BRIDGING THE GAP BETWEEN TOXICOLOGIC PATHOLOGISTS AND THE MEDICAL - - PowerPoint PPT Presentation

BRIDGING THE GAP BETWEEN TOXICOLOGIC PATHOLOGISTS AND THE MEDICAL DEVICE INDUSTRY

J OAN N C. L. SCH U H J CL SCH U H, PLLC BAI N BRI DGE I SLAN D, WA EM : SCH U H J@

J CLSCH U H.COM

SURVEY – SHOW OF HANDS

Are you involved with pathology or toxicology evaluations of biomaterials or medical devices, including for drug delivery, depots, scaffolds or combination products:

• Full-time / Exclusive – about 10%
• Never – about 25%
• Some of the time – 65% of audience

WHAT IS A MEDICAL DEVICE – FDA, 2018

A medical device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: 1. recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, 2. intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals,

• r

3. intended to affect the structure or any function of the body of man or other animals, and does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes. The term "device" does not include software functions excluded pursuant to section 520(o).

CHARACTERIZATION OF BIOMATERIALS AND DEVICES

Types:

• Biomaterials
• Metals, ceramics, glass, textiles, polymers, nanomaterials and animal-derived tissues/materials
• Medical Devices
• Single or multiple biomaterials, microelectronics, computers and software and diagnostic devices

Persistence:

• Permanent
• Biodegradable - tunable

Forms:

• Solids
• Injected liquids
• Suspensions or particles
• Thermoresponsive gels

Clinical Indication:

• Structural/functional support or replacement, electrical monitoring or signaling therapy, create physical

access, ablation, pumps, reproductive functional changes Organ Systems:

• Cardiovascular, skeletal, integument, reproductive, respiratory, special senses, nervous, digestive

KEY POINTS FOR MEDICAL DEVICES

Safety assessment of medical devices has followed a different path than drugs

• Engineers rather than chemists and biologists
• Mechanical, chemical, material sciences and bioengineers
• Often use chemical analysis and literature-based risk

assessment rather than in vivo evaluations

• Testing requirements and specifications based within

international and national standards organizations

• Standards originally meant characterize and test physical

materials have been extended to cover biological testing

• No involvement of veterinary pathologists in setting the

standards

REGULATORY STANDARDS AND BODIES

• International Organization for Standardization (ISO) standards

(www.iso.org)

• FDA Center for Devices and Radiological Health (CDRH)
• U.S. Pharmacopeial (USP) Convention (www.usp.org)
• ASTM International (www.astm.org)
• European Notified Bodies (acting for EMA) – Certification by

Conformité Européene (CE) marking of medical device products

• The Organisation for Economic Co-operation and Development

(OECD)

• GLPs apply to animal studies
• ICH guidelines selectively applied

DETERMINE BIOCOMPATIBILITY

• Biocompatibility is difficult to define
• FDA - The ability of a device material to

perform with an appropriate host response in a specific situation.

• Other - Ability of a biomaterial to perform its

desired function with respect to a medical therapy, without eliciting any undesirable local

• r systemic effects in the recipient.
• Determination made based on results of all

testing

POTENTIAL TESTING FOR BIOCOMPATIBILITY

Cytotoxicity Extractables and leachables Sensitization Hemocompatibility Pyrogenicity Particulates, contaminants and degradants Genotoxicity Implantation (local tissue tolerance) In vivo toxicity (acute to chronic) Safety Pharmacology Carcinogenicity Reproductive & development toxicity

ISO 10993 STANDARDS EMPHASIZING IN VIVO STUDIES AND HISTOPATHOLOGY

ISO 10993 Part (Publication Year) Title Content 1 (2009) Evaluation and testing within a risk management process General Principles; includes a master table for test selection by medical device category 3 (2014) Tests for genotoxicity, carcinogenicity and reproductive toxicity Need for and principles of carcinogenicity genotoxicity and reproductive toxicity testing 4 (2017) Selection of tests for interactions with blood In vivo testing for materials and devices contacting blood 6 (2016) Tests for local effects after implantation Study designs and suggested histopathology scoring methods (Annex E) 11 (2017) Tests for systemic toxicity Study design including histopathology 20 (2006) Principles and methods for immunotoxicology testing of medical devices Immunotoxicology testing principles 22 (2017) Guidance on nanomaterials Nanomaterial testing principles

