III):Approval for marketing (Class III):PMA ApplicationPMA Application

Required of all new Class III devicesRequired of all new Class III devicesPMA application: demonstrate safety and PMA application: demonstrate safety and effectiveness through:effectiveness through:–– Design validationDesign validation–– Manufacturing controlManufacturing control–– Performance testingPerformance testing–– Animal studiesAnimal studies–– Clinical trialsClinical trials

Label: Scientific JustificationLabel: Scientific Justification

DrugDrug–– Description (Chemical info)Description (Chemical info)–– PharmacologyPharmacology

»» Mechanism of action Mechanism of action »» PK, metabolismPK, metabolism

–– Clinical studiesClinical studies–– Indications and usageIndications and usage–– ContraindicationsContraindications–– PrecautionsPrecautions–– Warnings Warnings –– Adverse reactionsAdverse reactions–– OverdosageOverdosage–– Dosage and AdministrationDosage and Administration–– How suppliedHow supplied

DeviceDevice–– Device descriptionDevice description–– Indications for useIndications for use–– ContraindicationsContraindications–– Warnings Warnings –– PrecautionsPrecautions–– Summary of clinical studiesSummary of clinical studies–– Adverse events, potential Adverse events, potential

complicationscomplications–– Individualization of Individualization of

treatment (patient selection)treatment (patient selection)–– How suppliedHow supplied–– Operator instructionsOperator instructions–– Imaging, postImaging, post--op F/U, op F/U,

patient trackingpatient tracking

HOW?HOW?

Investigational Device Exemptions Investigational Device Exemptions (IDE)(IDE)

Purpose: Purpose: –– Promoting the public health: encourage Promoting the public health: encourage

discovery and development of devices useful discovery and development of devices useful for human usefor human use

–– Protecting the public healthProtecting the public health

IDE review: think in terms of a failure IDE review: think in terms of a failure modes and effects analysismodes and effects analysis

Investigational Device Investigational Device Exemptions (IDE)Exemptions (IDE)

Discovery and development of new devices Discovery and development of new devices requires exemption from the requirements requires exemption from the requirements that apply to devices in commercial that apply to devices in commercial distributiondistributionIDE regulation:IDE regulation:–– Encourages discovery and development of Encourages discovery and development of

devices consistent with protection of public devices consistent with protection of public health and safety and with ethical standardshealth and safety and with ethical standards


Conduct of a clinical investigation of a Conduct of a clinical investigation of a medical device requires approval under the medical device requires approval under the IDE regulationIDE regulationInvestigation: a clinical investigation or Investigation: a clinical investigation or research, which involves one or more research, which involves one or more subjects, to determine the safety or subjects, to determine the safety or effectiveness of a deviceeffectiveness of a device


IRB: responsible for determination of SR/NSRIRB: responsible for determination of SR/NSRNonNon--significant risk study: IRB approvalsignificant risk study: IRB approvalSignificant risk study: Significant risk study: –– IRB approval and approved IDE application IRB approval and approved IDE application

are required before study may beginare required before study may beginReferences/requirementsReferences/requirements–– http://www.fda.gov/cdrh/http://www.fda.gov/cdrh/–– Device adviceDevice advice

Development and ValidationDevelopment and Validation of Devices of Devices to Treat Vascular Diseaseto Treat Vascular Disease

Regulatory Science 400Regulatory Science 400

Device/Drug Development ProcessDevice/Drug Development Process

Pre-IDE IDE Pre-PMA PMA

Conception

Pre-clinicalFeasibility

Pre-clinical Testing

ClinicalFeasibility

Clinical Trial

DataCompilation/Formatting

Final Labeling

Market

Post-Market

Pre-IND IND Pre-NDA NDAIDE: Investigational Device Exemption

IND: Investigational New Drug

PMA: Pre-Market Approval

NDA: New Drug Application

PrePre--Market Development and Testing Market Development and Testing Requirements: Bench to BedsideRequirements: Bench to Bedside

Preclinical benchPreclinical bench–– Design criteriaDesign criteria–– Performance criteriaPerformance criteria–– Safety/failure modesSafety/failure modes

»» BiocompatibilityBiocompatibility»» ToxicologyToxicology»» BiomaterialsBiomaterials»» DurabilityDurability

Preclinical animal Preclinical animal --SafetySafety-- Failure modesFailure modes-- Predictive valuePredictive value

Clinical investigationClinical investigation--feasibilityfeasibility–– SafetySafety–– PerformancePerformance

Clinical investigationClinical investigation--pivotalpivotal–– Final product configurationFinal product configuration–– SafetySafety–– EffectivenessEffectiveness

PostPost--market studiesmarket studies–– SafetySafety–– EffectivenessEffectiveness

New and Emerging TechnologyNew and Emerging Technologye.g., Drug eluting implante.g., Drug eluting implant

What is new ?What is new ?a)a) The technology itselfThe technology itselfb)b) A component or biomaterial or coatingA component or biomaterial or coatingc)c) A combination of new technology with old A combination of new technology with old

technologytechnologyd)d) The benefit or riskThe benefit or riske)e) All of the aboveAll of the above

Total Product Life Cycle VisionTotal Product Life Cycle Vision

e.g., Druge.g., Drug--eluting implanteluting implant

How does the material perform How does the material perform in the device? (e.g., stent wear in the device? (e.g., stent wear characteristics)characteristics)Can failure modes be anticipated Can failure modes be anticipated from the design? (e.g., coating from the design? (e.g., coating biocompatibility )biocompatibility )

