Making Models Publicly Available - Critical Path Institute · Successes and lessons learned in the use of M&Sby FDA, industry, and public‐private‐partnerships ... Making Models

Making Models Publicly Available:Successes and Challenges

Tina Morrison PhD

Office of Device EvaluationCenter for Devices and Radiological Health

U.S. Food and Drug Administration

Modeling & Simulation for Medical Products Workshop

Workshop ObjectivesIntegrated approaches to modeling & simulation (M&S) for developing medical products and regulatory review.• Drug development and regulatory review has become

increasingly challenging and resource intensive. An integrated strategic approach to developing and applying M&S tools in drug development will enhance decision‐making processes. This workshop will examine: Novel tools and approaches to accelerate the development of

efficacious medicines with optimal benefit/risk profiles Successes and lessons learned in the use of M&S by FDA,

industry, and public‐private‐partnerships Challenges & opportunities for these innovative approaches


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Advancing Regulatory Science at FDA

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.

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Future of M&S for medical device product development and evaluationDigital Patients: Designers download 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.

Session III: Future Perspectives for M&S Tool Development & Applications

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CDRH Mission

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“The mission of the Center for Devices andRadiological Health (CDRH) is to protect andpromote the public health. …We facilitatemedical device innovation by advancingregulatory science, providing industry withpredictable, consistent, transparent, andefficient regulatory pathways, and assuringconsumer confidence in devices marketed inthe U.S.”


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

• Comprehensive evaluation of a marketing application for a therapeutic medical device typically supported by a combination of valid scientific evidence from four types of models: animal, bench, computational, and human.

• Each model has its strengths and limitations for predicting clinical outcomes.

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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

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Medical Device Development with Modeling & Simulation (M&S)

The Total Product Life CycleVIRTUAL

PROTOTYPING

DESIGN OPTIMIZATION

DESIGN IDEATION

PREDICT FAILURES?

PREDICT SUCCESS?

ROOT CAUSE

REDESIGNS

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Areas of Active Research

• Computational Solid Mechanics Stents, Heart Valve Frames, Occluders, Vena Cava Filters Spine & Joint Implants

• Computational Fluid Dynamics and Acoustics Blood Pumps, Heart Valves, Endovascular Grafts Drug Eluting Stents, Virus and Aerosol Transport Ultrasound Propagation Heat Transfer and Thermal Bioeffects

• Computational Toxicology• Computational Electromagnetics• Virtual Clinical Trials

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Virtual FamilyFDA/CDRH, IT’IS Foundation, Mobile Manufacturer Forum

FDA PI: Wolfgang Kainz (OSEL/DP)

• 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


Human Head ModelsFDA/CDRH, IT’IS Foundation

Kainz, Angelone, Cohen, Iacono, Akinnagbe, Majdi (OSEL/DP)

A functional high resolution human head model for analysis of efficacy of medical devices


MRI RF Coil ModelsFDA/CDRH, IT’IS Foundation

Kainz, Angelone, Iacono, Lucano, Mendoza, Bassen(OSEL/DP)

Development and distribution of validated MRI RF Coil Models


FDA Digital Library Modeling and Simulation

It will be a mechanism for curating a public open‐use repository of 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 M&S and data

related to medical products• Mechanism for FDA to transparently communicate utility and

expectations of M&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 Modeling and Simulation

• Hosted public workshop in June 2013 to introduce concept and openly discuss the Libraryhttp://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm346375.htm

• Developed key aspects of the infrastructure and framework for use of the Library

• Anticipate initially that they’ll curate DATA for creating models and validating simulations, and reference problems

• Prototype is underway with sights on pilot in 2014• Contact: [email protected]

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CHARGE: Discuss Success and Challenges with Making Models

Publicly Available

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Lots of Model Repositories


Making Models Publicly Available

• Who is making models publicly available? Who as in the authority

o Hosting institution/information system administrators Who is maintains stewardship?

o Addresses the ethical questions of care, advocacy, preservation?

