www.medinstitute.com

What do you do when regulatory requirements exceed that of reasonable engineering controls? Examples and lessons learned from 25 years in the trenches

Justin Metcalf MS, Brian Choules, PhD, MED Institute, Inc.

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Overview

• Company introduction: Who is MED Institute? • What is ISO 17025 and why is it important? • Requirements

– Regulatory – Company – How they interact

• Methods for rectifying the gap between regulatory and company requirements

• Practical examples • Conclusion

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MED Institute Introduction

• MED Institute is a Cook Group Company, located in West Lafayette, IN

• We have been in business since 1983, and have over 30 years of experience in the medical device industry

– Nonclinical Testing Services

– Regulatory Consulting

– Clinical Trial Management

• ISO 17025 Accredited Laboratory (cert 2194-01)

• ISO 13485 Certified (BSI)

• Inspected to Good Laboratory Practices (GLP)

• We sit on 16 medical device standard committees (ISO, ASTM, AAMI)

• 250 staff members including physicians, nurses, engineers, regulatory scientists, physiologists, biologists, veterinarians, and statisticians

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MED Institute Introduction

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• Experience with regulatory bodies

– FDA, CFDA, PMDA, CE notified bodies

• Work with companies around the globe

• Additional areas of specialization: – Publications and research – Vascular – Urology – Endoscopy – Orthopedic

– Ophthalmology – Obstetrics/Gynecology – Pediatrics – Cardiac – Critical Care Medicine

MED Institute Introduction

• 90 test methods accredited to ISO 17025 including: – MRI Safety Analysis and Testing – Durability/fatigue testing – Failure analysis (FTIR, SEM, EDS) – Simulative use – Corrosion – Particulate counting and sizing – Radiopacity

• Complete ISO 25539 series as well as many other standards list on

our accreditation cert # 2194-01 • Multiple areas of research and publication including fatigue to

fracture, failure analysis, and corrosion

CERT #2194-01 Testing

Laboratory

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What is ISO 17025 and why is it valuable?

• ISO/IEC 17025 is a set of general requirements for the competence of testing and calibration laboratories and is the predominant ISO standard used by testing laboratories

– Method validation required for non-standardized methods

– Promotes best scientific practices through:

• Uncertainty analysis

• Interlaboratory comparisons

• Test method monitoring

• Calibration traceability

• A proper scientific foundation is important and accreditation is one way to prove your expertise

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Definition of a requirement

• A thing demanded or obligatory: Dictionary.com

• Something that is needed or that must be done: Merriam-Webster

• Requirement synonyms: need, wish, demand, want, necessity, prerequisites, requisite, precondition, stipulation, specification…

• It is crucial to assess your requirements carefully before initiating nonclinical testing

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Regulatory requirements: some sources

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Requirements

Guidance documents

Reference to standards

(ISO, ASTM…)

Equivalence to predicate

devices

Literature

Company requirements: some sources

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Requirements for a “new

device” Physician interactions

Feasibility clinical studies

Bench and animal work

Literature

Requirements for a device

with a predicate

Guidance documents

Reference to standards

(ISO, ASTM…)

Equivalence to predicate

devices

Literature Company requirements are documented in risk analyses or design inputs.

We all have the same goal: a safe medical device. Occasionally, the regulatory and company requirements are the same.

Ideal Situation

Company Requirements

= Regulatory

Requirements

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Real World

The practice of medicine may result in each global regulatory body having requirements that differ from the company requirements. These differences will need to be reconciled to gain approval.

Company Requirements

Regulatory Requirements

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Reasons for the differences in requirements

• Regulatory bodies can adopt requirements without the knowledge and clinical experience that many companies have

• Knowledge and technology advancements occur faster than regulatory bodies can adjust requirements

• Example: Standardized physiologic models and acceptance criteria are rare and once they are developed, science or medical devices have generally moved onto a new front

• Regulatory requirements are not generally publicized and companies must determine acceptance criteria during device development

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Reasons for the differences in requirements

• Standards lag technology

– Standards might lack all the necessary requirements that help establish the safety and effectiveness of the device.

– It should be noted that standards cannot always envision new design concepts or can have requirements that become outdated based on emerging knowledge. Thus, complete compliance to standards might not always make sense.

• We all want to help patients, but to fulfill a regulatory requirement that is not warranted is expensive and time consuming.

• How do we resolve a difference in a way that minimizes effort?

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So how do we resolve differences between regulatory requirements and company requirements?