Failure modes analysisFailure modes analysisAre there Are there criticialcriticial performance performance specifications? (e.g., coating specifications? (e.g., coating thickness and elution profile)thickness and elution profile)

Early Product Life CycleEarly Product Life Cycle

Toxicology Toxicology /Immunogenicity//Immunogenicity/PharmacokineticsPharmacokinetics

-- What is already known ?What is already known ?-- Drug amount and elution Drug amount and elution

profile? profile? -- Standards: ISO, CDER, Standards: ISO, CDER,

CBER, CDRHCBER, CDRH-- Limitations of preclinical Limitations of preclinical

modelsmodels

Early Product Life CycleEarly Product Life Cycle

Clinical EvaluationClinical Evaluation–– With final manufactured With final manufactured

product or prototype ?product or prototype ?–– Least burdensome Least burdensome

source of clinical source of clinical evidence ?evidence ?

°° ControlsControls°° Questions to be left Questions to be left

for postmarketing for postmarketing period ?period ?

Mid Product Life CycleMid Product Life Cycle

Full Scale ManufacturingFull Scale Manufacturing–– Know your supplierKnow your supplier

°° Can you detect Can you detect changes in changes in componentscomponents

–– LiabilityLiability

Mid Product Life CycleMid Product Life Cycle

EndEnd--ofof--Life ProblemsLife Problems–– Customer complaintsCustomer complaints–– User ErrorsUser Errors–– Product FailuresProduct Failures

°° PostPost--market failure market failure modes analysismodes analysis

Late Product Life CycleLate Product Life Cycle

PremarketPremarket PostmarketPostmarket

Product Life CycleProduct Life Cycle

Regulatory CycleRegulatory Cycle

Science CycleScience Cycle

LumenLumen

MuscleMuscle

LesionLesion

Preclinical TrialsPreclinical Trials Clinical TrialsClinical Trials

Developing Technologies for the Developing Technologies for the Treatment of Cardiovascular DiseaseTreatment of Cardiovascular Disease

PrePre--MarketMarket

Purpose of Preclinical TrialsPurpose of Preclinical Trials

Provision of reasonable evidence of safety Provision of reasonable evidence of safety (effectiveness) prior to human clinical trial(effectiveness) prior to human clinical trialModel selection is critical Model selection is critical -- in vivo feasibility (define or refine a in vivo feasibility (define or refine a

modelmodel……refine the technology) refine the technology) -- in vivo safety and effectiveness (S&E) (refine in vivo safety and effectiveness (S&E) (refine

technology, S&E studytechnology, S&E study))

AtheromaAtheroma

Evaluative ToolsEvaluative Tools

Failure Modes/SignalsFailure Modes/SignalsPredictive ModelsPredictive Models

Methods DevelopmentMethods Development

Coronary Coronary RestenosisRestenosis

Coronary Ischemia

RegulatoryRegulatory--BasedBasedTranslationalTranslational

ResearchResearch

Sample Study EndpointsSample Study EndpointsHemodynamic ChangesHemodynamic Changes

Vasospasm Vasospasm HemorrhageHemorrhage

Thrombosis (early and late) Thrombosis (early and late) Inflammatory ResponseInflammatory Response

Progression of Underlying DiseaseProgression of Underlying DiseaseHealing: Vascular Remodeling Healing: Vascular Remodeling Patency: Stenosis/Restenosis Patency: Stenosis/Restenosis

Cardiovascular Interventional Device Cardiovascular Interventional Device Performance and Performance and Failure Mode sFailure Mode sLL

Preclinical Evaluation ToolsPreclinical Evaluation Tools

ImagingImagingHistologyHistologyMorphometryMorphometryImmunohistochemistryImmunohistochemistry…………………………..and beyond..and beyond

Angioplasty BalloonsAngioplasty Balloons

19771977 20102010

StentsStents

Landscape: CatheterLandscape: Catheter--Based Interventional Based Interventional Devices for the Treatment of Vascular DiseaseDevices for the Treatment of Vascular Disease

PrePre--Intervention: Swine CoronaryIntervention: Swine CoronaryThe Standard ApproachThe Standard Approach

InterventionIntervention

Stent

Coronary Stent PlacementCoronary Stent Placement

EvaluationEvaluation

ExplantExplant: Gross and Radiographic Follow: Gross and Radiographic Follow--UpUp

Stent

Marked Restenosis

Thrombosis

Smooth Luminal Surface

Failure Modes/Signals Failure Modes/Signals

Inflammation

Morphometric &Morphometric & Morphologic EvaluationMorphologic Evaluation

Restenosis Vessel Area

LumenArea

Stenosis( Intimal Area = Intimal Hyperplasia)

Media

ExplantExplant HistologyHistology

Vessel Vessel AreaAreaLumenLumen

AreaArea

No measurable Intimal AreaNo measurable Intimal Area

MediaMediaInternal elastic laminaInternal elastic lamina

LumenLumenAreaArea

NormalNormal

Human Failure Mode:Human Failure Mode: RestenosisRestenosis


19771977

DESDES

20102010

StentsStents

CatheterCatheter--Based Interventional Devices for the Based Interventional Devices for the Treatment of Vascular Disease: LDDTreatment of Vascular Disease: LDD

MaterialMaterial

Drug + CarrierDrug + Carrier

Combination ProductsCombination ProductsMultiple Component Approach to DrugMultiple Component Approach to Drug--Device DesignDevice Design

Treatment Approaches Treatment Approaches StenosisStenosis and and RestenosisRestenosis

