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Transcript
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 How does the material perform in the device? (e.g., stent wear characteristics) Can failure modes be anticipated from the design? (e.g., coating biocompatibility ) Failure modes analysis Are there criticial performance specifications? (e.g., coating thickness and elution profile) Early Product Life Cycle Toxicology /Immunogenicity/ Pharmacokinetics - What is already known ? - Drug amount and elution profile? - Standards: ISO, CDER, CBER, CDRH - Limitations of preclinical models Mid Product Life Cycle 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 Full Scale Manufacturing – Know your supplier ° Can you detect changes in components – Liability Late Product Life Cycle 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 Drug Eluting Stents (DES) Catheter-Based (ie, non-implant based) Drug Infusion Balloons (DIB) Micro Infusion Catheters (MIC) Stop Flow Infusion Catheters (SFIC) Drug Eluting Balloons (DEB) Vascular Wraps 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