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BRIDGING THE GAP BETWEEN TOXICOLOGIC PATHOLOGISTS AND THE MEDICAL DEVICE INDUSTRY
JOANN C. L. SCHUH
JCL SCHUH, PLLC
BAINBRIDGE ISLAND, WA
SURVEY – SHOW OF HANDSAre 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, 2018A 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, or
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 DEVICESTypes:
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 changesOrgan Systems:
Cardiovascular, skeletal, integument, reproductive, respiratory, special senses, nervous, digestive
KEY POINTS FOR MEDICAL DEVICESSafety 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 or systemic effects in the recipient.
Determination made based on results of all testing
POTENTIAL TESTING FOR BIOCOMPATIBILITYCytotoxicityExtractables and leachablesSensitizationHemocompatibilityPyrogenicityParticulates, contaminants and degradantsGenotoxicityImplantation (local tissue tolerance)In vivo toxicity (acute to chronic)Safety PharmacologyCarcinogenicityReproductive & 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 UNIVERSALFDA 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 PATHWAYSDRUG
505(j) Abbreviated NDA (ANDA)
Petitioned ANDA
505(b)(2) NDA
505(b)(1) New Drug Application (NDA)
DEVICE 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
RISK
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 PATHOLOGISTSVeterinary 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 possessVeterinary pathologists often accidentally enter the field of biomaterial and medical device testing
Learn by self-study Limited mentoring, formal training and continuing education
VETERINARY PATHOLOGISTSVeterinary 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 standardsReferences 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 ISSUESRegulatory 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 organizations
REGULATORY CHANGESIncreasing 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 GAPWhat 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 GAP2) Publications in Toxicologic Pathology Sporadic but increasing
Gad SC and Schuh JCL. 2018. Toxicologic pathology forum opinion 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) 2019Lots 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 GAP3) 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 GAP4) 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 GAP5) 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 GAP6) 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 GAP6) 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 GAP6) 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 GAP7) 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 PathologistEngineer/Investor
BRIDGING THE GAP8) 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
