Integrating Alternative Methods for Safety Assessment at ... · 10/25/2018 · ISO Round Robin: Reconstructed Human Epidermis (RhE) Model as an In Vitro Skin Irritation Test for

Integrating Alternative Methods for Safety Assessment at FDA’s Center for

Devices and Radiological Health

Peter Goering, PhD, DABT, ATSUSFDA

Center for Devices and Radiological HealthOffice of Science and Engineering Laboratories

NCAC‐SOT Fall SymposiumIntersection of Predictive Toxicology Roadmaps ‐ Tox21, FDA’s Predictive

Toxicology Roadmap, and ToxCast

National Library of MedicineOctober 25, 2018

www.fda.gov

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Disclaimer

• The findings and conclusions presented have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy.

• The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by Department of Health and Human Services.

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OSEL/ DBCMS:Ron BrownRosalie ElespuruChris ForreyJi GuoIrada IsayevaDustin JanesDave SaylorDave SimonShelby SkoogSteve WoodJiwen Zheng

ORISE Research Fellows:Vaishnavi ChandrasekarDebargh DuttaJosh JamisonLaura SaveryPaul TurnerMegan Young

FDA Collaborators:Steven Bauer (CBER)Kenya Brothers (ODE/DCD)Brendan Casey (ODE/DSD)Hany Demian (ODE/DOD)Maureen Dreher (OSEL/DAM)Jen Goode (ODE/DCD)Jeff Fisher (NCTR)Srin Nagaraja (OSEL/DAM)Michael Owens (ODE/DOD)Pushya Potnis (ODE/DRGUD)Erica Takai (OCD)Belay Tesfamariam (CDER)

Funding Sources Critical Path: “Assessing the Risk of Colorants Used in Medical Devices” Chief Scientist: “Assessing the Biological Impact of Degradants Evolving from Biodegradable/Bioresorbable Polymeric Medical Products”CDER: “Safety Evaluation Testing of Biodegradable Polymers: Implications for Drug‐Eluting Stents”

External Collaborators:National Institute for Standards and Technology University of Oregon (MTA)University of North Carolina (MTA)Harvard University (MTA)University of MarylandAdvamedUniformed University of Health Sciences

Acknowledgements

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Medical DevicesMedical Devices

Ophthalmic and Ear, Nose and

Throat

Cardiovascular

Neurological and Physical Medicine

Surgical

Anesthesiology, General Hospital, Respiratory, Infection Control, and

Dental

Reproductive, Gastro‐Renal, and Urological

Orthopedic

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X – recommended by ISOO – recommended by CDRH

From: FDA‐CDRH Guidance Document – Use of International Standard ISO 10993‐1, “Biological evaluation of medical devices –Part 1: Evaluation and testing within a risk management process”

Biocompatibility Evaluation Endpoints

Traditionally, a significant number of animal tests recommended

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FDA Tox Roadmap

• Organizing Committee• Training• Continued Communication

• Collaborations• Research• Oversight

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Key Messages

FDA Toxicology Roadmap (ToxRM), Implications for CDRH:

1. FDA ToxRM is consistent with CRDH regulatory science priorities

2. FDA ToxRM is consistent with 2016 CDRH Biocompatibility Guidance

3. FDA ToxRM goals are consistent with current CDRH collaborative activities with ICCVAM and standards development organizations

4. Ongoing CDRH research supports FDA ToxRM goals

5. New alternative methods are being considered for MDDT development

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FY2017 CDRH Regulatory Science Priorities:Modernize biocompatibility/biological risk

evaluation of device materials

While animal studies have historically been used to predict long‐term safety and effectiveness, tests for carcinogenicity, reproductive toxicity and systemic toxicity are expensive, time consuming, use large numbers of animals and sometimes do not provide results that are easily translatable into a human risk assessment. New, less burdensome approaches that are more patient‐centric and predictive of real‐world device performance are needed to modernize and transform biocompatibility evaluation of medical devices and their materials.

http://www.fda.gov/downloads/MedicalDevices/ScienceandResearch/UCM521503.pdf

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Key Messages







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Toxicological risk assessment is an important component of the biological safety evaluation of many devices

• CDRH Biocompatibility Guidance outlines the importance of toxicological risk assessment for the biological evaluation of devices.

• Identifies when a toxicological risk assessment should be conducted.

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2016 CDRH Biocompatibility Guidance What it says about the use of alternative approaches

“…FDA agrees with the ISO 10993‐1:2009 revision focus on minimizing the “number and exposure of test animals by giving preference to chemical constituent testing and in vitromodels, in situations where these methods yield equally relevant information to that obtained from in vivomodels.”

https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm348890.pdf

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2016 CDRH Biocompatibility Guidance Risk assessment approaches for biocompatibility evaluation

Biocompatibility testing of extracts or intact device

Chemical characterization/toxicological

risk assessment

CDRH is now reviewing more chemical characterization/risk assessments in submissions as an alternative to animal testing to

evaluate some biological endpoints in a biocompatibility evaluation.