Standards have to be purchased from www.ISO.org or www.ASTM.org

ISO 10993 SERIES ACCEPTANCE NOT UNIVERSAL

• FDA issued a ISO 10993-1 usage guide in 2016
• Use of International Standard ISO 10993-1, "Biological

evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"

• Concurrences and differences to address biocompatibility

testing issues

• Use risk management to address biocompatibility and to

leverage existing testing

• Clarify their expectation on evaluation endpoints
• Preference for GLPs

ISO 10993 SERIES ACCEPTANCE NOT UNIVERSAL

FDA issued a draft animal guide in 2015 "General Considerations for Animal Studies for Medical Devices”

• FDA recommends ACVP board-certified pathologists
• “FDA strongly recommends that you work with a pathology expert such as a veterinarian

boarded by the American College of Veterinary Pathology to develop the study protocol.”

• “…we recommend that you seek the expertise of board-certified veterinary or clinical

pathologists when developing and executing methods for preparing tissues for histomorphometric analysis. We also recommend that you identify appropriate expertise to develop pre-specified objective methods for scoring and analyzing observations of injury and inflammation of all tissue.”

• GLPs apply to animal studies
• Conduct definitive animal studies on the market ready device (final clinical

design) except as required to scale, if needed, to implant in the animal model

• Consider refinement, replacement, and reduction (3R) of animal testing –

address question of whether an animal study is necessary

KEY POINTS FOR MEDICAL DEVICES

• Preclinical safety and efficacy is tested prior to clinical studies
• Efficacy is the performance of the device under ideal and controlled

circumstances

• Human clinical effectiveness of the device relative to the intended

medical condition may only be proven post-marketing

• Regulatory authorities assess safety and efficacy of high risk devices
• The manufacturer performs the assessment of safety and efficacy of lower

risk devices

• Predicate devices (marketed device), even those previously removed from

market, can be used to expedite device approval with little to no nonclinical data by showing that your device is substantially similar

FDA DEVICE VS DRUG SUBMISSION PATHWAYS

DRU G

• 505(j) Abbreviated

NDA (ANDA)

• Petitioned ANDA
• 505(b)(2) NDA
• 505(b)(1) New Drug

Application (NDA)

DEV I CE

• Premarket Notification 510(k) –

Class I

• With or without exemptions
• Premarket Notification 510(k) –

Class II

• With or without exemptions
• Premarket Approval (PMA) –

Class III

• De Novo reclassification (lack

predicate)

• Investigational Device

Exemption (IDE)

• Humanitarian Device

Exemption (HDE)

Low Medium High

RI SK

BODY CONTACT CHARACTERIZATION SUGGESTS POTENTIAL TESTING PROGRAM

1) Nature of the body contact

• Surface device
• Intact skin, mucosal membrane, breached or compromised

surface

• External communicating device
• indirect blood path, tissue/bone/dentin, circulating blood
• Implant device
• Tissue/bone, blood

2) Duration of the body contact

• Limited (≤24 hr), Prolonged (>24hr), Permanent (>30 day)

KEY POINTS FOR PATHOLOGY

• Pathologists will mostly see Class III and some

Class II devices

• Generally no dose response
• Control versus one treatment group
• Acceptable to use uneven treatment groups
• Often use multiple implant sites in a single animal

– animal may have both the control and test item

KEY POINTS FOR PATHOLOGY

• Test for both safety and efficacy in animals

studies

• Local implantation
• Systemic toxicology
• Other possible animal studies – carcinogenicity
• Carcinogenicity are a problem due to non-genotoxicity tumor induction due to

physiochemical characteristics of materials (Oppenheimer effect)

