Tina M. Morrison, Ph.D.Advisor, Computational Modeling
Office of Device Evaluation
CDRH/U.S. FDA
Regulatory Science
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The science of developing new tools, standards,and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated productso Benefits patients by speeding the rate of
important technologies reaching marketo Reduces time and resources needed for device
development, assessment, and review. For example:
• Can lead to quicker, more efficient device approvals
• Can decrease the size and duration of pre-market clinical trials
Faster, Cheaper, SaferFDA Strategic Plan, August 2011Advancing Regulatory Science at FDA
What is Modeling and Simulation?
Modeling refers to the development of a mathematical representation of a physical/chemical/biological reality‐of‐interest
Simulation refers to the procedure of solving the equations that resulted from model development
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What is a model?
Model: a description or representation of a system, entity, phenomena, or process. • Data used to generate a model are considered part of the model
Models may be mathematical, physical, or logical representations of a system, entity, phenomenon, or process. Models can be used by simulation to predict a future state, if so desired.
In vitro(cells)
In vivo(animals)
In silico(mathematics)
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What is a model?
At worst, a model is a concise description of a body of data.
At best, it captures the essential physics/chemistry/biology of the problem, it illuminates the principles that underline the key observations, and it predicts behavior under conditions which have not yet been studied (or conditions which are not evaluable with any other model).
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What is a model?
Computational model: the numerical implementation of the mathematical model performed by a means of a computer.
Mathematical model: the equations, boundary values, initial conditions, and modeling data needed to describe the conceptual model.
Models can occur on one scale (e.g., structural mechanics of a hip implant) or on multiple scales (e.g., transmission of molecular dynamic properties of red blood cells and their affect on blood damage).
Models can also be multi‐discipline or multi‐physics (e.g., molecular dynamics and continuum mechanics)
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What is a simulation?
Simulation: the imitation of the characteristics of a system, entity, phenomena, or process using a computational model.
Simulation refers to the procedure of solving the equations that resulted from model development.
For example, numerically solve a set of differential equations with different initial/boundary conditions.
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Science Priority Areas#1 Modernize Toxicology#2 Stimulate Innovation in Clinical Evaluations and Personalized Medicine to Improve Product Development and Patient Outcomes#4 Ensure FDA Readiness to Evaluate Innovative Emerging Technologies#5 Harness Diverse Data through Information Sciences to Improve Health Outcomes
(Q)SAR models to predict human risk Computer models of cells, organs, and systems to better predict product safety and efficacy
Virtual physiologic patients for testing medical products
Clinical trial simulations that reveal interactions between therapeutic effects, patient characteristics, and disease variables
Knowledge building tools Methods to verify, store, share
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RegulatoryScience/UCM268225.pdf
FDA has identified an important role for CM&S in its strategic priorities.
Center for Devices and Radiological Health (CDRH)
Center for Devices and Radiological Health
Office of the DirectorJeffrey Shuren, MD, JD
Office of In Vitro Diagnostic Device Evaluation and Safety
Office of Surveillance and Biometrics
Office of Compliance
Office of Communication, Education and Radiation Programs
Office of Management Operations
Office of Science and Engineering Laboratories
Office of Device Evaluation
What we do …
CDRH is responsible for regulating firms who manufacture, repackage, re‐label, and/or import medical devices sold in the U.S.
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CDRH Mission
“The mission of the Center for Devices and Radiological Health (CDRH) is to protect and promote the public health. …We facilitate medical device innovation by advancing regulatory science, providing industry with predictable, consistent, transparent, and efficient regulatory pathways, and assuring consumer confidence in devices marketed in the U.S.”
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CDRH Mission
Medical Device Classifications
Class IGeneral ControlsMost exempt from premarket submission
Class II Special ControlsPremarket Notification [510(k)]
Class IIILife‐supporting, life‐sustainingPremarket Application [PMA]
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CM&S as valid scientific evidence
e.g., fatigue safety factors
CM&S is the medical device
e.g., clinical decision support
The Role of CM&S at CDRH
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CM&S embedded in a medical device e.g., physiological
model in a control system
The Role of CM&S at CDRH
medicalnewstoday.com
CM&S embedded in a medical
device e.g., logical algorithm in a control system
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The Role of CM&S at CDRH
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heartflow.com
CM&S is the medical device
e.g., clinical decision support
The Role of CM&S at CDRH
16Kelm, Int J of Med Sci 2009
Bluestein, PLOS ‐ 2012
CM&S as valid scientific evidence
e.g., fatigue safety factors
Safety and Effectiveness
There is reasonable assurance that a device is safe when it can be determined, based upon valid scientific evidence, that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use,outweigh any probable risks.
