Toxicological Testing for Devices Versus Drugs & Biologics


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Presentation at the American College of Toxicology Annual Meeting, November 7, 2012, Orlando Fl

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Toxicological Testing for Devices Versus Drugs & Biologics

  1. 1. Toxicological Testing for DevicesVersus Drugs & Biologics L. Bruce Pearce, Ph.D. November 7, 2012 American College of Toxicology Orlando, Florida
  2. 2. Device Any thing which is …. intended for use in the diagnosis of disease …or in the cure, mitigation, treatment, or prevention of disease…, or intended to affect the structure or any function of the body of man…, and which does not achieve its primary intended purposes through chemical action …and which is not dependent upon being metabolized for the achievement of its primary intended purposes”ACT Annual Meeting Slide 2
  3. 3. Scope of Medical Devices Extremely broad category of items, such as bandages, crutches and wheel chairs, sutures, needles and syringes, catheters, contact lenses and lens care solutions, orthopedic implants, dental fillings, pacemakers, thermometers, glucose meters, surgical tools and instruments, respirators, infusion pumps that deliver drugs, and equipment that monitor and measure blood pressure and heart rate, surgical meshes, vascular stents, etc.ACT Annual Meeting Slide 3
  4. 4. Drugs vs. Devices: Fundamental Differences Drugs Devices Pure molecules Complex components Toxicology Biocompatibility Short half-life Durable equipment Long market life Rapid product cycles Drug Interactions Malfunction Wrong Drug/Dose User Error Clinically studied Bench studied Good Manufacturing Practices Quality Systems (ISO 9000) Karanian. J.W. MD-TIP UVA 9-26-2011ACT Annual Meeting Slide 4
  5. 5. Drugs vs Devices: Toxicology  The toxicological effects of devices are not an extension of the pharmacological effects at higher doses..this does not exist  The toxicological effects of devices are related to the materials devices are made from, their breakdown products, precursor molecules and contaminants produced during manufacturing  “Chemistry” is only responsible for toxicological and not the beneficial effects of devicesACT Annual Meeting Slide 5
  6. 6. Context of the Evaluation is Very Different  If a toxicologist is involved in evaluating a device this most likely means that the product is going the 510(k) route or a PMA  Only 2% are PMAs so 98% of the time we are talking a 510(k)  If a 510(k) then there is at least one predicate device, this means there is prior exposure of humans to many if not all the chemicalsACT Annual Meeting Slide 6
  7. 7. Context of the Evaluation is Very Different  FDA generally relies, in part, on FDA’s prior determination that a reasonable assurance of safety and effectiveness exists for the predicate device  The toxicological evaluation can be the last evaluation of biologic safety before the device becomes available for human useACT Annual Meeting Slide 7
  8. 8. Evaluation of Class II or III Devices RequiringClinical Trials  Investigational Device Exemption (IDE), analogous to IND and requires preclinical evidence of safety  If a PMA, the extent of information required to support safety can be much greater and clinical testing is required . ACT Annual Meeting Slide 8
  9. 9. What Are We Assessing? Biological Hazards and Risks  Physical and chemical characteristics of the materials  Any existing toxicology and other biological safety data on product and component materials  History of clinical use or human exposure data  Test procedures, in vitro and in vivo ISO 14971:2009 (Annex I)ACT Annual Meeting Slide 9
  10. 10. Biological Hazard and Risk Assessment: Where Do We Begin?Risk assessment has only recently been integrated into international standards andendorsed as an integral part of chemical characterization and biocompatibility studies formedical devices.The first step for a biological hazard/safety assessment is to characterize the potentialtoxicants.Manufacturing, assembling, packaging, and sterilization of medical devices tend toresult in a multiplicity of process chemicals that can potentially migrate into surroundingtissues and body fluids.Many of these chemicals are complex mixtures, often with poorly defined toxicologicalprofiles. The profiles can become increasingly important because moving from a chemicalwith well-established risks to a chemical we know less about can make it difficult to definethe hazard, so a higher risk is assigned.ACT Annual Meeting Slide 10
  11. 11. Elements of Risk Analysis  Identification of all the chemicals that can leach out of the device and into the patient  Review of the existing toxicology data with emphasis on NOAELs in multiple animal species and information regarding toxicological effects in humans and exposure limits such as PEL if available—provide a complete toxicological profile  Estimation of Tolerable Exposure (TE) based on information like NOAELs from animal studies and uncertainty factors to provide an appropriate margin of safety  Estimation of exposure to all the leachables and compare to TE to assess margin of safetyACT Annual Meeting Slide 11
  12. 12. Risk Assessment/Analysis Report • The guidelines for the preparation of a risk analysis report can be found in: • ISO 10993 Part 17 Establishment of Allowable Limits for Leachable Substances • When do you consider evaluation of inherent toxicity of materials? • This should begin in the design phase to aid in the selection of materials, manufacturing process design and sterilization, etc.ACT Annual Meeting Slide 12