• Safety and efficacy testing can be independent or together
• Efficacy is mostly surgical models
• Outbred animals, species/strains not used in drug development and limited

background histopathology data available (large hound dogs, ruminants, rabbits, chinchilla, guinea pigs)

KEY POINTS FOR PATHOLOGY

• Compare biologic response of test to control material
• Appropriate control biomaterials and devices can be difficult to

find

• USP sells defined control polymers that may not match

(chemistry, production and form)

• Novel, unique and tunable biomaterials often mismatched
• High risk devices often contain multiple biomaterials
• Surgical or room controls may be need
• Predicate devices do not match (chemistry, production and

form)

KEY POINTS FOR PATHOLOGY

• Local biocompatibility evaluation
• Use ISO 10993-6:2016 Annex E for examples of

scoring protocols (semi-quantitative or quantitative) for tissue responses to implanted biomaterials

• Subcutaneous, muscle, bone and brain
• Reports generally have no morphological

diagnoses and no to little explanatory narrative

ISO 10993-6:2016 ANNEX E

ISO 10993-6:2016 ANNEX E

REACTION SCORES

• Prior to ISO 10993-6:2016 was an

irritancy score

• Reported as:

“Under the conditions of this study, the test sample was considered to demonstrate the following: __ minimal or no reaction (0.0 to 2.9); _X slight reaction (3.0 to 8.9); __ moderate reaction (9.0 to 15.0); __ severe reaction (>15.1) to the tissue as compared to the negative control sample.”

10993-6:2016 EXAMPLES MAY NEED TO BE MODIFIED

• Does not account for all implantable sites or tissues
• E.g. intravaginal – modify Annex E or use published scoring

method

• May need to use vertical (other ISO standards) and

horizontal references for certain tissues

• Established (published) histomorphometry protocols for certain

nonbiodegradable and complex devices (cardiovascular, bone)

• Lymph node evaluations
• Should lymph nodes reactions be scored or described?
• If scored, how?

KEY POINTS FOR PATHOLOGY

• Systemic in vivo biocompatibility evaluation
• Use ISO 10993-11:2016
• Annex D – clinical pathology evaluations
• Annex E – organ list using a tiered approach
• FDA may request full tissue list
• Annex F – limited histopathology list
• Surgical/implant site, regional tissues, draining lymph

nodes and selected major organs

KEY POINTS FOR PATHOLOGY

• Systemic biocompatibility reporting
• Simple adaptation of 10993-6:2016 scoring

templates to complex medical devices and systemic tissues is not appropriate

• Ideal
• Score the device, provide morphological diagnoses of

tissue:device interface and regional responses

• Morphological diagnoses of other tissue responses
• Descriptive narrative incorporating histomorphometry as

determinants of systemic biocompatibility

KEY POINTS FOR MEDICAL DEVICES

• Dogma – Medical devices produce local and physical or functional

effects but not regional or systemic effects

• But we have not been looking hard enough?
• ISO 10993-6 and -11 now suggest collecting regional lymph nodes
• Some systemic effects have been reported
• Device components can fracture, fragment and move
• Metal ions / wear particulates (joint replacements) may have systemic effects –

“metalosis”, allergy to metals

• Bisphenol and phthalate release from cardiovascular devices may impair

immune system and recovery

• Shang, J. et al. 2018. Recovery From a Myocardial Infarction Is Impaired in Male C57bl/6 N

Mice Acutely Exposed to the Bisphenols and Phthalates That Escape From Medical Devices Used in Cardiac Surgery. Toxicological Sciences, 168(1), 78-94.

