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 AdministrationValerie.Merkle@fda.hhs.gov

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?