testing your medical device idea: bench tests, animal tests,...

University of Minnesota Paul A. Iaizzo, PhD

Testing Your Medical Device Idea:

Bench Tests, Animal Tests, Clinical Trials

and Regulatory Issues

Paul A. Iaizzo, Ph.D.

Professor of Surgery, Integrative Biology and Physiology,

and the Carlson School of Management

Associate Director of the Institute for Engineering in Medicine

Director of Education of the Lillehei Heart Institute

Medtronic Professor of Visible Heart Research


Disclosures:

or important experiences to note

about that person!!!

Faculty in NPDBD Course at University of Minnesota

Co-organizer of the Annual Design of Medical Device

(DMD) conference in Minneapolis

Consultant: Medtronic Inc.


Lecture Goals: Have you understand the broad definition of a

medical device.

Identify the typical steps in medical device design.

Define GMP and GLP.

Discuss steps of clinical research.

Provide examples of clinical research.


First Battery Powered Wearable Medical Device:


First “Wearable” Pacemaker:

Bakken based his

pacemaker design

from “Popular

Electronics” plans

for a transistorized

metronome. He

devised a

paperback sized,

battery-powered

pacemaker with a

9-volt direct

current pulse.

Minnesota Historical Society

Oral History Collection; Sept. 9, 1997


Food and Drug Administration (FDA):

One of the United States Executive Department which is responsible for protecting and promoting public health through the regulation and supervision of:

food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications),

vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED),

veterinary products, and cosmetics.

The US Federal Food and Drug Administration has opened a Middle East office in Israel,

FDA

created

in 1938,

Covered

Medical

Devices

1976

http://en.wikipedia.org/wiki/Food_safety

http://en.wikipedia.org/wiki/Tobacco_products

http://en.wikipedia.org/wiki/Dietary_supplement

http://en.wikipedia.org/wiki/Prescription_drug

http://en.wikipedia.org/wiki/Over-the-counter_drug





http://en.wikipedia.org/wiki/Pharmaceutical_drug

http://en.wikipedia.org/wiki/Vaccine

http://en.wikipedia.org/wiki/Biopharmaceutical

http://en.wikipedia.org/wiki/Blood_transfusion

http://en.wikipedia.org/wiki/Medical_device

http://en.wikipedia.org/wiki/Medical_device

http://en.wikipedia.org/wiki/Electromagnetic_radiation

http://en.wikipedia.org/wiki/Veterinary_medicine

http://en.wikipedia.org/wiki/Cosmetics


Medical devices range from: simple tongue depressors and bedpans, to

complex programmable pacemakers with micro-chip technology and laser surgical devices.

in vitro diagnostic products, such as general purpose lab equipment, reagents, and test kits, which may include monoclonal antibody technology.

Certain electronic radiation emitting products with medical application and claims meet the definition of medical device. Examples include diagnostic ultrasound products, x-ray machines and medical lasers.


Key Features of Regulatory Pathways:

US - FDA

Safety and efficacy Applications are on

paper. 510(k)- 3-12 months

PMA- years

Manufacturing regulated through GMP regulations and inspections.

FDA and ISO systems are becoming very similar.

Clinical testing of 510(k) devices (before approval) is difficult in the US (unless part of the approval process- i.e. a heavy 510(k))

Europe - CE/ISO

Primarily safety ISO certification is done

through a Notified Body. The Notified Body is a private company licensed by an EU government. It acts as the regulatory agency.

ISO regulations govern design, manufacturing and service processes.

Approval timing generally shorter than US.

Geneva Washington DC


Required Good Manufacturing

Practice (GMP):

FDA continues to revise GMP. FDA

approval is needed for most biomedical

devices.

Standards established by the

International Organization for

Standardization (ISO).

ISO 9000 series of standards states that:

The design input phase should be carefully

planned to be an integral part of the overall

product development process.


ISO 9000 and14000: in brief The ISO 9000 and ISO 14000 families are among ISO's most widely known

standards ever. ISO 9000 and ISO 14000 standards are implemented by

some 760 000 organizations in 154 countries.

ISO 9000 has become an international reference for quality management

requirements; in business-to-business dealings. The ISO 9000 family is

primarily concerned with "quality management". This means what the

organization does to fulfill:

- the customer's quality requirements, and

- applicable regulatory requirements, while aiming to

- enhance customer satisfaction, and

- achieve continual improvement of its performance in pursuit of these objectives.

