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

1. Toxicological Testing for Devices
Versus Drugs & Biologics
L. Bruce Pearce, Ph.D.
November 7, 2012
American College of Toxicology
Orlando, Florida

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”
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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.
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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 9-26-2011
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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 devices
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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 chemicals
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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 use
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8. Evaluation of Class II or III Devices Requiring
Clinical 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
.
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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)
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10. Biological Hazard and Risk Assessment: Where Do
We Begin?
Risk assessment has only recently been integrated into international standards and
endorsed as an integral part of chemical characterization and biocompatibility studies for
medical devices.
The first step for a biological hazard/safety assessment is to characterize the potential
toxicants.
Manufacturing, assembling, packaging, and sterilization of medical devices tend to
result in a multiplicity of process chemicals that can potentially migrate into surrounding
tissues and body fluids.
Many of these chemicals are complex mixtures, often with poorly defined toxicological
profiles. The profiles can become increasingly important because moving from a chemical
with well-established risks to a chemical we know less about can make it difficult to define
the hazard, so a higher risk is assigned.
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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 safety
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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.
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13. There are Two Elements to Risk Assessment
• Chemical Data: Inherent toxicity and risk analysis
• Biological Data: Biocompatibility Testing
• Specified by international standards
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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).
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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 2006
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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?
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17. Intended Use vs Evaluations
ISO/FDA Test Chart
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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 devices
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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 outcome
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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.
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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 exposure
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