  13. 13. There are Two Elements to Risk Assessment • Chemical Data: Inherent toxicity and risk analysis • Biological Data: Biocompatibility Testing • Specified by international standardsACT Annual Meeting Slide 13
  14. 14. Biocompatibility Testing• Toxicological testing of devices comes under the rubric of “Biocompatibility Testing”• Safety assessment of medical devices is guided by toxicology studies recommended by the Biological Evaluation of Medical Devices Technical Committee of the International Organization for Standardization (ISO) documents 10993 (ISO 10993 Technical Committee). • The ISO guidelines are compendial methods; • described in the U.S. Pharmacopoeia (USP) or • in the standards published by the American Society for Testing and Materials (ASTM). ACT Annual Meeting Slide 14
  15. 15. ISO 10993 Biological Evaluation of Medical Devices Part Title PublicationRevision Year 1 Evaluation and Testing with A Risk Management System Fourth Edition 2009 2 Animal Welfare Requirements Second Edition 2006 3 Tests for Genotoxicity, Carcinogenicity, and Reproductive Toxicity Second Edition 2003 4 Selection of Tests for Interactions with Blood and Amendment 1 Second Edition 2002 Amendment 1 2006 5 Tests for In Vitro Cytotoxicity Third Edition 2009 6 Test for Local Effects after Implantation Second Edition 2007 7 Ethylene Oxide Sterilization Residuals Second Edition 2008 Correction 2009 8 Withdrawn -- 9 Framework for Identification and Quantification of Potential Degradation Products Second Edition 2009 10 Tests for irritation and Delayed Type Hypersensitivity and Amendment 1 Third Edition 2010 11 Tests for Systemic Toxicity Second Edition 2006 12 Sample Preparation and Reference Materials Third Edition 2007 13 Identification and Quantification of Degradation Products from Polymeric Medical First Edition 1998 Devices 14 Identification and Quantification of Degradation Products from Ceramics First Edition 2001 15 Identification and Quantification of Degradation Products from Metals and Alloys First Edition 2000 Correction 2001 16 Toxicokinetic Study Design for Degradation Products and Leachables Second Edition 2010 17 Establishment of Allowable Limits for Leachable Substances First Edition 2002 18 Chemical Characterization of Materials First Edition 2005 19 Physicochemical, Morphological, and Topographical Characterization of Materials First Edition 2006 20 Principles and Methods for Immunotoxicity Testing of Medical Devices First Edition 2006ACT Annual Meeting Slide 15
  16. 16. FDA vs ISO Biocompatibility Testing Matrix • Prior to 1995 biocompatibility testing of medical devices in the US was usually conducted by the use of the #G87-1 Tripartite Biocompatibility Guidance (1987). • FDA issued the #G95-1 guidance document in 1995 which was a modified version of ISO 10993, "Biological Evaluation of Medical Devices—Part 1.“ • This document is really in agreement with the ISO testing matrix with a number of exceptions • Assume we are discussing Class II and III medical devices • The number of tests required for a device depends on the intended use and duration of exposure • Is this a device that is placed on the skin or implanted in the body and for how long?ACT Annual Meeting Slide 16
  17. 17. Intended Use vs Evaluations ISO/FDA Test ChartACT Annual Meeting Slide 17
  18. 18. Toxicity Testing Devices Vs Drugs/Biologics Devices Biologics Drugs Cytotoxicity - - Skin Sensitization - - Irritation (dermal or ocular) - - Intracutaneous Reactivity √* √* Pyrogenicity √ √ Genotoxicity √ √ Acute Toxicity √ √ Subchronic Toxicity Chronic Toxicity √ √ Carcinogenicity √ √ Reproductive Toxicity √ √ Implantation - - *with intracutaneous or intramuscular administration, especially for vaccines and Included in general tox study design not as a separate study like for devicesACT Annual Meeting Slide 18
  19. 19. Biocompatibility • Biomaterials or devices interact with tissues and produce some level of reaction in contrast to drugs/biologics • The major category of tissue reactions is the “Foreign Body Response” or FBR • This can be modified by surgical trauma or implant procedure and also things like; • sutures used in the placement of the device eg. tissue mesh • contaminates from manufacturing and pyrogens • Can be very complicated and a good pathologist can be important to avoiding a bad outcomeACT Annual Meeting Slide 19
  20. 20. Summary • Enormous diversity of devices; surgical gloves to stents, • Efficacy does not involve chemical action or metabolism— you are not thinking about other pharmacological sites of action as a source of adverse events or toxicity • 98% of the time a 510(k) which may lead to “FDA-release”, not approval, the latter reserved for successful PMA • A predicate device is the reference • The goal is to establish substantial equivalence • No clinical trials to prove safety and efficacy majority of the time • FDA generally relies, in part, on FDA’s prior determination that a reasonable assurance of safety and effectiveness exists for the predicate device.ACT Annual Meeting Slide 20
  21. 21. Summary • Biological Hazard/Risk Assessment • The toxicologist can have a unique role in the 510(k) process • Assessing the toxicological risk of the leachables and contaminants that are well defined-Risk Analysis : ISO-10992-17 • In vitro and in vivo Biocompatibility testing including systemic tox in animals  ISO-10993 the Holy Grail with additions by FDA  Extent of testing depends on route and duration of exposureACT Annual Meeting Slide 21