The ISO 14000 family is primarily concerned with "environmental

management". This means what the organization does to:

- minimize harmful effects on the environment caused by its activities, and to

- achieve continual improvement of its environmental performance.

http://www.iso.ch/iso/en/ISOOnline.frontpage

http://www.iso.ch/iso/en/ISOOnline.frontpage


GMP: Quality Assurance/System Requirements

Organization and personnel.

Design practices and procedures.

Buildings and environmental control.

Design of labeling and packaging.

Controls for components, processes, packaging and labeling.

Device holding, distribution and installation.

Device evaluation.

Device and manufacturing records.

Complaint processing.

QA system audits.

Design control is a requirement of ISO 9001, the most

comprehensive standard that includes requirements for: design,

development, production, installation, and servicing of products. (Link D, New Challenges for device design: FDA’s revised GMP. Medical Device & Diagnostic Industry, pp.64-67, 1993.)


Regulatory Boards Require:

Evidence to support claims.

Evidence that a technology is safe and effective.

Scientific evidence as to a claim that a technology

is cost-effective;

“ more value for the money spent when compared with the

most reasonable alternative. A cost-effective technology

may actually cost more, but the improvement in outcomes is

judged to be worth the extra cost.”

(http://www.devicelink.com)


Enhanced Steps in the Development

of a Medical Device: 2015

Lab notebook, smart phone, or Ipad (w/ clinician).

Fancy animations or visualizations.

Prototype development (rapid, working, polished prototypes and/or computer simulations).

Bench testing (safety, wear, biocopatability testing).

Redesigns: until a final design freeze.

Animal testing: safety - no needed redesigns.

Clinical testing and appropriate approvals.

Corporate acquisition or product market release.


The Fancy Animation:


Need for Bench Testing:

Optimize product design.

Simulate various clinical anatomies.

Accelerated wear testing.

Ongoing verification as to the utility of a technology

Freeze design before pre-clinical studies are initiated


Critical Understanding of Cardiac

Anatomy and Pathological Changes:

Analyze images from clinical cases.

Study anatomical specimens.

Consult with clinical and anatomical experts.

Develop 3D models.

Computer simulations.

Special Issue on Cardiac Anatomy: Journal of

Cardiovascular Translational Research: Iaizzo PA,

Anderson RH, Hill AJ (editors) in press, 2013


CMR of Perfusion Fixed Hearts: These images were from a preserved

human heart diagnosed with congestive

heart failure (HH70) and were acquired

using a slice thickness of 1 mm in a 3T

Siemens scanner. The in-plane

resolution of the images ranges from 0.3

mm to 0.5 mm.

Short Axis View: 4-Chamber View:


LV Volume Calculations:

M. Bateman C. Rolfes S. Howard I. Ankonvich B. Howard


3D Modeling of Cardiac Vasculature:

J. Spencer

Spencer JH, Larson AA, Drake R, Iaizzo PA. A

Detailed Assessment of the Human Coronary

Venous System using Contrast-Computed

Tomography of Perfusion-fixed Specimens. Heart

Rhythm. 2013 Oct. 18, 13: 1212-1215.


Analysis of the Tissue-Device Interface:

An Active Fixation Lead in RV


Reperfusion In Vitro: defibrillation

Sigg DC, Iaizzo PA: In vivo versus in vitro comparison of swine cardiac performance: Induction of

cardiodepression with halothane. European Journal of Pharmacology, 543:97-107, 2006. .

Sigg, DC, Coles JA Jr, Gallagher WJ, Oeltgen PR, Iaizzo PA: Opioid preconditioining: myocardial

function and energy metabolism. The Annals of Thoracic Surgery, 72: 1576-1582, 2001.

J. Coles

D. Sigg


Know your Anatomy: RAA


Fancy Visualization: Micra

Eggen M, Bonner M, Williams E, Iaizzo PA: Multimodal imaging of a

transcatheter pacemaker implantation within a reanimated human heart.

Heart Rhythm 11(12):2331-2, 2014


Coronary Stenting: Provisional Technique

Burzotta F, Cook B, Iaizzo PA, Singh J, Louvard Y, Latib A: Coronary

bifurcations as you have never seen them: the Visible Heart® Laboratory

bifurcation programme. EuroIntervention, 9;11 Suppl V:V40-V43, 2015.

