Modern Approaches and Special Cases. Whitney V. Christian, Ph.D.

Transcription

1 Modern Approaches and Special Cases Whitney V. Christian, Ph.D.

2 I am a medical device toxicologist employed by Medtronic. Any views presented herein are those of the author and should not be construed to represent the views of Medtronic. Formerly I was an external consultant to DePuy Orthopaedics, which funded some of the work presented herein. Neither myself nor any members of my immediate families have any financial interest or affiliation with DePuy Orthopaedics.

3 An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, 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 intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of 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 any of its primary intended purposes. FDA, 2015:

4 Class Description Percent Examples I Non-invasive 47% II Invasive 43% Band-Aids, examination gloves, hospital beds Infusion pumps, bone fixation screws, condoms III Life supporting/sustaining, implanted, or present potential unreasonable risk of illness/injury 10% Pacemakers, total hip arthroplasty (MoMs), breast implants Biocompatibility: The ability of a material to perform with an appropriate host response in a specific application. ISO standards are testing recommendations and guidelines for evaluating the biocompatibility of medical devices Chester Consensus Conference, 1986 FDA, 2015: FDA, 2014:

5 ANSI/AAMI/ISO :2009 Cor 1:2010/(R)2013 FDA GPM #G95-1: Table 1 & Attachment B Table 2, 1995

6 ISO Standard Title Immunological Endpoint Tests for local effects after implantation Foreign-body response Tests for irritation and skin sensitization Irritation (erythema/edema), sensitization Tests for systemic toxicity Material-mediated pyrogenicity * *Standard not recognized by the FDA Principles and methods for immunotoxicology testing of medical devices Inflammation, immunosuppression, immunostimulation, hypersensitivity, auto-immunity

7 Leveraging big data for regulatory decision making Leveraging evidence from clinical experience and employing evidence synthesis across multiple domains in regulatory decision making Improving the quality and effectiveness of reprocessing reusable medical devices Developing computational modeling technologies to support regulatory decision making Enhancing performance of digital health and medical device cybersecurity Incorporating human factors engineering principles into device design Modernizing biocompatibility/biological risk evaluation of device materials Advancing methods to predict clinical performance of medical devices and their materials Advancing the use of patient-reported outcome measures in regulatory decision making Collecting and using patient experience/preference in regulatory decision making AAMI, 2015:

8 Modern Approaches: In Vitro Assays for Risk Assessment

9 Toxicology in the 21 st Century (Tox21) Development/validation of in vitro cell-based assays to quickly and efficiently determine the potential of chemicals to disrupt processes in the human body that may lead to negative health effects. In vitro toxicity/risk assessment Adverse outcome pathways (AOP) framework Perturbations of toxicity pathways apical endpoints Molecular Initiating Event (MIE) Intermediate Key Events (KEs) Adverse Outcome (AO)

10 ISO Endpoint Current Animal Test Number of Animals In Vitro Alternatives Irritation Rabbit skin irritation test 3 6 Sensitization Guinea pig maximization test Pyrogenicity Rabbit pyrogen test 3-5 EpiSkin, SkinEthic TM RHE, EpiDerm TM SIT DPRA, KeratinoSens, h-clat, mmusst, SenCeeTox PyroCheck, Endosafe TM -IPT, PyroDetect OECD, 2010; Coleman et al., 2015; Hartung, 2015

11 OECD, 2012; Coleman et al., 2015

12 Assay AOP Sensitization Key Event Description DPRA Haptenation (1) KeratinoSens Keratinocyte activation (2) h-clat Dendritic cell activation (3) mmusst Dendritic cell activation (3) SenCeeTox Haptenation (1) Keratinocyte activation (2) Measure chemical reactivity with Cys and Lys containing synthetic peptides Measure Keap1-Nrf2-ARE pathway activation in HaCaT cells transfected with ARE-Nrf2 luciferase reporter Measure cell surface expression of CD86 and CD54 in THP-1 cells via FLOW cytometry Measure cell surface expression of CD86 in U937 cells via FLOW cytometry Measure cell viability (LDH release), GSH depletion, and gene expression changes in ARE/Keap1/Nrf2, AhR/ARNT/XRE, and Nrf1/MTF/MRE pathways (qrt- PCR) in HaCaT cells or RHE (EpiDerm/SkinEthic) Natsch et al., 2013; Urbisch et al., 2015; Coleman et al., 2015

13 Special Cases: Sensitization from MoM Wear Debris

14 Corrosion, fretting wear, articulation, and dissolucytosis generate: Metal ions Metal particulate Depuy, 2013; Langton et al., 2011; Gill et al., 2012; Cooper et al., 2012; Kop et al., 2009; Dunbar, 2010; Higgs et al., 2013; Gascoyne et al., 2014; Soh et al., 1996; Topolovec et al., 2013

15 Are well functioning MoMs capable of inducing sensitization? At what dose does wear debris from a well functioning MoM induce sensitization?