KEY POINTS FOR PATHOLOGY

• Masked/blind review infrequently done
• No expectation of peer review
• Peer review is often independent repeat of ISO 10993-

6:2016 type of scoring

• Evaluate other tissue responses and narrative if present
• Frequent confounding lesions
• Surgical models, secondary devices used (staples, sutures),

adhesives, infections (sterility of device, procedures used, and manufacturing contaminants and chemical residues

• Animal species and strains not used in other toxicology

studies (hound dogs, small ruminants, rabbits, guinea pigs) – incidence of background/spontaneous tissue changes often not available

YES, THERE REALLY IS A GAP

VETERINARY PATHOLOGY REGULATORY MEDICAL DEVICE INDUSTRY

VETERINARY PATHOLOGISTS

Veterinary pathology profession not proactive in this field

• Not an intentional part of veterinary pathology training
• Foreign body reactions to biological materials usually considered incidental – e.g.

sutures, orthopedics, other (hair, plants awns)

• Historically, medical device histopathology scoring often conducted by

medical pathologists and Ph.D. scientists

• Gross pathology may be done by surgeons or engineers

Medical device industry barely knows that veterinary pathologists exist and the skills we possess Veterinary pathologists often accidentally enter the field of biomaterial and medical device testing

• Learn by self-study
• Limited mentoring, formal training and continuing education

VETERINARY PATHOLOGISTS

Veterinary pathologists evaluating medical devices are often working in isolation

• CROs, large medical device companies, independent

consultants and consulting or retired academic pathologists Veterinary pathologists not invited to participate in defining study design and testing standards

• ISO 10993 series
• Standards organizations are for profit and commercial

members define and write the standards References and textbook resources with tissue responses are mostly scattered throughout the field of engineering

MEDICAL DEVICE INDUSTRY

• Development of biomaterials and devices
• Mechanical, chemical or materials science engineers and

bioengineers

• Prefer to test for deleterious effects by in vitro/ ex vivo

modeling, analytical chemistry and use literature for risk assessment

• Engineers want numbers; do not understand the “art of

pathology”

MEDICAL DEVICE INDUSTRY

• Innovators (Engineers) and Investors
• Few large companies and lots of little companies
• Desire to limit time-to-market for devices
• Low risk 18 mo, High risk 3-7 years to market
• Desire to limit cost-to-market
• Do minimum of studies, animals, tissues and evaluations
• Do not like to pay upfront for studies or pathologists
• Prefer to pay at backend for recalls, revision surgeries and to

resolve litigation

PUBLISHED DEVICE DEVELOPMENT LIFECYCLE ?

• NONCLINICAL REQUIREMENTS OFTEN ASSUMED TO BE MINIMAL

van Overbeeke, E. et al. 2019. Factors and situations influencing the value of patient preference studies along the medical product lifecycle: a literature review. Drug discovery today 24:57-68

REGULATORY ISSUES

Regulatory Oversight

• Standards not present until the 1970’s
• FDA memorandum in 1987
• Matrix for testing based on device location and duration
• Little to no consideration for histopathology evaluations

Dogma - Biomaterials are inert

• Adverse effects not recognized until the late 1980’s
• Still poorly characterized
• Study design/conduct and histopathology spun out of

characterizing general materials through standards

• rganizations

REGULATORY CHANGES

Increasing regulatory oversight over devices

• EU device regulatory changes come into force 25 May 2020
• Broaden definitions of medical devices
• Reclassification of devices
• Increase safety measures and risk management
• Legacy devices (CE marking) will have to meet new safety

conditions

• FDA has increased need for more safety and longer safety

and efficacy studies

• Reclassification of devices
• Increase safety measures and risk management
• New guidances documents

CONSEQUENCES OF THE GAP

• Patients are injured or killed
• The lawyers are circling - Medical device class action lawsuits:
• Inferior vena cava filters – fracture, detachment, migration and vena

cava puncture, death

• Hernia or transvaginal mesh – migration, organ damage or

perforation, pain, sepsis

• Power morcellators (fibroma removal) – spread of undiagnosed

uterine cancer

• Essure birth control – device fractures, migration, perforation,

pregnancy, metal allergy, death

• Bone cement – fragmentation, leakage into blood, bone cement

implantation syndrome

• Joint implants – Metal ion/particle release, premature failure,

fractures, osteolysis

• Textured breast implants – breast implant-associated anaplastic

large cell lymphoma

THE “IMPLANT FILES”