• Educate yourself on the clinical environment

– Research

– Cadaver studies

– Physician interactions

– Clinical feedback

• Explants and clinical performance

– Endurance limit testing

• Educate your regulatory body

– Submission specific meetings

– General information meetings

– Industry wide working groups

– Collaborative research

– Project based agreement prior to development or after model/test development

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So how do we resolve differences between regulatory requirements and company requirements?

• Testing (“A good test is worth 10,000 words, a bad test is worth 1,000,000”)

– Develop physiologically relevant model

• Validate with physician feedback

• Existing device performance

– Build your rationale

– Model improvement

• Clinical performance vs. bench

• Clinical feedback

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Practical Examples

• Example 1: Clinically relevant bifurcation tracking model

– Company requirement

• Device must advance, deploy and withdraw in an appropriate clinically relevant anatomy

– Regulatory requirement

• Justify your model to include tortuosity and a bifurcation radius that is representative of a worst case anatomy

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Practical Examples

• Example 1 cont.

– Option 1: Agree with the regulatory body

• Find an overall worst case

– Option 2: Justify why your current requirements are adequate

• Use literature and physician feedback

– Option 3: Work with regulators to come to an agreement on an appropriate new solution

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Does a perfect model exist?

Bing images 2/5/14

Everyone wants to find and test out the worst case The “one size fits all” solution doesn’t exist

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Practical examples

• Example 2: Tissue replacement therapy

– Company requirement

• An experienced operator must deliver the cadaveric tissue to its intended location without damage and results must be better than or equal to the standard of care

– Regulatory requirement

• Model and results must match those of a recognized scientific journal article

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Practical examples

• Example 2 cont.

– Option 1: Agree with the regulatory body

• Perform the test as specified by the regulatory referenced journal article

– Option 2: Justify why your current requirements are adequate

• Physician feedback and publication

– Option 3: Work with regulators to come to an agreement on an appropriate new solution

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Practical examples

• Example 3: Breakdown Corrosion for implantable metals

– Company requirement

• Breakdown potential to be greater than that of a device with successful clinical use

– ASTM agrees with the criterion

– Regulatory requirement

• Breakdown potential must be greater than 600 mV

– This was an example of regulatory bodies and companies reaching for a relevant acceptance criterion without appropriate scientific backing

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Practical examples

• Example 3 cont.

– Option 1: Agree with the regulatory body

• Set 600 mV as the criteria

– Option 2: Justify why your current requirements are adequate

• Educate the regulatory body on an alternative appropriate criterion

• Clarify language in the standard

– Option 3: Work with regulators to come to an agreement on an appropriate new solution

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Practical examples

• Example 4: Stent durability conditions

– Engineering requirement

• Stent must maintain its function for predetermined number of cycles to clinically relevant loads

– Regulatory requirement

• 10 year fatigue life justified but without specific loading conditions

• Bridging the gap between a clinically relevant fracture rate is difficult in a global regulatory environment

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Mean Strain

Alte

rnat

ing

Stra

in

Practical examples

• Example 4 cont. – Option 1: Agree with the regulatory body

• Redefine loading conditions or redesign the device

– Option 2: Justify why your current requirements are adequate

• Physician feedback and publication

– Option 3: Work with regulators to come to an agreement on an appropriate new solution

– Educate yourself on the clinical relevance of fractures

– Educate the regulatory body on clinical relevance of fracture

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Practical examples

• Example 5: MR device deflection

– Engineering requirement

• Device should not have a deflection force that is clinically impactful

– Regulatory requirement

• “If the mean value is less than 45°, the magnetically induced deflection force, is less than the force on the device to due gravity (its weight)” ASTM F2052-06

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This is a statement in the standard that has been adopted as a criterion

Practical examples

• Example 5 cont. – Option 1: Agree with the regulatory body

• Label your device unsafe

– Option 2: Justify why your current requirements are adequate

• Physician feedback and publication

• Clarify language in the standard

– Option 3: Work with regulators to come to an agreement on an appropriate new solution

– Educate yourself on the clinical relevance of deflection force

– Educate the regulatory body on clinical relevance of deflection force

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Conclusions

• A proper scientific foundation is of the utmost importance

• Appropriate multi-device criteria and models are rare, most devices require a specific model and criteria

• Education and scientific publication is important

• Communication with regulatory bodies early and often is necessary

• Continuous improvement of models and methods is needed

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MED Institute

• Booth 3194

• Our Mission

– Through forward looking test development and careful bench testing, we apply scientific and engineering principles to help safe and effective devices efficiently reach the global market to benefit patients

Medinstitute.com

Brian Choules bchoules@medinstute.com

Justin Metcalf jmetcalf@medinstitute.com

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