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

BRIDGING THE GAP BETWEEN TOXICOLOGIC PATHOLOGISTS AND THE MEDICAL DEVICE INDUSTRY J O A N N C. L. S CH U H J CL S CH U H , PLLC B AI N BRI DGE I SLAN D , WA EM : S CH 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, 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 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 or 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 Title Content (Publication Year) Evaluation and testing within a risk General Principles ; includes a master table for 1 (2009) management process test selection by medical device category Tests for genotoxicity, carcinogenicity and Need for and principles of carcinogenicity 3 (2014) reproductive toxicity genotoxicity and reproductive toxicity testing In vivo testing for materials and devices 4 (2017) Selection of tests for interactions with blood contacting blood Study designs and suggested histopathology 6 (2016) Tests for local effects after implantation scoring methods (Annex E) 11 (2017) Tests for systemic toxicity Study design including histopathology Principles and methods for immunotoxicology 20 (2006) Immunotoxicology testing principles testing of medical devices 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 RI SK DEV I CE DRU G  505(j) Abbreviated  Premarket Notification 510(k) – Low NDA (ANDA) Class I  Petitioned ANDA  With or without exemptions  Premarket Notification 510(k) – Medium Class II  With or without exemptions 505(b)(2) NDA  High  Premarket Approval (PMA) – Class III  De Novo reclassification (lack  505(b)(1) New Drug predicate) Application (NDA)  Investigational Device Exemption (IDE)  Humanitarian Device Exemption (HDE)

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)