WEBSITE - HTTPS://MEDICALDEVICES.ICIJ.ORG/

International Consortium of Investigative Journalists (ICIJ)

• Global investigation into medical device harm
• Compiled an international medical devices database (IMDD)
• Recalls, Safety Alerts and Field Safety Notices about medical

devices distributed worldwide – up to Oct, 2018

• Putting pressure on regulatory authorities
• In 2018, FDA proposed Medical Device Safety Action Plan to

strengthen and modernize the 510(k) program

• In 2019 ending “alternative summary reporting”
• “Hidden” faulty device reports exempted from public

manufacturer and user facility device experience (MAUDE) database

CONCLUSION

• The medical device industry is a mess
• Medical device development is

confusing and not well monitored

• Medical device approvals and

clearances are not always based on good science

BRIDGING THE GAP – TOXICOLOGIC PATHOLOGISTS

Ideal professional to provide:

• Safety assessment for biocompatibility
• Safety and efficacy evaluations of medical products in animals
• Assist medical device development teams to set study design

and endpoints

• The FDA recommends our involvement in study design and

evaluations (draft guidance on animal studies, 2015)

• Nikula, KJ., Funk, K. 2016. "Regulatory Forum Opinion Piece:

An experienced pathologist should be present at necropsy for novel medical device studies." Toxicologic Pathology 44 (1):9- 11.

BRIDGING THE GAP

What have we done and what can we do:

1) Formed Special Interest Groups

• STP - Medical Device Special Interest Group

(MD-SIG)

• Provide education, partnerships, and best

practices

• SOT - Medical Device Specialty Section

BRIDGING THE GAP

2) Publications in Toxicologic Pathology

• Sporadic but increasing
• Gad SC and Schuh JCL. 2018. Toxicologic pathology forum
• pinion paper: Considerations for toxicologic pathologists

evaluating the safety of biomaterials and finished medical

• devices. Toxicologic pathology 46.4 (2018): 366-371.
• Annual symposium session in 2008 - 4

papers

• Special issue

TOXICOLOGIC PATHOLOGY – MEDICAL DEVICE SPECIAL ISSUE

Vol 47(3) 2019

Lots of good information on theory and practice

• Species used, study design,

gross, histology, general and tissue-specific design and evaluations for single, complex and combination products, basic and advanced techniques, regulatory, 3R’s

BRIDGING THE GAP

3) Need more reference books and chapters in toxicologic pathology of biomaterials and medical devices:

• Sahota, P. S., Spaet, R. H., Bentley, P., & Wojcinski, Z. (Eds.). 2019. The

Illustrated Dictionary of Toxicologic Pathology and Safety Science. CRC Press.

• Funk, KA, Hampshire, VA, Schuh, JCL. 2018. Nonclinical Safety Evaluation of

Medical Devices. In: Toxicologic Pathology: Nonclinical Safety Assessment (Sahota, PS, et al. eds.). CRC Press, Boca Raton, FL.

• Goad, MEP, and DL Goad. 2013. Biomedical Materials and Devices. In: Haschek

and Rousseaux's Handbook of Toxicologic Pathology, edited by Wanda M Haschek, Colin G Rousseaux and Matthew A Wallig, 459-77. San Diego, CA: Academic Press.

• Alves, A, Metz, A, Render, J. 2012. Microscopic and ultrastructural pathology in

medical devices. In: Biocompatibility and Performance of Medical Devices (Boutrand, J.-P. ed.), pp. 457-499. Woodhead Publishing, Philadelphia, PA.

BRIDGING THE GAP

4) Other publication venues are important

• Engineers and engineering

publications need to improve the quality of their presentation of pathology and biocompatibility data

• Peer review by toxicologic pathologists?
• Cross-over publications to bioengineering
• Regulatory Forum compilations?