AntiAnti--IInflammatorynflammatoryImmunomodulatorsImmunomodulators

DexamethasoneDexamethasone

MM--prednisoloneprednisolone

Interferon Interferon γγ--1b1b

LeflunomideLeflunomide

SirolimusSirolimus

TacrolimusTacrolimus

Everolimus Everolimus

Mycophenolic acid Mycophenolic acid

MizoribineMizoribine

CyclosporineCyclosporine

TranilastTranilast

AntiAnti--PProliferativeroliferative

TaxolsTaxols

Actinomycin Actinomycin

MethothrexateMethothrexate

AngiopeptinAngiopeptin

VincristineVincristine

MitomycineMitomycine

StatinsStatins

C MYC antisenseC MYC antisense

Abbott ABTAbbott ABT-- 578578

RestenASERestenASE

22--chlorochloro--deoxyadenosinedeoxyadenosine

PCNA PCNA RibozymeRibozyme

Migration InhibitorsMigration InhibitorsECMECM--ModulatorsModulators

BatimastatBatimastat

ProlylProlyl hydroxyls hydroxyls inhibitorsinhibitors

HalofuginoneHalofuginone

CC--proteinaseproteinaseinhibitorsinhibitors

ProbucolProbucol

Promote Healing Promote Healing & & ReRe--EndothelializationEndothelialization

BCP671BCP671

VEGFVEGF

EstradiolsEstradiols

NO donorsNO donors

EPC antibodiesEPC antibodies

BiorestBiorest

Advanced coatingsAdvanced coatings

StentStent

Drug Drug

CarrierCarrier


A PostA Post--Market Signal Market Signal with Drug Eluting Stentswith Drug Eluting Stents

Delayed HealingDelayed Healing

InflammationInflammationThrombosisThrombosis

Courtesy of Courtesy of RenuRenu VirmaniVirmani, , CVPathCVPath

LESSONLESSON

The Science of Evaluating Combination ProductsThe Science of Evaluating Combination Products

The combination of a biologic or drug with a The combination of a biologic or drug with a medical device for the therapeutic treatment of medical device for the therapeutic treatment of disease raises new scientific and technical issues disease raises new scientific and technical issues such as the potential for complex tissue interactions such as the potential for complex tissue interactions which may result in unanticipated hazardswhich may result in unanticipated hazards

Do Preclinical Failure Modes & Signals Do Preclinical Failure Modes & Signals Predict Human Adverse Events?Predict Human Adverse Events?

Laboratory for ImageLaboratory for Image--Guided StudiesGuided Studies

DrugsDrugsDevicesDevices Database SubsetsDatabase SubsetsAnimal Animal –– HumanHumanIn vivo imagingIn vivo imagingExplantExplant imagingimagingAnalysis Analysis

Intra‐ Extra‐Cranial

Celiac

Mesenteric

Renal

Abdominal Aorta

Iliac

Popliteal

Tibial

Coronary

Thoracic Aorta

Subclavian and Foreleg

Carotid

Femoral

Target Vessel

Valves

Case Study: Stent Fracture and Wear

Failure modesFailure modesRestenosisRestenosisMalappositionMalappositionFractureFractureInflammationInflammation

Modeling Implant Environment

Failure Mode: Loss of Stent IntegrityFailure Mode: Loss of Stent Integrity

Chowdhurdy and Renato, N Engl J Med, (3478, August 22, 2002

Brita et al, ACC 2008

FractureFracture

CorrosionCorrosion

Treatment of Human SFA diseaseTreatment of Human SFA disease

USUHS, USUHS, MedPixMedPix

courtesy of Dr. C. Bonsignorecourtesy of Dr. C. Bonsignore

Clinical Lesson: SIROCCO TrialClinical Lesson: SIROCCO Trial

The ProblemThe Problem……Human Human explantexplant data suggests evidence of mechanical & data suggests evidence of mechanical & chemical corrosion chemical corrosion in vivoin vivoLimited data forLimited data for–– Prevalence of fracture Prevalence of fracture in vivoin vivo–– Fracture modeFracture mode–– Design, configuration and site specificityDesign, configuration and site specificity

Objective: To investigate the mechanisms by which Objective: To investigate the mechanisms by which stents fracturestents fracture–– Effects of single Effects of single vsvs overlapping dissimilar stentsoverlapping dissimilar stents–– Associations with site and arterial deformationsAssociations with site and arterial deformations

Longitudinal Imaging of Stent Integrity Longitudinal Imaging of Stent Integrity Delivery

ExplantExplant180 days180 days90 days90 days

0 days 30 days30 days30 days 60 days60 days

Stainless Steel (SS)Stainless Steel (SS)Nitinol (Nitinol (NiTiNiTi))

Implant*Implant*

*OL *OL -- NiTiNiTi implanted implanted first and SS stent implanted proximally with target overlap lengfirst and SS stent implanted proximally with target overlap length of 6mmth of 6mm

Stent Stent Fracture RateFracture Rate Across Implant SiteAcross Implant Site

FemoralFemoralCoronaryCoronary50%50% 100%100%

OverlappingOverlapping SingleSingle OverlappingOverlapping SingleSingle75%75% 0%0% 100%100% 100%100%

SS StentsSS Stents75%75%

•• No stent fractures in No stent fractures in NiTiNiTi stentsstents

LADLAD RFCARFCA

Vascular Geometry and Implant Performance:Vascular Geometry and Implant Performance:

Animal vs. HumanAnimal vs. Human

Vascular Motion and DeformationVascular Motion and DeformationStent Design, Implant Configuration and Implant SiteStent Design, Implant Configuration and Implant Site