There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.
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Medical Device Evaluation
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Comprehensive evaluation of a premarket submission for a therapeutic medical device is typically supported by a combination of valid scientific evidence from four types of models: animal, bench, computational, and human.
Because each model has different strengths and limitations for predicting real‐world clinical outcomes, the data portfolio for different use‐conditions will vary.
Models and Their Advantages
* M&S in medical devices, as compared to other industries, is nascent and is the one model with the most potential for refinement/improvement because the other models are fairly mature.
Adapted from Victor Krauthamer
Current Uses of CM&S in Premarket Review
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Modeling is mainly considered a development and design optimization tool, rather than a method by which physical performance of final devices can be demonstrated.
Mainly the modeling studies are supplemental information (to complement mechanical bench testing) for
• 510(k) – class II devices• Pre‐Market Approval – class III devices• Investigational Device Exemption – Clinical Studies
Current Uses of CM&S in Premarket Review
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Computational Solid MechanicsStents / Heart Valve Frames / Occluders / Vena Cava Filters / AnnuloplastyRings / Dental Implants / Spine & Joint Implants / Bone Plates & Screws / Surgical Tools
Determine the implant size in a device family that is expected to perform the worst under simulated in vivo conditions
o Reduces the amount of physical testingo Calculate Safety Factors for static and cyclic loads
Evaluate the effect of manufacturing tolerances Predicate Comparison Demonstrate a modification (e.g., dimensional) is minor and has minimal affect on performance
Current Uses of CM&S in Premarket Review
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Computational Fluid DynamicsVentricular Assist Devices / Total Artificial Heart / Blood pumps / Heart Valves / Endovascular Grafts / Drug Eluting Devices
Characterize the flow field by identifying regions of high shear stress, wall shear stress, or areas of low flow or flow stagnation
o especially in regions that cannot be visualized on the bench
Determine blood damage, thrombosis potential, and drug transport using fluid flow properties
Current Uses of CM&S in Premarket Review
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Computational ElectromagnetismPassive and Active Cardiology Implants / Peripheral Implants / Joint and Spinal Implants / Deep Brain Stimulators / MR‐guided Interventional Devices
Simulate the radiofrequency energy absorbed by patients undergoing magnetic resonance imaging (MRI)
o Especially worst‐case conditions that cannot be replicated in an animal model and cannot be tested ethically in humans
Radiofrequency‐induced currents and heating of (external) devices for electrophysiological recordings
Simulate the electric/magnetic field generated by a device during use to provide evidence of effectiveness
Current Uses of CM&S in Premarket Review
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Physiological Closed‐Loop Controllers & AlgorithmsAnesthesiology Devices / Respiratory Devices / Artificial Pancreas / Neurodiagnostic Tools
Use the simulation as an alternative validation method to demonstrate device performance and robustness
In silico simulation model (control algorithm) of diabetes replaces in vivo animal testing for evaluating artificial pancreas
Signal modeling (EEG source localizing software) for brain activity analysis
Current Uses of CM&S in Premarket Review
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Computational Thermal MappingAblation Devices
Determine the thermal field distributions generated by tissue ablation devices (e.g., High Intensity Ultrasound, radiofrequency)
Assess potential damage to surrounding tissue, organs and bones
CM&S are typically Relative• Design Optimization• Virtual Prototyping• Rationale for Pre‐Clinical Evaluation• Root Cause Investigations + Redesigns• Next Generation Designs
Medical Device Development with CM&S
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CMS REIMBURSEMENT
POSTMARKET
MONITORING
CMSEVALUATION
CMSREIMBURSEDECISION
REAL‐WORLDPRODUCT
PERFORMANCE
FDAREGULATORYDECISION
PRODUCTLAUNCHCLINICAL
PRE‐CLINICALINVENTION
+PROTOTYPING
DISCOVERY+
IDEATION
NEXT GENERATIONPRODUCT
DEVELOPMENT
The Total Product Life Cycle
CM&S OpportunityPredict Product Success/Failure to support:
Regulatory decisionsReimbursement decisions
Medical Device Development with CM&S
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CMS REIMBURSEMENT
POSTMARKET
MONITORING
CMSEVALUATION
CMSREIMBURSEDECISION
REAL‐WORLDPRODUCT
PERFORMANCE
FDAREGULATORYDECISION
PRODUCTLAUNCHCLINICAL
PRE‐CLINICALINVENTION
+PROTOTYPING
DISCOVERY+
IDEATION
NEXT GENERATIONPRODUCT
DEVELOPMENT
The Total Product Life Cycle
Some of the challengeswith the current practice …
… have led us to address the need for:
guidance on documentation and reporting CM&S results in premarket submissions;• FDA DRAFT Guidance on Reporting of Computational Modeling
Studies in Medical Device Submissions – published Jan 20142
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2, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm371016.htm
FDA Guidance
Reporting1 Computational Modeling Studies in Medical Device Regulatory Submissions (DRAFT)2
• Main body discusses the purpose of computational modeling and simulation in regulatory submissions
• Main body presents recommendations for reporting different elements of the computational modeling study
• There are five subject matter appendiceso Fluid & Mass Transport, Solid Mechanics, Electromagnetism, Thermal Transport, and Ultrasound
• DRAFT guidance is available for public comment untilApril 17th!
