Toxicological Testing for Devices

Versus Drugs & Biologics

L. Bruce Pearce, Ph.D.

November 7, 2012

American College of Toxicology

Orlando, Florida

Slide 2ACT Annual Meeting

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”

Slide 3ACT Annual Meeting

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.

Slide 4ACT Annual Meeting

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

Slide 5ACT Annual Meeting

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

Slide 6ACT Annual Meeting

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

Slide 7ACT Annual Meeting

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

Slide 8ACT Annual Meeting

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

.

Slide 9ACT Annual Meeting

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)

Slide 10ACT Annual Meeting

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.

Slide 11ACT Annual Meeting

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

Slide 12ACT Annual Meeting

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.

Slide 13ACT Annual Meeting

There are Two Elements to Risk Assessment

• Chemical Data: Inherent toxicity and risk analysis

• Biological Data: Biocompatibility Testing

• Specified by international standards

Slide 14ACT Annual Meeting

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).

Slide 15ACT Annual Meeting

ISO 10993 Biological Evaluation of Medical Devices

Part Title Publication\Revision 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

Devices

First Edition 1998

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

Slide 16ACT Annual Meeting

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?

Slide 17ACT Annual Meeting

Intended Use vs Evaluations

ISO/FDA Test Chart

Slide 18ACT Annual Meeting

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 andIncluded in general tox study design not as a separate study like for devices

Slide 19ACT Annual Meeting

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

Slide 20ACT Annual Meeting

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.

Slide 21ACT Annual Meeting

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