ImageImage--Based Interventional StudiesBased Interventional StudiesImproved ModelingImproved Modeling–– Bedside: animal to humanBedside: animal to human–– ComputationalComputational

Vascular DeformationVascular DeformationToeToe

Head

Head

MeasuresMeasures

ForcesForces AnimalAnimal

HumanHuman

Coronary Coronary vsvs Femoral Motion Femoral Motion Angiograms in SwineAngiograms in Swine

Evaluation of vascular motion and geometric deformation Evaluation of vascular motion and geometric deformation

Human Model: Bending the Human Model: Bending the StentedStented LegLeg

courtesy Dr. Jeancourtesy Dr. Jean--Paul BeregiPaul Beregi

Human Femoral Arteries: DeformationHuman Femoral Arteries: DeformationSupineSupine Fetal PositionFetal Position

courtesy of Chris Chengcourtesy of Chris Cheng

vs. Swine Femoral Arteriesvs. Swine Femoral Arteries

Image Image Acquisition Acquisition

Image Image Enhancement & Enhancement &

ProcessingProcessing

Image Image Segmentation of Segmentation of

VasculatureVasculature

Geometric Geometric Model Model

ConstructionConstruction

Geometric & Geometric & Kinematic Kinematic AnalysisAnalysis

Computational Computational ModelingModeling

ImageImage--Based Modeling of Vascular CharacteristicsBased Modeling of Vascular CharacteristicsAnimalAnimal--Human: Human: AortoAorto--IliacIliac

Bedside Quantification and Modeling Simulation

2D 3D Solid Model Data2D 3D Solid Model Data

27.5 27.5 ±± 4.84.897.4 97.4 ±± 12.312.3--6.5 6.5 ±± 1.11.11. Abdominal1. AbdominalAortaAorta

+112.2 +112.2 ±± 4.94.90.46 0.46 ±± 0.060.06--5.37 5.37 ±± 0.21 0.21 ((--25.8 25.8 ±± 0.8)0.8)

IlioIlio--FemFem--Pop (1Pop (1--5)5)

+13.0 +13.0 ±± 13.813.80.17 0.17 ±± 0.030.03--10.1 10.1 ±± 0.70.76. Proximal 6. Proximal PoplitealPopliteal

+26.0 +26.0 ±± 3.03.058.0 58.0 ±± 7.87.8--31.9 31.9 ±± 1.01.05. Distal5. DistalFemoralFemoral

+68.3 +68.3 ±± 8.08.067.7 67.7 ±± 2.22.2--26.2 26.2 ±± 3.03.04. Middle 4. Middle FemoralFemoral

--4.9 4.9 ±± 2.52.566.4 66.4 ±± 5.45.4--33.2 33.2 ±± 0.80.83. Proximal 3. Proximal FemoralFemoral

27.5 27.5 ±± 4.84.887.5 87.5 ±± 36.036.0--11.8 11.8 ±± 2.32.32. Iliac2. Iliac

Axial TwistAxial Twist°°Curvature Curvature

Change,Change, cmcm--1 1

(% change)(% change)

Axial Axial length, cmlength, cm(% change)(% change)

Arterial Arterial SegmentSegment

Geometric model and vascular deformation of Geometric model and vascular deformation of aortoaorto--iliaciliac--femfem--pop pop vessel in extended and flexedvessel in extended and flexed positionposition

Extended Flexed

90% increase in peak curvature 90% increase in peak curvature from extension to flexionfrom extension to flexion

Geometric Model of Geometric Model of AortoAorto--Iliac Artery Curvature Iliac Artery Curvature

0

1

Norm

alized Curvature

Renal branch points

Aorta

Iliac

Extended

Flexed

0.2

0.4

0.6

0.8

1

30

210

60

240

90

270

120

300

150

330

180 0

0.2

0.4

0.6

0.8

1

30

210

60

240

90

270

120

300

150

330

180 0

Elevation Angle (+81%)Elevation Angle (+81%) Separation Angle (Separation Angle (--17%)17%)

ExtendedExtended

TorquedTorqued

Changes in Elevation and Separation Angle Between Iliacs Changes in Elevation and Separation Angle Between Iliacs from Extension to Flexed&Torqued Positionfrom Extension to Flexed&Torqued Position

(Cartesian plots)(Cartesian plots)

Norm

alized Curvature

Geometric Model of Right IliacGeometric Model of Right Iliac--Femoral Artery Curvature Femoral Artery Curvature

Extended

Flexed2

4

2

5

3

High CurvatureHigh Curvature

Norm

alized Curvature

Image Image Acquisition Acquisition

Image Image Enhancement & Enhancement &

ProcessingProcessing

Image Image Segmentation of Segmentation of

VasculatureVasculature

Geometric Geometric Model Model

ConstructionConstruction

Geometric & Geometric & Kinematic Kinematic AnalysisAnalysis

Computational Computational ModelingModeling

Bedside Quantification and Modeling Simulation

2D 3D Solid Model Data2D 3D Solid Model Data

ImageImage--Based Modeling of Vascular CharacteristicsBased Modeling of Vascular CharacteristicsAnimalAnimal--Human: Human: Coronary Coronary

Coronary (LAD) Geometric Deformation Coronary (LAD) Geometric Deformation Swine: Systole vs. DiastoleSwine: Systole vs. Diastole

