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Innovative Medical Devices: Developing Multidisciplinary Safety & Efficacy Testing Strategies for Combination Products

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John Iannone, Program Manager, Toxikon Corporation

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Innovative Medical Devices: Developing Multidisciplinary Safety & Efficacy Testing Strategies for Combination Products

  1. 1. HAI Solutions & Innovative Medical Devices: Developing Multidisciplinary Safety & Efficacy Testing Strategies John Iannone, BME
  2. 2. » Nearly 40 yrs of experience in Medical Device, Pharma, & Biotech Industry • Biocompatibilty/Material Qualification • Toxicology Testing • Extractables & Leachables • Microbiology » FDA Registered » ISO 17025 Accredited » GLP & GMP Compliant testing 1 Toxikon Company Profile
  3. 3. HAI Solutions and Innovative Medical Devices » Healthcare Associated Infections (HAIs) • Significant risk to public health • Responsible for excess medical costs • Multibillion dollar opportunity » Revisit Old Approaches to Combat HAIs • Reusable device reprocessing (Case Study) » New Approaches to Combat HAIs • Unique designs, Engineering Solutions (Case Study) • AM Combination products, Innovative Materials (Case Study) » Safety & Efficacy Testing • Biocompatibility • Microbiology • Chemical Characterization/ E&L • Toxicology2
  4. 4. Healthcare Associated Infections (HAIs) » Emergence of Antibiotic Resistance » Antibiotic Drug Development » Centralized Introduction and Exposure » Inability to Eradicate Pathogens from Healthcare Institutions » Susceptible Patient Populations 3
  5. 5. Antibiotic Resistance over Time 4 Centers for Disease Control and Prevention
  6. 6. Antibiotic Pipeline 5
  7. 7. » FDA GAIN Act • Qualifying Pathogens » CDC • Antibiotic Resistance Healthcare Associated Infections 6
  8. 8. Major Site of Infection Estimated Number of Infections Healthcare-Associated Infection (all HAI) 1,737,125 Surgical Site Infection (SSI) 290,485 Central Line Associated Bloodstream Infections (CLABSI) 92,011 Ventilator-associated Pneumonia (VAP) 52,543 Catheter associated Urinary Tract Infection (CAUTI) 449,334 Clostridium difficile-associated disease (CDI) 178,000 Klevens, RM; Edwards, JR; Richards, CL; Horan, T; Gaynes, R; Polloc,k D; Car,d D. Estimating healthcare-associated infections in U.S. hospitals, 2002. Public Health Rep 2007;122:160-166. R. Douglas Scott II. The Direct Medical Costs of Healthcare-Associated Infections in U.S. Hospitals and the Benefits of Prevention. CDC CS200891-A. CDC - 2,299,442 Infections due to antibiotic resistance pathogens. $28.4 – 45.0 Billion Healthcare Associated Infections 1:20 Some HAIs will no longer qualify for reimbursements. 7
  9. 9. Spot Light on HAI Solutions
  10. 10. HAI Solutions – Process Focus CONFIDENTIAL9 Draft Guidance for Industry & FDA Staff Processing/Reprocessing Medical Devices in Health Care Settings: Validation Methods & Labeling Draft Guidance, May 2, 2011
  11. 11. Why are Reprocessing Validations Important? CONFIDENTIAL10 Lawrence F. Muscarella, Clinical Gastroenterology and Hepatology 2010;8:577-580.
  12. 12. HAI Solutions – Products Focus 11
  13. 13. In the News: Recently, Covidien launched 2 new product lines: 1. Disinfectant Cap (Excelsior Medical) 2. Needleless Connector (NP Medical) Improve compliance with standard Infection Prevention Protocols 12 New Products Designed to Improve Compliance w/Standard Infection Control Protocols Kendall prefill syringe with removable luer access disinfectant cap • Integrates the cap into the plunger of the syringe • Design makes cap readily available • Using disinfectant cap can • help prevent pathogens from entering vascular access devices • promote compliance with infection control protocols Kendall neutral displacement needleless connector • Designed to complement best clinical practices to help reduce the risk of catheter-related blood stream infections
  14. 14. 13 New Products Designed to Improve Compliance w/Standard Infection Control Protocols NEEDLELESS CONNECTORS: • A flat, smooth septum surface promotes proper disinfection • Maintaining the septum surface integrity over the life of the product promotes proper disinfection • If use & reuse generates gaps or openings, it creates new surfaces that cannot be easily reached during disinfection • Improper disinfection due to compromised septum surface can result in infusing contaminated pathogens into the blood stream
  15. 15. • nPulseTM Needle-free Connector has a self-opening split septum (SOSSTM) • Avoids forcing the male Luer tip through the septum & eliminates need for an internal cannula that drags against the critical septum seal surface 14 New Products Designed to Improve Compliance w/Standard Infection Control Protocols 7 day extreme use conditioning • 168 activation cycles & 168 hour activation period • Staphylococcus aureus inoculation upon the device septum at a clinically high level (~500 CFU) • Incubation followed by wiping septum w/ alcohol nPulse™ test samples showed no growth!