291, Erdemir, Guess, Halloran, Tadepalli, Morrison, J Biomech. 2012 February 23; 45(4): 625–6332, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm371016.htm
Some of the challengeswith the current practice …
… have led us to address the need for:
guidance on documentation and reporting CM&S results in premarket submissions;• FDA DRAFT Guidance on Reporting of Computational Modeling
Studies in Medical Device Submissions – published Jan 20142
systematic assessment and understanding of device‐use conditions;• Critical Path Innitiative3
• FDA Library of Models and Simulation4
• Medical Device Innovation Consortium5
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2, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm371016.htm3, http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/default.htm4, http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm346375.htm5, http://mdic.org/projects/computer‐modeling/
FDA Digital Library of M&S
The vision is that the Library will be a mechanism for curating public open‐use models and simulations in a non‐competitive space to foster collaboration and advance research, development and evaluation of medical devices.
Serve as a reference for access to state‐of‐the‐art CM&S and data related to medical products
Mechanism for FDA to transparently communicate utility and expectations of CM&S in a regulatory setting
Being a space for companies to share their “smaller datasets”, e.g., pediatric population, to create a “larger datasets”
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FDA Digital Library of M&S
Hosted public workshop in June 2013 to introduce concept and openly discuss the Library
Developed key aspects of the infrastructure and framework for use of the Library
Anticipate initially that the Library will be used for curating DATA for creating models and validating simulations, and reference problems
Prototype is underway with sights on pilot in 2014
32“Virtual Physiological Patient”
Medical Device Innovation Consortium
A Public‐Private Partnership collaborating on Regulatory Science to make patient access to new medical device technologies faster, safer and more cost‐effective
Formed in December 2012
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www.deviceconsortium.org
MDIC Strategic Approach
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MDIC Initial Program Areas
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Some of the challengeswith the current practice …
… have led us to address the need for:
methodologies to experimentally validate CM&S;• FDA Critical Path Initiative to evaluate CFD in blood pump
sensitivity analyses and uncertainty quantification; and• CDRH is actively engaged with the ASME Verification &
Validation Standards Committeeo ASME V&V 10 – Subcommittee on Solid Mechanicso ASME V&V 20 – Subcommittee on Fluid Dynamics and Heat Transfer
ASME V&V 40 – Subcommittee on CM&S for Medical Devices
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ASME V&V 40 Subcommittee
Subcommittee of ASME V&V Committee• Established in January 2010
Charter: Provide procedures to standardize verification and validation (V&V) for computational modeling of medical devices
Developing a general methodology for industry and academia to establish a V&V plan to assess credibility of CM&S used in medical device design and evaluation
Subgroups working on general methodology, solid mechanics, fluid mechanics and some device specialties (e.g., cardiovascular, orthopedics)
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Credibility Strategy Overview
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Risk Assessment
Establish Context of Use
CM&S Risk: combination of decision influence and consequence Decision Influence: contribution of
CM&S outcome to the decision being made
Consequence: impact if the CM&S outcomes prove incorrect
Risk assessment• Directs/guides V&V activities• Defines model credibility thresholds
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LOW
MEDIUM
HIGH
CONSEQUENCE
INFLUEN
CE
Framework to Assess Credibility
Ensuring that the credibility of the CM&S is commensurate with the associated risk provides the confidence that the CM&S is appropriate for the intended COU
Multiple factors contribute to CM&S credibility:
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Code Verification Sample Characterization
Solution Verification Control Over Test Conditions
System Configuration Measurement Uncertainty
System Properties Discrepancy of Inputs/Outputs
Boundary Conditions Rigor of Output Comparison
Governing Equations Applicability to Context of Use
Topic of Lecture on April 28, 2014
Applicability of V&V Activities