34 34 °°--72%72%--5.7%5.7%33

--43 43 °°NSNS2.7%2.7%22

17 17 °°--145%145%2.7%2.7%11

25 25 °°--145%145%--2%2%66

Axial TwistAxial Twist°°Curvature Change, cmCurvature Change, cm--1 1

(% change)(% change)Axial length, cmAxial length, cm

(% change)(% change)SegmentSegment

Coronary line pathsCoronary line paths

11

22

33

Solid model Solid model curvagramcurvagram -- End diastole End diastole

66

Segmentation of coronary vesselsSegmentation of coronary vessels Line pathsLine paths

SystoleSystole

DiastoleDiastole

Coronary CTA and Geometric ModelCoronary CTA and Geometric ModelHuman: Systole vs. DiastoleHuman: Systole vs. Diastole

Coronary (LAD) Geometric Deformation Coronary (LAD) Geometric Deformation Human: Systole vs. DiastoleHuman: Systole vs. Diastole

1414°°-- 18.2%18.2%--10.7%10.7%33

--49 49 °°-- 100.0%100.0%12.1%12.1%22

nsns-- nsns--19.3%19.3%11

2 2 °°--79.6% 238.5%79.6% 238.5%--7.4%7.4%66

Axial TwistAxial Twist°°Curvature Change, cmCurvature Change, cm--1 1 TortuosityTortuosity(% change) (% change)(% change) (% change)

Axial length, cmAxial length, cm(% change)(% change)SegmentSegment

Coronary line pathsCoronary line paths Solid model Solid model curvagramcurvagram

LAD LAD RCA

RCA

LCxLCx

LAD LAD RCA

RCA LCxLCx

Norm

alized Curvature

Coronary (LAD) Model Coronary (LAD) Model Swine vs. Human at Systole and DiastoleSwine vs. Human at Systole and Diastole

CurvatureCurvature

*Normalized to maximum curvature = highest human curvature at systole

Swine Human

Diastole

Proximal end

Impact of Vascular Motion and DeformationImpact of Vascular Motion and Deformation

Implant DesignImplant Design

Implant Configuration Implant Configuration

Implant SiteImplant Site

StentedStented Swine Femoral Motion AngiogramSwine Femoral Motion Angiogram

125.6 125.6 ±± 10.710.7+166.9 +166.9 ±± 18.118.1--39.739.7 ±± 2.32.3NativeNative

147.4 147.4 ±± 18.118.1+55.5 +55.5 ±± 66--15.4 15.4 ±± 4.44.4StentedStented

Axial TwistAxial Twist°°Curvature Change,Curvature Change, cmcm--1 1

(% change)(% change)Axial length, cmAxial length, cm

(% change)(% change)CohortCohort

XX Represent high flexion pointsRepresent high flexion points

Geometric ModelGeometric Model Of Native And Of Native And StentedStentedSwine Femoral Curvature In Flexed PositionSwine Femoral Curvature In Flexed Position

Supine position

35 °

88 °

Bent position

Translational Modeling and TestingTranslational Modeling and TestingRecommendations for Implant StudiesRecommendations for Implant Studies……

cour

tesy

Dr.

Chr

isto

pher

Che

ngco

urte

sy D

r. C

hris

toph

er C

heng

A. Swine

. Human

BenchBench ComputationalComputational BedsideBedside

0

1

cour

tesy

Dr.

Chr

isto

pher

Che

ngco

urte

sy D

r. C

hris

toph

er C

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CoronaryCoronaryFemoralFemoral

AortoAorto--iliaciliacCoronary (LAD)Coronary (LAD)

HumanHuman

SwineSwineSwineSwine


19771977

Infusion CathetersInfusion Catheters

DIBDIB

DEBDEBMICMIC

DrugDrug--Eluting BalloonsEluting Balloons

SFICSFIC

DESDES

20102010

StentsStents

CatheterCatheter--Based Interventional Devices for the Based Interventional Devices for the Treatment of Vascular Disease: LDDTreatment of Vascular Disease: LDD

CatheterCatheter--Based Local Drug Delivery Based Local Drug Delivery The DevicesThe Devices

Drug Eluting Stents (DES)Drug Eluting Stents (DES)CatheterCatheter--Based (Based (ieie, non, non--implant based)implant based)

Drug Infusion Balloons (DIB)Drug Infusion Balloons (DIB)Micro Infusion Catheters (MIC)Micro Infusion Catheters (MIC)Stop Flow Infusion Catheters (SFIC)Stop Flow Infusion Catheters (SFIC)Drug Eluting Balloons (DEB)Drug Eluting Balloons (DEB)

Vascular WrapsVascular WrapsDrugs may be delivered Drugs may be delivered

SystemicSystemicLuminalLuminalIntimalIntimalAdventitialAdventitial

Is safety and efficacy delivery modeIs safety and efficacy delivery mode-- and siteand site--dependent?dependent?

• Delivery efficiency

• Site of administration

• Ease of use

Devic

e Ch

arac

teris

tics

•• Physicochemical properties

• Diffusivity in specific tissues

• Therapeutic index

• Dose (formulation, IC50)

• Administration (number, location)Drug

Characteristics

•• Anatomic structure (→ PK)

• Geometry

• Existing pathology

Vessel Characteristics

Catheter-Based Local Drug DeliveryDeterminants of Safety and Efficacy

Devic

e Ch

arac

teris

tics

Drug

Characteristics

Vessel Characteristics

Devic

e

Vessel

Drug

Prevent RestenosisStab

ilize

Lesio

ns

Disease Regression

Safety&

Efficacy

Modeling CatheterModeling Catheter--Based Local Drug Delivery Based Local Drug Delivery PK and DrugPK and Drug--Induced Vascular/Tissue Injury (DIVI/DITI)Induced Vascular/Tissue Injury (DIVI/DITI)