  16. 16. Combination Products, per 21 CFR 3.2(e) Combined (Physically, Chemically, or Combined/Mixed): 1. Pre-filled Syringes with Drug or Biologic 2. Meter Dosed Inhaler 3. Drug Coated Stents 4. Antimicrobial Treated Catheter Co-packaged: 1. Disposable or re-use injector with Drug or Biologic 2. Delivery Pump with Drug or Biologic Separately packaged and cross-labeled: 1. Surgical Kit and Drug 15
  17. 17. Antimicrobial Agents – Innovative Materials » Main Classes: • Antibiotics, Antivirals, Antifungals, Preservatives » Antimicrobial Active Ingredients are: • Blended into a product • Bonded onto a material's surface • Coating treatments applied to another surface » Utility: • Resist microbiological growth • Protect the device formulation • Protect the patient 16
  18. 18. Why Combination Products? Drive to improve existing medical devices • All issues can't be solved with mechanically performing devices Integrate new technologies to solve existing problems • Medical device function can be enhanced by including a therapeutic agent Build a better Mousetrap! Example: • The mechanical septum of a needless connector provides a barrier which slows ingress of microorganisms that may cause infection • The integration of an effective antimicrobial agent could stop microbial growth/ingress Typical purpose of a Combination Product may be to: 1. use a drug coating in order to augment a property of a medical device, or 2. to use the device as a delivery method for a drug
  19. 19. Focus on Solving HAI Problems » Cardiac Implantable Electronic Devices (CIED) • Post surgery infections growing 5x faster than implant procedures • Treatment/ Resolution costs: MEAN: >$50K / per patient REACHING: >$100K/ per patient 1. Voigt et al. J Amer Coll Cardiol. 2006;48(3):590-591. 2. Voigt et al. PACE 2010;33(4):414-419. 18
  20. 20. Focus on Solving HAI Problems » TyRx, a NJ based startup, Takes Notice » Develops Antimicrobial pouch • Deliver targeted antibiotics for CIED related infections • Delivery is targeted at surgical site • Delivery is sustained during critical time » Preclinical data demonstrates effectiveness » Clinical data exhibits a 94% reduction in infection rates » Medtronic buys company early 2014 for $160 million 19
  21. 21. Regulatory Path: Multi-disciplinary Testing Needs
  22. 22. Biocompatibility Chemical Characterization Toxicity & Efficacy Microbiology Multi-disciplinary Testing Needs 21 CONFIDENTIAL
  23. 23. Microbiological Efficacy
  24. 24. Antimicrobial Efficacy Testing Designing Your Efficacy Program » Neutralization Validation (AM related) » Recovery Efficiency (Material/Device related) » Microbial Growth & quantitation • Log Reduction • Kill Time 23 Efficacy Kinetics
  25. 25. Medical Device Testing - Biocompatibility
  26. 26. Biocompatibility Testing Categories » Cytotoxicity » Sensitization » Irritation & Intracutaneous Reactivity » Acute Systemic Toxicity » Subacute & Subchronic Systemic Toxicity » Genotoxicity » Implantation Reactivity » Hemocompatibility » Chronic Systemic Toxicity » Carcinogenicity 25
  27. 27. Biocompatibility Testing Matrix 26 Contact duration Cytotoxicity Sensitivity/Sensitization Irritation/Intracutaneous Reactivity SystemicToxicity (Acute) Pyrogenicity Subacuteand/orSub chronictoxicity Genetic Toxicity/Genotoxicity Implantation Hemocompatibility ChronicToxicity Carcinogenicity Reproductive/ Developmental Biodegradation/ Biodegradable Category Contact less than 24 hours    24 hours to 30 days    more than a 30 days    less than 24 hours    24 hours to 30 days        more than a 30 days          less than 24 hours      24 hours to 30 days        more than a 30 days          less than 24 hours       24 hours to 30 days        more than a 30 days            less than 24 hours      24 hours to 30 days         more than a 30 days           less than 24 hours        24 hours to 30 days          more than a 30 days            less than 24 hours      24 hours to 30 days         more than a 30 days           less than 24 hours         24 hours to 30 days          more than a 30 days             = Evaluation required by ISO, FDA and MHLW  = Evaluation required by ISO and FDA  =Evaluation required by FDA  =Evaluation required by ISO Circulating Blood Initial Evaluation Supplemental Body Contact Tissue/Bone/Dentin Device Categories Tissue/Bone Blood Skin Mucous/Mucosal Membrane Breached/Compromised Surface Blood Vessels/Blood Path Indirect Body Surface Contact Device/Surface Device Devices connecting the internal to the external/External communicating device Internally implanted devices/Implant device
  28. 28. Chemical Characterization