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FDA Tox Roadmap



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Key Messages







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ICCVAM Roadmap“This strategic roadmap is a resource to guide U.S. federal agencies and stakeholders seeking to adopt new approaches to safety and risk assessment of chemicals and medical products that improve human relevance and replace or reduce the use of animals. This document was developed with input from members of 16 federal agencies, multiple interagency workgroups, and input from the public. As such, it represents a consensus perspective that does not necessarily reflect opinions or policy of any specific agency or workgroup, and should not be taken as a commitment by any federal agency.”

*Consistent with FDA’s Toxicology RoadMap

https://ntp.niehs.nih.gov/iccvam/docs/roadmap/iccvam_strategicroadmap_january2018_document_508.pdfPublished: 1/31/2018

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ICCVAM Working Groups (WGs)

CDRH is participating or has an interest in multiple ICCVAM WGs:

• Skin Sensitization WG • Read‐Across WG • Acute Toxicity WG• Developmental and Reproductive Toxicity WG • Reference Chemicals WG – for DART WG• In Vitro to In Vivo Extrapolation (IVIVE) WG • Ocular and Dermal Irritation WG

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Biological Evaluation of Medical Devices: Irritation Testing

Rabbit Irritation or Intracutaneous Reactivity Testing

• Normal human keratinocytes cultured on an inert filter at the air‐liquid interface

• Model is histologically similar to in vivo human epidermis

• Validated for irritation testing of neat chemicals (OECD TG 439)

Human Skin Irritation Test

Reconstructed Human Epidermis (RhE) Model

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ISO Round Robin: Reconstructed Human Epidermis (RhE) Model as an In Vitro Skin Irritation Test for Detection of Irritant Activity

in Medical Device Extracts• Organizer: ISO/TC 194 Biological and clinical evaluation of medical devices, WG 8

Irritation and sensitization

• Objective: Evaluate RhE tissue models to detect the presence of strong skin irritants at low levels in dilute medical device polymer extracts

• Participants: International effort included 3 government laboratories, 10 contract research organizations, 3 medical device companies, 2 university laboratories, and the 2 RhE model companies.

MatTek EpiDermTM EpiSkin SkinEthicTM RHE

Stratum corneumStratum granulosum

Stratum spinosum

Stratum basale

Epidermal cell layers

Substrate

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In Vitro Tissue Models: RhE tissue models used in the validation study: • MatTek EpiDermTM

• EpiSkin SkinEthicTM RhE

Test Samples: • 4 experimental polymers (PVC, silicone) fabricated with

known irritants• 3 negative control materials • 2 vehicle controls (saline and sesame oil)

Protocol: • Polymer samples extracted in polar and non‐polar vehicles• Extracts applied to the surface of the RhE tissues • Tissues incubated for 18‐24 h with extracts• After exposure, tissue viability was measured• A reduction of tissue viability >50% indicated irritant activity


in Medical Device Extracts

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• Results: – RhE tissue models can detect the presence of strong skin irritants at low

levels in dilute medical device polymer extracts.– Therefore, these models may be suitable in vitro alternatives to the rabbit

skin irritation test for biological evaluation of medical devices.

• Publication:– W.H. De Jong et al. Round robin study to evaluate the reconstructed human

epidermis (RhE) model as an in vitro skin irritation test for detection of irritant activity in medical device extracts. Toxicology In Vitro 2018

• Standards Development: – The RhE in vitro method has been included in the recent working draft for

ISO 10993‐23 standard for irritation.


in Medical Device Extracts

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FDA Tox Roadmap



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Key Messages







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Using alternative approaches to advance biocompatibility/biological risk evaluation of device materials

Biocompatibility

Exposure Toxicity

Extraction Testing

Biokinetic Models

Transport Properties

In Vitro Toxicity Testing

Computational Toxicology

Risk Assessment

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Exposure Capability #1: Extraction and Chemical Characterization

SalineWaterHexaneEthanol

GPC

MS

UV‐Vis

Test Sample

Extraction Analysis

Traditional methods to estimate exposure do not apply to all devices; need proper protocols for specific biomaterials.

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Exposure Capability #2: Biokinetic Models

Local (material & tissue) Systemic

2 7 20 70M

Serum

Tissues

UrineGut

LocalDevice

kg ku

ktskst

kl

(1− F)Md

FMd

E.g., Ni release and tissue distribution from an NiTi (nitinol) septal occluder

E.g., arterial drug deposition from DES

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Development of a local tissue exposure modelComplimentary, local model to predict the potential for local toxicity

Serum

Tissues

UrineGut

LocalDevice

kg ku

ktskst

kl

(1− F)Md

FMd

Heart chamber

atrial wall

occluder NiTi wire

Currently exploring the use of QIVIVE approach to validate model‐derived predictions of local

nickel tissue concentrations

Saylor DM et al., 2016

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Exposure Capability #3: Transport Properties

Diffusion experimentsMolecular dynamics

15 min 30 min 1 h 2 h

4 h 8 h 1 day 3 days

Predict properties that dictate compound release and validate based on experiments with actual device materials

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Toxicity Capability #1: In vitro Biocompatibility Testing

Hemocompatibility Testing

Cytotoxicity Testing

Hemolysis

Coagulation

Inflammation

Oxidative Stress

Morphology

Cell Viability

Red Blood Cells Platelets

Monocytes

Osteoblasts

Fibroblasts

Coronary Artery Endothelial Cells

Human Blood

Cell Culture Media

Collected Sample

Thrombosis

Traditional methods may not be clinically relevant; need to optimize cell models and test conditions:

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Toxicity Capability #2: Computational Toxicology

Computational toxicology modeling can be used to predict toxicity values e.g., tolerable intake values, for compounds released from devices.