Case Study: Drug Infusion CathetersCase Study: Drug Infusion Catheters

Karanian et al, JVIR 2010;Karanian et al, JVIR 2010;Karanian et al Karanian et al CardiovascCardiovasc RevascRevasc Med 11(4), 2010Med 11(4), 2010

Evaluation of Local Drug DeliveryEvaluation of Local Drug Delivery

Comparison of delivery technologiesComparison of delivery technologiesComparison of vascular bedsComparison of vascular bedsSafety (PK, device safety/failure modes)Safety (PK, device safety/failure modes)ReliabilityReliabilityEffectivenessEffectivenessToward more predictive animal modelsToward more predictive animal models

Karanian et al, J Vasc Interv Radiol, 21(9), 2010Karanian et al, J Vasc Interv Radiol, 21(9), 2010

DrugDrug

Modes of Delivery: Infusion CathetersModes of Delivery: Infusion Catheters

Drug Infusion Balloons (DIB)Drug Infusion Balloons (DIB)Micro Infusion Catheters (MIC)Micro Infusion Catheters (MIC)Stop Flow Infusion Catheters (SFIC)Stop Flow Infusion Catheters (SFIC)

MICMIC

SFICSFIC DIBDIB

ArteryArtery

The Pharmacokinetics of AntiThe Pharmacokinetics of Anti--Proliferative DrugsProliferative DrugsFrom CatheterFrom Catheter--Based Local Drug Delivery SystemsBased Local Drug Delivery Systems

What are the determinants of safety and efficacy?What are the determinants of safety and efficacy?

Coronary (LAD) marker distribution (log Coronary (LAD) marker distribution (log scale) showing the disparity (> 2 orders of scale) showing the disparity (> 2 orders of magnitude) between the adventitial magnitude) between the adventitial (black) and the intimal (gray) and (black) and the intimal (gray) and luminal delivery (white). A bellluminal delivery (white). A bell--shaped shaped distribution pattern is more apparent for distribution pattern is more apparent for the adventitial than for the intimal or the adventitial than for the intimal or luminal delivery method (p<0.001). luminal delivery method (p<0.001).

Coronary marker distribution following Coronary marker distribution following luminal, intimal and adventitial delivery. luminal, intimal and adventitial delivery. All values were normalized to total DPM All values were normalized to total DPM detected in each coronary (LAD) section to detected in each coronary (LAD) section to allow for comparison of the longitudinal allow for comparison of the longitudinal distribution pattern along the blood vessel.distribution pattern along the blood vessel.

Karanian et al, J Vasc Interv Radiol, 21(9), 2010Karanian et al, J Vasc Interv Radiol, 21(9), 2010

Efficiency of Drug Delivery to the Coronary Arteries in Swine Efficiency of Drug Delivery to the Coronary Arteries in Swine is Dependent on the Route of Administrationis Dependent on the Route of Administration

Assessment of luminal, intimal and adventitial coronary artery dAssessment of luminal, intimal and adventitial coronary artery delivery methodselivery methods

0.001%

0.010%

0.100%

1.000%

10.000%

100.000%

P3 P2 P1 Inj slice D1 D2 D3 D4

Adventitial (MIC‐A)

Luminal (MIC‐NA)

Intimal (DIB)

0%10%20%30%40%50%60%70%80%90%

100%

P3 P2 P1 Inj slice D1 D2 D3 D4

Adventitial (MIC-A)

Luminal (MIC-NA)

Intimal (DIB)

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.

Coronary (LAD) Femoral A. Carotid A.Renal A.

PharmacoPharmaco--Image of Surrogate Drug Marker Across Coronary Image of Surrogate Drug Marker Across Coronary and Peripheral Arteries Following Adventitial Delivery (MIC)and Peripheral Arteries Following Adventitial Delivery (MIC)

Comparison of Surrogate Drug Marker Retention Across Comparison of Surrogate Drug Marker Retention Across Arteries Following Adventitial Delivery (MIC)Arteries Following Adventitial Delivery (MIC)

All values were determined as a percentage of the control sample from each delivery

Sample Detected Across Four Major Arteries(Percent of Respective Controls)

0%

20%

40%

60%

80%

100%

Coronary (LAD) Renal Femoral Carotid

Perc

ent D

ose

Det

ecte

d ±

SEM

Reported AntiReported Anti--Restenotics: Safety & EfficacyRestenotics: Safety & Efficacy

AntiAnti--IInflammatorynflammatoryImmunomodulatorsImmunomodulators

DexamethasoneDexamethasone

MM--prednisoloneprednisolone

Interferon Interferon γγ--1b1b

LeflunomideLeflunomide

SirolimusSirolimus

TacrolimusTacrolimus

Everolimus Everolimus

MycophenolicMycophenolic acid acid

MizoribineMizoribine

CyclosporineCyclosporine

TranilastTranilast

AntiAnti--PProliferativeroliferative

QPQP--22

PaclitaxelPaclitaxel (PTX)(PTX)ActinomycinActinomycin

MethothrexateMethothrexate

AngiopeptinAngiopeptin

VincristineVincristine

MitomycineMitomycine

StatinsStatins

C MYC antisenseC MYC antisense

Abbott ABTAbbott ABT-- 578578

RestenASERestenASE

22--chlorochloro--deoxyadenosinedeoxyadenosine

PCNA PCNA RibozymeRibozyme

Migration InhibitorsMigration InhibitorsECMECM--ModulatorsModulators

BatimastatBatimastat

ProlylProlyl hydroxyls hydroxyls inhibitorsinhibitors

HalofuginoneHalofuginone

CC--proteinaseproteinaseinhibitorsinhibitors

ProbucolProbucol

Promote Healing Promote Healing & & ReRe--endothelializationendothelialization

BCP671BCP671

VEGFVEGF

EstradiolEstradiol

NO donorsNO donors

EPC antibodiesEPC antibodies

BiorestBiorest

Advanced coatingsAdvanced coatings

Safety: DIVI/DITISafety: DIVI/DITI

PaclitaxelPaclitaxel (PTX) Across Delivery Method and Vessel(PTX) Across Delivery Method and Vessel