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Some of the challengeswith the current practice …
… have led us to address the need for:
methodologies to experimentally validate CM&S; sensitivity analyses and uncertainty quantification; and
• CDRH is actively engaged with the ASME Verification & Validation Standards Committee
o ASME V&V 10 – Subcommittee on Solid Mechanicso ASME V&V 20 – Subcommittee on Fluid Dynamics and Heat Transfer
ASME V&V 40 – Subcommittee on CM&S for Medical Devices
better elicitation of the consequence of the CM&S being incorrect.• CDRH is getting ready to launch a pilot program to expand the
current uses of CM&S in premarket submissions
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Pilot Program at CDRH
CDRH is launching a pilot program this Spring to implement and evaluate the Credibility Strategy in the review of new uses of CM&S in premarket submissions• Collaboration with OSEL and ODE• Focus on Cardiovascular and Orthopaedic Devices
The Credibility Strategy will also be evaluated as part of the qualification process for the Medical Device Development Tool6 program
It will also be used to help determine which CM&S can be a part of the FDA Library of Models and Simulation
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6, http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm374427.htm
Medical Device Development Tools
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MDDT Qualification
Clinical Outcome Assessments
Biomarker Tests
Nonclinical Assessment Models
NAMS are used in device development or evaluation that reflect device function or in vivo performance
• In vitro test methods• In silicomodels
Research – The VPP“Virtual Physiological Patient”A collection of models and data for developing and evaluating medical devices (cardiovascular, orthopaedic, …)
Assessment of plaque composition, dynamic biomechanics, and therapeutic outcomes in subjects implanted with endovascular devices (ASPECT-1)
Goals1. Prospectively collect data on superficial femoral artery (SFA)
deformations and plaque composition in symptomatic patients before and after stent implantation.
2. Create a model using computational simulation techniques to investigate sensitivity to various dimensions and deformations observed in the clinical study.
3. Disseminate and leverage the data collected during the study using open source and educational initiatives.
Tortuosity, Bending & Twisting
Smouse et al. Presented at Transcatheter Cardiovascular Therapeutics (TCT 2004) – published with permission
Bending
Stent
Axial Compression
Walking, climbing stairs, sitting in a chair can deform a stent in different ways.
https://simtk.org/home/opensim
ASPECT‐1• ASPECT is designed to provide
vessel morphology, plaque composition1, and dynamic deformation data that can be used to create realistic models of symptomatic peripheral vascular disease
• Goal is to yield more clinically predictive results from nonclinical evaluation– less reliance on human clinical
testing and unrepresentative animal testing; more durable and effective medical implants.
[1] Bishop PD et al. Arterial calcification increases in distal arteries in patients with peripheral arterial disease. Ann Vasc Surg. 2008
Axial atherosclerotic tissue maps
3D Atherosclerotic tissue maps
ASTM Stent Axial Fatigue Round Robin
Examine stent durability using fatigue to fracture methodology • mechanical testing & FEA of generic, stainless steel design
CDRH/OSEL is conducting mechanical testing, along with many industry laboratories
Interlaboratory test data may be included in a potential “Fatigue to Fracture” standard and be compared to computational modeling results in the future
Typical FractureAxial Fatigue Test Sample Data50
“Virtual Physiological Patient”A collection of models and data for developing and evaluating medical devices (cardiovascular, orthopaedic, …)
CFD Round Robin Study (2010)
GOALS: Improve the use of CFD to evaluate device performance and blood damage safety;
create a data repository of results for public use, and contribute to standards and guidance for using CFD in
regulatory submissions
Phase 1Simple nozzle model
Interlaboratory evaluations• CFD modelers: 28 groups from 6 countries• Validation of velocity fields using quantitative flow visualization
techniques: 3 labs• Blood damage testing of the device: 3 labs
4 mm12 mm 12 mm
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Laminar Flow Turbulent Flow
Axial Centerline Velocity
Lines: CFD Symbols: Experiment
Phase 1 Results
Large variations between CFD simulations and the experimental data1
531, Stewart SFC, Paterson EG, Burgreen GW, Hariharan P, Giarra M, Reddy V, Day SW, Manning KB, Deutsch S, Berman MR, Myers MR, Malinauskas RA, Cardiovasc Eng Technol. 2012:3;139‐60.