16 Induction establishment of memory T cells Proliferative response Elicitation activation of memory T cells Janeway et al., 2001

17 Are well functioning MoMs capable of inducing sensitization? At what dose does wear debris from a well functioning MoM induce sensitization? Basketter et al., 2003

18 Assay Animal Route Type Guinea Pig Maximization Test (GPMT) Guinea pig Intradermal (injection into dermis) Qualitative Buehler Test (Closed-Patch Test) Guinea pig Dermal (topical) Qualitative Local Lymph Node Assay (LLNA) Mouse Dermal (topical) Quantitative

19 LLNA (Ian Kimber) Ear application (daily, 3x) Day 1-3 Inject label ([ 3 H]-TdR/ [ 125 I]-IUdR+ FUdR) Day 6 Sac, isolate auricular lymph nodes, make single-cell suspension of LNC 2 Days 5 hours X Post in-life phase Quantify proliferation (Liquid Scintillation) PLNA Footpad injection (1x) Day 1 Inject label ( 3 H-TdR/BrdU) Sac, isolate popliteal lymph nodes, make single-cell suspension of LNC 4-10 Days 5 hours X Post in-life phase Quantify proliferation (Liquid Scintillation/FLOW) Positive response: SI >3 Basketter et al., 1996; Chamberlain and Basketter, 1996; Kimber et al., 1998 De Bakker et al., 1990; Bloksma et al., 1995; Schielen et al., 1996; Ravel and Descotes, 2005

20 Year Investigator Study/Finding 1970 Ford et al. Injection of histo-incompatible lymphocytes produced GvH reaction, PLN enlargement Gleichmann 1989 Kimber et al. Footpad injection of anticonvulsant diphenylhydantoin increases PLN weight (PLNA born). PLNA may be useful for studying drug/chemical induced auto-immunity (ISO ). FDA (2002) supports PLNA for immunotoxicological evaluation of new drugs. LLNA identifies contact allergens. PLNA may be useful for studying sensitizing or immunostimulatory chemicals Kammüller et al. PLNA responses to contact allergens. PLNA is useful for detecting sensitizing chemicals Schuhmann et al. PLNA responses to Au 3+. Suggests PLNA can be used to assess metal sensitization Artik et al. PLNA responses to Ni 3+ /Ni 2+. Suggests PLNA can be used to assess metal sensitization.

21 Surrogate MoM wear debris: mixture of commercial metal particles and metal ions (from metal salts) Test article: Cr 2 O 3 particles + Co 2+, Cr 3+, and Ni 2+ ions Physiological relevance of doses Dose Low Medium High Cumulative Wear at 1 mm 3 /yr 10 days 20 years 40 years

22 Proliferative response Quantify immune response Lymph node weight, cellularity, and SI In situ proliferation vs. lymphocyte influx Footpad swelling Characterize immune response Immunoprofiling (CD3/B220, CD4/CD8, I-A D /CD69) H&E histology on PLN sections Distinguish between irritation and sensitization responses

23 Administered Compound SI WI CI Footpad Swelling B220+/ control CD4+ CD8+ I-A D + CD69+ Histology Negative Control Weak sensitizer DCNB <3 C C <1.25 C C C Irritant SDS <3 C C ++ >1.25 C C C Positive Control Strong sensitizer Metal sensitizer DNCB >3 >C >C ++ >1.25 >C >C >C + AuCl 3 >3 >C >C ++ >1.25 >C >C >C Test Article NOAEL Low <3 C C - <1.25 C C C LOAEL Med >3 >C >C + >1.25 >C >C >C SI stimulation index; WI weight index; CI cellularity index C equivalent to control; >C significantly greater than control Gerberick et al. 2002

24 The PLNA is a useful model for evaluating the induction threshold for deep tissue metal sensitization A dose of surrogate wear debris representing 20 years of well functioning MoM wear induced immune stimulation Doses of metal ions alone (i.e., without Cr 2 O 3 particulate) induced similar immune stimulation Patients with normal wearing MoMs are unlikely to become sensitized to wear debris

25 Incomplete characterization of dose-response Assess doses between NOAEL (10 days of wear debris) and the LOAEL (20 years of wear debris) Kinetics of immunological response Assess PLNA response at different times after administration (4 days vs. 10 days) Route of exposure PLNA (footpad) vs. MoM patient (articulating joint) Duration of exposure PLNA (acute) vs. MoM patient (chronic) Extrapolation to humans Differences in inter-individual immune responses (weak vs. moderate vs. strong responders)