IVIV

MICMICSFICSFIC

MICMIC

Delivery Delivery MethodMethod

50 mg50 mg50 mg50 mgSystemic Systemic DoseDose

PTX PTX DosesDoses

CoronaryCoronary(0.3 ml)(0.3 ml)

PeripheralPeripheral(1.5 ml)(1.5 ml)

Low DoseLow Dose 10 10 μμg in 0.3 mlg in 0.3 ml 50 50 μμg in 1.5 mlg in 1.5 ml

High DoseHigh Dose 100 100 μμg in 0.3 mlg in 0.3 ml 500 500 μμg in 1.5 mlg in 1.5 ml

MIC: MicroMIC: Micro--infusion infusion catherercathererSFIC: Stop flow infusion catheterSFIC: Stop flow infusion catheter

IV: IntraIV: Intra--venousvenous

1Hr Coronary PTX Levels 1Hr Coronary PTX Levels (vessel segment: cm, negative=proximal, 0=center, positive=dista(vessel segment: cm, negative=proximal, 0=center, positive=distal)l)

Karanian et al, Karanian et al, CardiovascCardiovasc RevascRevasc Med 11(4), 2010Med 11(4), 2010

Delivery: Adventitial (MIC)Delivery: Adventitial (MIC) Adventitial (MIC) Intimal (SFIC)Adventitial (MIC) Intimal (SFIC) IVIVDose: 10ug Dose: 10ug 100ug 100ug 100ug100ug 50mg50mg

Pacl

itaxe

l con

cent

ratio

n in

cor

onar

y ar

terie

s (lo

gM) a

fter d

eliv

ery

of 0

.3 m

l to

coro

nary

ar

terie

s or

sys

tem

ic IV

dos

e

3D Coronary PTX Levels 3D Coronary PTX Levels (vessel segment: cm, negative=proximal, 0=center, positive=dista(vessel segment: cm, negative=proximal, 0=center, positive=distal)l)


Pacl

itaxe

l con

cent

ratio

n in

cor

onar

y ar

teri

es (

Pacl

itaxe

l con

cent

ratio

n in

cor

onar

y ar

teri

es ( l

ogM

logM

) )

afte

r th

e de

liver

y of

1.5

ml t

o ar

tery

afte

r th

e de

liver

y of

1.5

ml t

o ar

tery

Delivery: Adventitial (MIC)Delivery: Adventitial (MIC) Adventitial (MIC) Adventitial (MIC) Intimal (SFIC)Intimal (SFIC)Dose: 10ug Dose: 10ug 100ug 100ug 100ug100ug

Pacl

itaxe

l Con

cent

ratio

n in

cor

onar

y ar

terie

s (

Pacl

itaxe

l Con

cent

ratio

n in

cor

onar

y ar

terie

s ( lo

gMlo

gM))

(afte

r del

iver

y of

1.5

ml t

o ar

tery

)(a

fter d

eliv

ery

of 1

.5 m

l to

arte

ry)

PTX Retention in Coronary and Femoral PTX Retention in Coronary and Femoral 1Hr to 3D1Hr to 3D

Retention in Coronary Artery (% of drug delivered)

0.0001%

0.0010%

0.0100%

0.1000%

1.0000%

10.0000%

100.0000%

1 hour 3 days

Retention in Femoral Artery (% of drug delivered)

0.0001%

0.0010%

0.0100%

0.1000%

1.0000%

10.0000%

100.0000%

1 hour 3 days

50ug Adventitial (MIC)


500ug Intimal (SFIC)

IV DOSE

Dose: Delivery Mode



50ug Intimal (SFIC)

IV DOSE

Dose: Delivery Mode

CoronaryCoronary Femoral Femoral

Stop FlowStop FlowInfusion Catheter Infusion Catheter ((SFIC:AccrotekSFIC:Accrotek ))

Systemic IV Systemic IV Delivery Delivery

Low Dose Low Dose High Dose High Dose High Dose High Dose Systemic Dose Systemic Dose

CoronaryCoronary 1.11 1.11 ±± 0.21 0.21 13.2 13.2 ±± 4.8 4.8 1.65 1.65 ±± 0.46 0.46 0.46 0.46 ±± 0.07 0.07

Peripheral Peripheral 10.3 10.3 ±± 1.7 1.7 46.0 46.0 ±± 15.3 15.3 1.43 1.43 ±± 0.31 0.31 0.19 0.19 ±± 0.02 0.02

CoronaryCoronary 0.12 0.12 ±± 0.03 0.03 0.19 0.19 ±± 0.03 0.03 0.20 0.20 ±± 0.050.05

Peripheral Peripheral 0.97 0.97 ±± 0.180.18 1.49 1.49 ±± 0.680.68 0.34 0.34 ±± 0.08 0.08

* Average * Average ±±SEM of all segments in 5cm range. Color coding based on literatuSEM of all segments in 5cm range. Color coding based on literature interpretation.re interpretation.