What is their motivation? Who is tracking the currency and accuracy?

o E.g., verification of source, version control

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• A model is a simplified representation of a real system• There are many types of models:

o Mathematical models of physics, biology, chemistryo Behavioral models o Animal modelso Statistical modelso Solid (geometrical) models

• What about the data to make the model?• Are metadata provided to fully describe the model?

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• Who is the public (i.e., user community, stakeholders)? Academicians Industry/Manufacturers Other government agencies Clinicians Patient advocate groups

• How is it made publicly available? Does public = open? Do some pay a fee, or contribute to the community? What are the sources of sponsorship?

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• What does it mean for the models to be available? To view the model To download and manipulate To share with others To modify and evolve To upload modified version

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Success

What defines success? That models are shared? That models are curated? That models are downloaded and used? That models evolve based on broad use? That publicly available models can minimize (development) resources?

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Challenges

• Interoperability Lack of common terminology, common platforms

• Discoverability• Policy/Governance• Sponsorship (e.g., for start‐up, sustainability)

• What about credibility? Credibility of the source? The model? The data? The validation? the context of use?

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Credible Practice of M&S in Healthcare

• Credible: dependable with a desired certainty level to guide research or support decision making within a prescribed application domain and intended use; establishing reproducibility & accountability.

• Practice: any activity involving development, solution, interpretation and application of computational representation of biological, environmental and man‐made systems and their interaction thereof.

• Modeling: specifically computational modeling; virtual representation of system(s) of interest in a usable form in order to provide descriptive and predictive metrics for timely and systematic exploration of the system(s).

• Simulation: computational solution of models to quantify descriptive and predictive metrics of system(s) of interest; including related post‐processing efforts to calculate these metrics from raw analysis results.

• Healthcare: any activity involving development, maintenance, advancement, or administration of medical care; including research, diagnosis, risk assessment, prevention, therapy, rehabilitation, surgery, intervention design, and regulation.

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Objectives of CPMS

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1. Unify M&S vocabulary and terminology2. Develop guidelines and “credibility principles3. Define and Demonstrate translational workflows4. Promote “good practice” through outreach5. Establish model certification process6. Identify new areas of research to improve 2 & 5

https://simtk.org/home/cpms


FDA is thinking about Credibility

• In conjunction with one of our standards organization, ASME, CDRH has developed a risk‐based Strategy to Assess Credibility of M&S. The level of credibility should be commensurate with the

context of use.• The goal is to utilize this strategy to assess whether models

are credible (valid scientific evidence) for regulatory decision‐making. Implementing the strategy in a pilot program in early 2014 for

M&S in pre‐market submissions. Aiming to “qualify” the Credibility Strategy as a Medical Device

Development Tool.

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Message – Think about Credibility

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• Need to clearly define the type model Describe how was it created

• Identify how it can be used Define the domain of validity Or the domain of invalidity

• Enable reproducibility Provide the references for input data Provide data for validation

• Meta data for accurate and appropriate use1 [1] Erdemir, Guess, Halloran, Tadepalli, Morrison

J Biomech. 2012 February 23; 45(4): 625–633


Acknowledgements

FDA• CDRH M&SWorking Group• Virtual Family

Leonardo Angelone Wolfgang Kainz

• FDA Library Team James Coburn Jessica Hernandez* Donna Lochner

• FDA Credible M&SWorking Group

NIH IMAG/MSM• CPMS

Ahmet Erdemir Lealem Mulugeta

• Data/Model Sharing Team

http://www.imagwiki.nibib.nih.gov/mediawiki/index.php?title=Main_Page

Contact Information

[email protected]

Office of Device EvaluationCenter for Devices and

Radiological Health

Documents

Making Models Publicly Available - Critical Path Institute · Successes and lessons learned in the use of M&Sby FDA, industry, and public‐private‐partnerships ... Making Models