FDA Perspective: Past vs. Current Expectations for
Toxicity and Biocompatibility Evaluations & Documentation
Valerie Merkle, Ph.D.Lead Reviewer/Biomedical Engineer
Vascular Surgery Devices BranchOffice of Device Evaluation
U.S. Food & Drug [email protected]
Stent Summit, September 6-8, 2017
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Objectives
• Describe biocompatibility review for a device through IDE & PMA process– With and without design/manufacturing changes
• Discuss common requests for additional information regarding biocompatibility reviews
• Please note that we will not delve into the details of the biocompatibility testing, itself or biocompatibility reviews for changes made to a device post-market
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Testing Strategy
Intended Use / Technology (Materials or Design) / Manufacturing
Identical Similar Unique
Same testing Test unique aspects
• Modeling• Functional Testing• Durability Testing• Simulated Use• Biocompatibility• Animal Study• Clinical Study
• Rationales for omission of testing
Check Standards and FDA Guidances
Check Literature References
Use your thinking cap!
X Do not perform a test just to check a box
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Biocompatibility Endpoints
• Cytotoxicity• Sensitization• Irritation or
IntracutaneousReactivity
• Acute Systemic Toxicity• Material-Mediated
Pyrogenicity
• Subacute/SubchronicToxicity
• Genotoxicity• Implantation• Hemocompatibility• Chronic Toxicity • Carcinogenicity
"2016 CDRH Biocompatibility Guidance” <https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm348890.pdf>
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Discovery Invention + Prototyping Nonclinical Clinical Regulatory
DecisionProduct Launch
Post Market Monitoring
Product Life Cycle
IDE PMA
Pre-Submission
No changes made during IDE or proposed at PMA
www.fda.gov
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Biocompatibility Evaluation: Investigational Device Exemption (IDE)• Feasibility Study
– Biocompatibility testing submitted– Future Consideration(s) Included
• Concerns to address at pivotal study and/or marketing submission
• Pivotal Study– No change to device design or manufacturing– Biocompatibility testing
• Most (if not all) of testing is re-submitted or reference to previous FDA submission provided
• Address any Future Considerations noted during Feasibility Study
– Future Consideration(s) Included• Concerns to address at marketing submission
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Biocompatibility Evaluation: Premarket Application (PMA)• Biocompatibility Testing
– No change to device design or manufacturing during IDE or device proposed for marketing
– Re-Submit test reports that FDA reviewed during IDE• Indicate what submission FDA previously reviewed the information
– Address any Future Considerations identified during Feasibility Study and Pivotal Study
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Discovery Invention + Prototyping Nonclinical Clinical Regulatory
DecisionProduct Launch
Post Market Monitoring
Product Life Cycle
Develop Validate Design
Redesign Bench Test
Study Data
Redesign Analyze
IDE PMA
Pre-Submissionwww.fda.gov
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IDE• Multiple design changes may
occur through IDE– Appropriate testing
completed/submitted for each change
– Future Consideration(s) identified are provided in respective approval letter(s)
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PMA• Biocompatibility Testing
– Most (if not all) testing is re-submitted– Address any/all Future Consideration(s) identified
during IDE review
• Is anything else needed at PMA?– Need to tell the story, but what does that mean?
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PMA: Documentation• Discuss any design/manufacturing changes, and specify which
were:– Made over course of the IDE, &– Proposed for the marketed device (i.e., not used in IDE)
• Address how the device intended for marketing was adequately evaluated for each biocompatibility endpoint– Discuss how tested device is identical to the proposed device for
marketing• Including components, materials, formulation, processing, cleaning,
sterilization, geometry, and that no other chemicals have been added (e.g., plasticizers, fillers, color additives, cleaning agents, mold release agents)
– For any differences, provide rationale why biocompatibility not affected for each applicable endpoint
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Biocompatibility Documentation• Table with device materials
– Endovascular Grafts• Provide separate tables for implant and delivery system
– Components of proposed device• Chemical Name, Trade Name• Supplier• Dimensions or amount (if applicable)• Whether the components have direct, indirect, or no contact with
the patient’s circulating blood and/or tissue– Implant
• Identify patient-contacting color additives including specific amounts of color additives in weight percent and mass
• Please note that this may also be requested for the delivery system, e.g., if test extracts have color/particulates
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Biocompatibility Documentation• Test Articles used in testing
– Is test article the medical device in its final, finished form?
• If answer is “no”, provide justification for test article used
– Discuss test article preparation, including extraction conditions (e.g., temperature, duration of extraction)
– Indicate appearance of extract• e.g., color, cloudy versus clear, presence of particulates• If the extract was not clear and/or particulates present, provide
rationale for the appearance
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Biocompatibility Documentation• Analysis of Results
– For any observed toxicities, provide an analysis as to why those observations are not indicative of an underlying biocompatibility concern
• Rationales– For leveraging or omitting any testing
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Biocompatibility Guidance Document• FDA Guidance – Issued June 16, 2016: Use of
International Standard ISO 10993-1 “Biological Evaluation of medical devices – Part 1: Evaluation and Testing within a risk management process”– Presents FDA’s current thinking on the topic
• Important to consider when telling your story
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FDA Biocompatibility Guidance• Attachment C: Summary Biocompatibility
Documentation– Applicable to any submission with biocompatibility
testing
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Pre-Submission• Biocompatibility Test Plans
– Test Selection for each biocompatibility endpoint• Including rationales for leveraging/omission
– Test Articles• Test article preparation, including extraction conditions
– Test Methods • e.g., chemical characterization
• Designing in vivo or ex vivo studies to address biocompatibility endpoints
• Need for additional biocompatibility evaluations if questionable or inconclusive findings have occurred in a previously completed test
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Pre-Submission• PMA
– Discuss design/manufacturing changes– Present Biocompatibility Test Plan for PMA
• Repeat testing on final device or provide rationales?
– Goal: Obtain feedback on the previously completed test plan to see if the plan, including rationales, are adequate for your future PMA
• Please note detailed test reports & toxicological risk assessments are not reviewed in a Pre-Submission
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ISO 10993 - 18• Chemical Characterization of Materials
• Effort to standardize chemical characterization methods
• Currently under revision– Contact AAMI to participate
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Summary• Consider submitting a pre-submission to obtain
feedback on test plan, protocols, and rationales for both IDE & PMA
• Never assume: Consult with FDA during the product development process
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Acknowledgements• Ms. Dorothy Abel
– FDA Vascular Prostheses Expert
• Ms. Jennifer Goode – ODE Biocompatibility Program Advisor
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Questions?