Phase 2: Blood Pump Model (2014)
Open to all CFD modelers Project website: visit https://fdacfd.nci.nih.gov
Blood Testing
Rotor Design
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“Virtual Physiological Patient”A collection of models and data for developing and evaluating medical devices (cardiovascular, orthopaedic, …)
Investigate Effect of Non-Circular Valve Configurations on Leaflet Dynamics –
Preclinical Test Methods
Non‐circular configurations after percutaneouslyimplanted heart valves (PHVs) depend on several factors
• Such as patient anatomy, number of calcified leaflets, and degree of calcification (Zegdi 2008, 2010; Schultz 2009)
Zegdi et al., 2008
FDA recognizes that there is limited public information on: • Valve preclinical testing characteristics• Leaflet kinematics on non‐circular configurations, and the
affects on leaflet failures CDRH is currently investigating:
• Acute measure of performance using hydrodynamic and accelerated wear tester, and
• Correlations between computational and validation‐specific studies on the tissue leaflets
Demonstrating differences in leaflet kinematics (testing) and stresses (modeling)
Investigate Effect of Non-Circular Valve Configurations on Leaflet Dynamics –
Preclinical Test Methods
Research – The VPPA collection of models and data for developing and evaluating medical devices (cardiovascular, orthopaedic, …)
Virtual Physiological Patient
Background
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Retrievals and clinical reports
Adverse Reactions to Metal Debris
Bearing wear and taper wear / corrosion
1 Matthies AK, et al. CORR 2012; 470(7):1895‐906 2 Natu S, et al. J Clin Path 2012; 65(5) 409‐183 Bowsher JG, et al. J Biomed Mater Res B. 2009; 91(1):297–3084 Goldberg et al. CORR. 2002; 401:149
1
2
3 4
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Results under gait loading
Pressure (M
Pa)
Eqv. stress (M
Pa)
Impact Unload Stance Swing
Stance Swing
A
A
Research – The VPP“Virtual Physiological Patient”A collection of models and data for developing and evaluating medical devices (cardiovascular, orthopaedic, …)
Virtual Family
9 different models available, more than 200 organs and 43 tissues,Direct import and automatic material assignment, voxel import of models
female adult1.60m, 58kg
obese adult, 1.78m, 120kg
8 year old boy1.40m, 26kg
8 y girl1.35m, 30kg
5 y girl1.09m, 16kg
male adult, 1.74m, 70kg
14 y boy1.65m, 50kg
11 y girl1.46m, 36kg
6 y boy1.17m, 20kg
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Human Head ModelsA functional high resolution human head model for analysis of efficacy of medical devices with electrical stimulation
neuronal connectome models for functional modeling of neuro‐stimulation devices.
Human Head Models
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MRI Radio Frequency Coil ModelsDevelopment and distribution of validated MRI RF Coil Models
MRI Radio Frequency Coil Models
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Future potential of CM&S for medical device development and evaluation
Digital Patients: Designers can access anatomic and physiologic computer models of (dozens, hundreds, thousands, …) of patients with a given disease.
Virtual Clinical Trials: New device concepts are “deployed” in digital diseased patients and performance is simulated leading to more effective bench testing, animal studies and (actual) clinical trials. Discover “Soft Failures”
Personalized Medicine: Physicians use simulation to predict safety and effectiveness of a given medical product for an individual patient.
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Summary
Computational modeling and simulation has revolutionized many industries.
CDRH is in the unique position to stimulate and advance device innovation through computational modeling and simulation efforts.
CDRH, through its partnerships, initiatives and projects, is helping to revolutionize and realize the future of CM&S for both design and evaluation.
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Lead Investigators at CDRH
ASTM Stent Axial Fatigue Non‐Circular Valve ConfigurationsMaureen Dreher, Ph.D. Nandini Duraiswamy, Ph.D.Jason Weaver, Ph.D.
CFD & Blood Damage Round RobinSandy Stewart, Ph.D.Rich Malinauskas, Ph.D.Prasanna Hariharan, Ph.D.
FDA Digital LibraryDonna Lochner
Virtual Family and MRI StudiesASPECT‐1 Leonardo Angelone, Ph.D.Lisa Lim, Ph.D. Wolfgang Kainz, Ph.D.
CD R H
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ASME V&V40: Verification and Validation in Computational Modeling of Medical Devices
Contact
FDANIH
INDUSTRY
ACADEMIA M&S
NSF
NIST
NASA
DARPA
MDIC
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Contact Information
Office of Device Evaluation, CDRH
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