F. Burzotta

A. Latib

Y. Louvard

B. Cook

Medscape

J. Singh

http://www.medscape.com/

http://www.medscape.com/


Need for Pre-Clinical Research:

Validate efficacy of a device within an appropriate animal model.

Obtain outcomes and safety data: needed both for 510(k) submissions for developing clinical trials.

Obtain bio-compatibility data.

Gain confidence in the technology itself.


Hierarchy of Pre-clinical Research Approaches versus

Amount of Data One Can Easily Collect versus Costs:

Hierarchy

Human hearts in vivo

Human hearts in vitro

Large mammalian hearts in vivo

Large mammalian hearts in vitro

Isolated perfused hearts

Isolated muscle preparations

Isolated cells

Subcellular fractions

Thus, e.g., if you wish to perform medical device design research in the field of a cardiac device, ideally you would

like to perform human trials in vivo, but this not only raises medical ethical issues, but is highly costly and may

provide useful data for one specific valve design and procedure. Whereas if you move the research approach

downward, i.e., employ an isolated large mammalian heart model in vitro, you can obtain more data at a lower cost,

but then you must justify the appropriateness of the chosen model. Yet, in one given study it may be possible to

perform multiple procedures for comparisons or at least multiple implants in multiple hearts with fairly consistent

anatomies

Relevance Data Cost


Important Limitations of

Animal Testing:

Cannot provide definitive statement regarding human safety and efficacy:

Subjectivity is enhanced by use of concurrent controls and historical performance data.

AND the experience of the investigator with the selected animal model will influence results.


Regulatory Requirements: FDA Mandates

Good Laboratory Practice (GLP)

All pre-clinical studies conducted to assess

clinical safety must be performed under GLP

conditions

Independent auditor

Documentation of all procedures,

instrumentation, personnel qualifications, data

archiving and analysis of results


Regulatory Requirements: Animal

Testing (ISO 5840, revised 2006)

For example, new cardiac valve technologies

will require considerably more testing:

10-15 experimental in Mitral and Aortic

2-4 controls in each position

Greater than 6 months desirable


Need for Clinical Research

Optimize product design.

Outcomes and safety data are needed for 510(k) submissions.

Ongoing verification as to the utility of a technology.

Improve process efficiency.


Why Perform Clinical Research?

Test the elements of clinical

practice.

Justify clinical decisions:

outcome economic factors

Intellectual pursuit of truth to

understand clinical events.


Clinical Research should be:

Empirical

Critical

Results must be:

Observable

Documented

Examined Critically


Pre-clinical and Clinical

Research cannot be reduced

to Finite Sciences:

There is no pure scientific method,

it requires:

• Intuition

• Creativity


In Vitro Testing = Bench

Durability/wear

Hemodynamics

Exceed physiologic limits

Fi

In Vivo Assessment = Animal

Safety

Catastrophic events

Mimic physiologic conditions

Clinical Trials = Human

Safety and efficacy

Common R&D Flow Patterns:


Example of one copy of a

corporate submission to the FDA.

(from Alex Hill)


Future - Virtual Prototyping:

U of MN’s Medical Device Center:

Atrial septal

defect: HH 143


Computational Assessment of

Cryoballoon Placements:

Goff RP, Spencer JH, Iaizzo PA: MRI reconstructions of human

phrenic nerve anatomy and computational modeling of cryoballoon

ablative therapy. Annals of Biomedical Engineering (in press), 2015. R. Goff J. Spencer


DMD in Minnesota, April 2016

http://www.dmd.umn.edu/ 15th Annual Meeting

April 12-15, 2015

The Commons Hotel,

U of MN Campus, Minneapolis, MN


Advance Cardiac Anatomy and

Physiology Course: Jan 4-8, 2016

http://physiology.med.umn.edu/short-courses/phsl-5510/index.htm


Questions?

http://www.vhlab.

umn.edu/atlas

Special Issue on Cardiac

Anatomy: Journal of

Cardiovascular Translational

Research: Iaizzo PA, Anderson

RH, Hill AJ (editors)

Volume 6 Number2, April 2013

http://www.vhlab

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