Micro Infusion CatheterMicro Infusion Catheter(MIC: (MIC: Mercator Mercator MedSystemsMedSystems))

Paclitaxel Paclitaxel Concentration Concentration ((µµ M) in Artery M) in Artery Wall at 1 hour Wall at 1 hour

Paclitaxel Paclitaxel Concentration Concentration ((µµ M) in Artery M) in Artery Wall at 3 days Wall at 3 days

PK Summary*PK Summary*


Therapeutic ValuesTherapeutic Values

Representative 3Representative 3--Day Histological Results Day Histological Results Following Adventitial PTX DeliveryFollowing Adventitial PTX Delivery

Focal features includedFocal features included•• Minor InflammationMinor Inflammation•• Minor fibrin depositionMinor fibrin deposition•• Moderate hemorrhageModerate hemorrhage

Control Control High DoseHigh Dose

(50ug)(50ug)Low DoseLow Dose

(10ug)(10ug)

Coronary Coronary

Femoral Femoral

Control Control High DoseHigh Dose(500ug)(500ug)

Low DoseLow Dose(50ug)(50ug)

Study Conclusion Study Conclusion PTX Local Drug DeliveryPTX Local Drug Delivery

Markedly more efficient and localized drug Markedly more efficient and localized drug retention along the femoral and coronary retention along the femoral and coronary artery following adventitial delivery artery following adventitial delivery compared to intimal delivery methods.compared to intimal delivery methods.

Minimal Minimal histologichistologic changes 3 days after low changes 3 days after low and high dose delivery.and high dose delivery.

Local Drug Delivery (Infusion Model): S&ELocal Drug Delivery (Infusion Model): S&E

Drug

Safety & EfficacySafety & Efficacy-- Delivery method dependentDelivery method dependent-- Site specific?Site specific?-- Drug specific?Drug specific?

EfficiencyEfficiency-- Agents delivered to outside of artery diffuse Agents delivered to outside of artery diffuse

circumferentially, longitudinally, circumferentially, longitudinally, transmurallytransmurally-- Lower loading dose and greater retention Lower loading dose and greater retention

possible with infusion possible with infusion of of lipophiliclipophilic drugsdrugs Artery

Impact and BeyondImpact and BeyondThe R&D PerspectiveThe R&D Perspective

Reproducible Reproducible in vivoin vivo model of highly localized model of highly localized surrogate/drug delivery for PK/PD studies.surrogate/drug delivery for PK/PD studies.

Evaluation of drug, device and combination therapy Evaluation of drug, device and combination therapy safety for key antisafety for key anti--restenotic drug.restenotic drug.

Demonstration of highly localized administration and Demonstration of highly localized administration and reduced systemic exposure associated with adventitial reduced systemic exposure associated with adventitial delivery that should minimize toxicity and provide delivery that should minimize toxicity and provide controlled dosing with increased therapeutic value.controlled dosing with increased therapeutic value.

Development of a delivery method with potential Development of a delivery method with potential impact on revascularization rates.impact on revascularization rates.

S&E testing (bench and animal)S&E testing (bench and animal)–– Predictive testsPredictive tests–– Predictive biomarkersPredictive biomarkers–– Translation to humansTranslation to humans

Identify and qualify S&E biomarkers for Identify and qualify S&E biomarkers for regulatory decision making regulatory decision making

Preclinical GoalsPreclinical Goals–– Match or outperform gold standards Match or outperform gold standards –– Succeed at predicting failure Succeed at predicting failure –– Enable technology developmentEnable technology development

Dev

elop

men

t Pro

cess

Dev

elop

men

t Pro

cess

SummarySummary

The Challenge for All StakeholdersThe Challenge for All StakeholdersPrePre--market premarket pre--clinical work that leads to technology changesclinical work that leads to technology changes

You are here in Charlottesville, You are here in Charlottesville, VaVa We are here in Laurel, MDWe are here in Laurel, MD

USFDA, CDRH, USFDA, CDRH, OSElOSEl, Laboratory of Cardiovascular and Interventional Therapeutics, Laboratory of Cardiovascular and Interventional [email protected]@cdrh.fda.gov

Thank Thank You!You!

William Pritchard, William Pritchard, MD,PhDMD,PhD

Alberto Alberto ChiesaChiesa, , DVM,PhDDVM,PhD

Brad Wood, MD (NIH)Brad Wood, MD (NIH)

Orlando Lopez, PhDOrlando Lopez, PhD

Mark Mark KreitzKreitz, PhD , PhD

RenuRenu VirmaniVirmani, MD (, MD (CVPathCVPath))

Peter Davies, PhD (UPENN)Peter Davies, PhD (UPENN)

Nadine Nadine AbiAbi JaudehJaudeh, MD (NIH), MD (NIH)

Mathew Mathew DreherDreher, PhD (NIH), PhD (NIH)

Karun Sharma, MD (NIH)Karun Sharma, MD (NIH)

Juan EsparzaJuan Esparza

SrinidhiSrinidhi NagarajaNagaraja, PhD, PhD

Maureen Maureen DreherDreher, PhD, PhD

JafarVossoughiJafarVossoughi, PhD, PhD

Dena Dena RadRad

Briana McDowellBriana McDowell

Ryan Ryan HaugheyHaughey

David Woods David Woods

Laboratory of Cardiovascular and Interventional TherapeuticsLaboratory of Cardiovascular and Interventional Therapeutics

John W John W KaranianKaranian, PhD, [email protected]@cdrh.fda.gov

Preclinical Testing Considerations - Biomedical …bme.virginia.edu/FDA/John Karanian MD-TIP UVA...

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