BRIDGING THE GAP

5) More training, mentoring and CE courses

• This meeting (STP Annual Symposium 2019 Continuing Education)
• CE2 – Medical Device Safety Assessment: The Frontiers of Safety

Assessment Pathology – Maureen O’Brien and Serge Rousselle

• ACVP
• Veterinary and medical pathologists without industry experience need

training in GLPs, ISO standards, proper report preparation and risk assessment

• Pathology training programs
• Need to bring medical device awareness to these programs through

education about this field and career opportunities

• Toxicology Societies - ACT and SOT
• Integrated pathology and toxicology position on medical device study

design and evaluations

BRIDGING THE GAP

6) Incorporation of advanced techniques - 1

• Electron microscopy already used
• Scanning and transmission EM heavily used by engineers to

characterization devices; our needs are often different

• In vivo imaging
• Angiography, ultrasonography, fluoroscopy, radiography or

microradiography, magnetic resonance imaging, micro-computed tomography (µCT) optical coherence tomography, intravital multiphoton imaging

• Obtain sequential data in life on location, movement, degradation

properties or integration of devices

• Improve the accuracy of sample collection and also supplement

histopathology

• Seldom used outside of research settings due to lack of

availability of instrumentation and cost of use

BRIDGING THE GAP

6) Incorporation of advanced techniques - 2

• Tissue microsampling for leachables and particulates
• X-ray fluorescence microscopy
• MALDI-TOF mass spectrometry
• Digital imaging
• Digital pathology example – GLP-compliant implantation

studies

• Gauthier, Béatrice E., et al. 2019. "Toxicologic Pathology Forum:

Opinion on Integrating Innovative Digital Pathology Tools in the Regulatory Framework." Toxicologic pathology. Vol 47(4):436-443

BRIDGING THE GAP

6) Incorporation of advanced techniques - 3

• Detailed immunological and inflammatory reaction evaluations
• Immunohistochemistry (IHC) to identify, localize and characterize

tissue responses

• Difficult sourcing of appropriate antibodies for some nonstandard

test species

• Requires extensive method development with optimization
• Immunotoxicology – ISO 10993-20:2006
• Antiquated and seldom used
• Flow cytometry and more clinical pathology to look at potential

systemic response

• The challenge for pathologists is to integrate more exacting

technologies to view the tissue-device interactions and to do so in a cost-effective manner

BRIDGING THE GAP

7) Foster closer ties with engineers in academia and

industry

• Attend and participate in biomaterial and medical

device industry meetings

• Contribute directly to education of bioengineers
• Showcase our skills and convince engineers to

improved safety and efficacy evaluations

• Biomaterials and medical devices are not inert
• Clinical failures are not acceptable
• New and complex devices require more attention to the

quality of in vivo testing

FATE AND ADVERSE SEQUELAE TO PERMANENT MEDICAL DEVICES PERCEIVED BY:

Toxicologic Pathologist Engineer/Investor

BRIDGING THE GAP

8) Influence regulatory standards

• Regulatory forum opinions pieces in Toxicologic Pathology
• Need best practice paper(s) on clinical pathology and histopathology

evaluation and biocompatibility of medical devices

• We need to extend harmonized nomenclature to biocompatibility and

medical devices

• INHAND tissue-specific and rabbit and pig monographs are a good start
• Extend current INHAND to unique responses seen with implantation studies and

unique species

• Nudge the ISO 10993-6 out of position or obtain direct influence and

pathology representation for next committee update

• Our collective scientific experience is required to bring higher quality pathology

and histomorphometric evaluations to risk assessment for biocompatibility and finished medical devices

WHY BOTHER BRIDGING THE GAP

• Increasing complexity of unique biomaterials,

medical devices and combination products

• Increasing regulatory demands for detailed safety

and efficacy testing

• Better risk assessment needed to prevent harm

and product failures

• Career opportunity for toxicologic pathologists