  29. 29. Biocompatibility Testing Matrix 28 Contact duration Cytotoxicity Sensitivity/Sensitization Irritation/Intracutaneous Reactivity SystemicToxicity (Acute) Pyrogenicity Subacuteand/orSub chronictoxicity Genetic Toxicity/Genotoxicity Implantation Hemocompatibility ChronicToxicity Carcinogenicity Reproductive/ Developmental Biodegradation/ Biodegradable Category Contact less than 24 hours    24 hours to 30 days    more than a 30 days    less than 24 hours    24 hours to 30 days        more than a 30 days          less than 24 hours      24 hours to 30 days        more than a 30 days          less than 24 hours       24 hours to 30 days        more than a 30 days            less than 24 hours      24 hours to 30 days         more than a 30 days           less than 24 hours        24 hours to 30 days          more than a 30 days            less than 24 hours      24 hours to 30 days         more than a 30 days           less than 24 hours         24 hours to 30 days          more than a 30 days             = Evaluation required by ISO, FDA and MHLW  = Evaluation required by ISO and FDA  =Evaluation required by FDA  =Evaluation required by ISO Circulating Blood Initial Evaluation Supplemental Body Contact Tissue/Bone/Dentin Device Categories Tissue/Bone Blood Skin Mucous/Mucosal Membrane Breached/Compromised Surface Blood Vessels/Blood Path Indirect Body Surface Contact Device/Surface Device Devices connecting the internal to the external/External communicating device Internally implanted devices/Implant device
  30. 30. Leachate Migration / Extraction 29 Polymer Migration Extraction Solution Environment of Concern
  31. 31. Extractables & Leachables 30 » Extractables: Extractables are compounds that migrate from the contact surface under more aggressive conditions such as elevated temperature, extended contact time, or aggressive solvent system. Any component that is added to or pulled from the device or the materials used to make the device, including degradants and residuals. What CAN come out. » Leachables: Leachables are compounds that migrate from the contact surface under normal conditions of exposure. Leachables are usually subset of extractables. What DOES come out.
  32. 32. Extractable/Leachable Relationship 31 Extractables/Leachables » LEACHABLES are typically a SUBSET of EXTRACTABLES » NOT ALL LEACHABLES are EXTRACTABLES
  33. 33. Chemical Characterization – Extractable & Leachable SOURCES OF LEACHATES » Polymer Additives  Antioxidants, Slip Agents, Fillers, UV Stabilizers, Plasticizers » Polymer Degradation Products  Sterilization, Storage/Shelf-Life, Processing » Residues  Monomers, Catalyst, Solvents » Manufacturing Impurities/ Migration from Secondary Materials  Adhesive, Ink, Paper Binders, Packaging » Drug/Chemical Additives  API, Excipients, Antimicrobial Agent 32
  34. 34. Extractable/Leachable Sources 33 Potential Inorganic Compounds of concerns Metals
  35. 35. Elution Profile Determination » Screening for what CAN be present • Identify Universe of potential compounds » Assess Leaching Behavior • How much MAY be present? » Focus on Quantitation of “Target” Compounds • Include Expected Elutents • Confirm expected release kinetics » Assess Potential Toxicological Consequence • What could be the impact to the Patient? 34
  36. 36. Premarket Notification [510(k)] Submissions for Medical Devices that Include Antimicrobial Agents Recomendations » Determine biocompatibility & toxicological affect of device to patient » Determine the safe levels of the Antimicrobial Agent (NOAEL) » Ensure that the integration of the Antimicrobial Agent with the device is still safe (this is not considered additive, but multiplicative).
  37. 37. Premarket Notification [510(k)] Submissions for Medical Devices that Include Antimicrobial Agents Recomendations » Low levels of toxic leachates exposed to patient with Antimicrobial Agent may result in new safety concerns. » Ensure the interaction of leachates & degradants from device are non- reactive with eluted antimicrobial agent & it’s degradation components. » Ensure antimicrobial loading is sufficient to demonstrate improved efficacy
  38. 38. Therapeutic Window: Balancing Efficacy & Safety » Higher concentrations of Antimicrobial should improve efficacy » Lower concentrations of eluted Antimicrobial should improve safety profile » Drive allowable limits for optimized BALANCE between Safety and efficacy 37
  39. 39. » Efficacy: Microbiologically Advantageous with Sustaining Effect – Agent is effective against pathogens of concern – Chemical Elution is adequately sustained » Safety: Biocompatibility, Toxicology per OECD, ISO etc. – Toxicological effects of the drug/biologic are known or determined – Evaluation of product use in combination product must demonstrate maintenance of safety Extractables/Leachables Controlled Elution - Promote Safety & Efficacy 38 » Therapeutic Window – Agent elution is controlled to ensure concentration is sufficiently sustained for Adequate Efficacy – Agent elution is controlled to ensure concentration does not exceed toxicologically concerning levels CONFIDENTIAL
  40. 40. Takeaway Message (Conclusion) 39 » Healthcare Associated Infections (HAIs) • Significant risk to public health • Responsible for excess medical costs » Solving the HAI Problem • Process Improvement • Product Innovation » Regulatory Pathway • Safety: Biocompatibility & Toxicology • Efficacy: Microbiology & Chemical Characterization
  41. 41. THANK YOU John Iannone Program Manager Technical Specialist john.iannone@toxikon.com 15 Wiggins Ave, Bedford, MA 01730 800-458-4141 x7142 40

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