ToxtreeDEREK,etc.

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Toxicity Capability #3: Risk Assessment

Combines exposure and toxicity information to infer potential risk to patients:

margin of safety (MOS) = tolerable intake (TI)exposure

dose‐response exposure

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Combinations of these tools address risks that specific biomaterials pose to patients

1) Assessing the risk of color additives used in medical devices

2) Analysis of degradation products in absorbable cardiovascular stents

3) Assessing endothelial cell biocompatibility of bioresorbable polymers used in vascular scaffolds

4) Biokinetics of nickel released from nitinol cardiovascular devices

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Regulatory Research Supports Guidance Development

• The results of this project will help FDA to more accurately determine the rate at which nickel is released from nitinol cardiovascular devices.

• This information can be used to assess the accuracy of in vitro nickel leach test methods described in current and future CDRH guidances.

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Key Messages







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Tool Developer

Device Industry

PatientsFDA-

Product Evaluators

FDA-Regulatory Scientists

MDDT reduces

regulatory burden

Fosters innovation Encourages collaboration Reduces resource expenditure Qualified MDDT applied in multiple

device submissions Efficiency in CDRH regulatory

review resources Minimizes uncertainty in regulatory

review process

Medical Device Development Tool (MDDT) Program: Benefits of Qualifying Tools

Promotes Efficient Medical Device Development

ResearchDevelopment

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What Is An MDDT?Medical Device Development Tool (MDDT) is a method, material, or measurement used to assess the effectiveness, safety, or performance of a medical device.

• A MDDT is scientifically validated and qualified for a specific Context Of Use(COU)

• COU describes the way the MDDT should be used, purpose in device evaluation and/or regulatory submission, and specific output/measure from the tool

• Qualification is a FDA conclusion that within the COU a MDDT can be relied upon to have a specific interpretation and application in medical device development and regulatory review

• CDRH reviewers should accept the MDDT outcomes within the qualified context of use (COU)) without the need to reconfirm the suitability and utility of the MDDT when used in a regulatory submission

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MDDT Types

Clinical Outcome Assessments

COA• Patient selection for clinical studies• Clinical study outcomes

• Objective and subjective

Nonclinical Assessment Models

NAM• Models (computational and animal) to

measure/predict a parameter of interest• Reduce / Replace animal testing• Reduce test duration or sample size

Biomarker Tests

BT• Objective measure of biologic process or

response to an intervention• Patient selection • Predict or identify outcomes

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MDDT Exciting Growth Opportunities

The MDDT program is seeking new MDDT submissions in the following key areas:

• Surrogate outcomes for clinical trials• Biomarker Tests for physiological safety (e.g., electrical hazard, light/EM radiation hazard, biocompatibility, toxicology)

• Bench Testing Evaluation Methodologies• Computational Modeling and Simulation tools• Phantom Tools• Image Databases with Ground Truth Annotation• Patient Preference Tools

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Resources for More InformationInquiries for Additional Information email: [email protected]

• FR notice announcing the MDDT Program (8/10/2017):https://www.federalregister.gov/documents/2017/08/10/2017‐16827/qualification‐of‐medical‐device‐development‐tools‐guidance‐for‐industry‐tool‐developers‐and‐food‐and

• MDDT Guidance Document:https://www.fda.gov/ucm/groups/fdagov‐public/@fdagov‐meddev‐gen/documents/document/ucm374432.pdf

• MDDT Public Webpage:http://www.fda.gov/MedicalDevices/ScienceandResearch/MedicalDeviceDevelopmentToolsMDDT/default.htm

• Q‐Submission Guidance Document:https://www.fda.gov/ucm/groups/fdagov‐public/@fdagov‐meddev‐gen/documents/document/ucm311176.pdf

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ConclusionsIntegrating Alternative Methods for Safety Assessment

• Regulatory landscape in CDRH and FDA is favorable for the use of new and emerging methods for toxicological risk assessment.

• The ability to use alternative approaches for toxicological risk assessment is described in ISO 10993 standards and in the 2016 CDRH Biocompatibility Guidance.

• CDRH is collaborating with ICCVAM and standards development organizations to support the qualification of new and emerging alterative methods.

• Research is being conducted in CDRH and elsewhere to develop and qualify new computational and in vitro models.

• MDDT can be used as a mechanism to qualify new and emerging methods for assessment of device biocompatibility.

www.fda.gov

Documents

Integrating Alternative Methods for Safety Assessment at ... · 10/25/2018 · ISO Round Robin: Reconstructed Human Epidermis (RhE) Model as an In Vitro Skin Irritation Test for