The iStent infinite® Trabecular Micro-Bypass System Model iS3 an implantable device intended to reduce the intraocular pressure (IOP) of the eye. It is indicated for use in adult patients with primary open-angle glaucoma in whom previous medical and surgical treatment has failed.

Device Description

The iStent infinite Trabecular Micro-Bypass System Model iS3 is a sterile, single-use injector system that is pre-loaded with three G2-W stents, and is designed to deliver the stents into Schlemm's canal. The G2-W stents are manufactured from implant grade titanium (Ti6Al4V ELI per ASTM F136) and are coated with stearalkonium heparin. An area of reduced outside diameter, midway along the device, is designed to provide retention within the trabecular meshwork, while multiple outlet lateral lumens (4 outflow orifices) are designed to provide an exit route for aqueous from the anterior chamber. The stent has a single piece design, is 360 um in diameter, 360 um in height, and the central inlet and outlet lumen has a diameter of 80 um. The head of the stent has four side outlets that each have a diameter of 50 um.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the iStent infinite Trabecular Micro-Bypass System, as presented in the provided FDA 510(k) summary, structured to answer your questions:

1. A table of acceptance criteria and the reported device performance

Please note that for the clinical effectiveness endpoints, explicit "acceptance criteria" are not stated as pass/fail thresholds in the provided text. Instead, the study reports the observed performance, and the FDA determined this performance supports substantial equivalence. For bench testing, direct pass/fail results against implicit or explicit criteria are mentioned.

Category	Acceptance Criteria	Reported Device Performance
Clinical Performance
Effectiveness:		(Reported at 12 months for ITT Population/Worst Postoperative IOP & Last Available Medication Classes):
Proportion of responders (>= 20% MDIOP reduction from baseline on same or fewer medications)	(Implicit criteria for substantial equivalence, not explicitly stated as a numerical threshold in the document, but assessed against predicate data for efficacy.)	72.1% (44/61 participants) with a 95% CI of (59.2%, 82.9%). Other imputation methods yielded similar results (e.g., 73.4% with multiple imputation).
Change from baseline in MDIOP	(Implicit criteria for substantial equivalence, not explicitly stated as a numerical threshold in the document, but assessed against predicate data for efficacy.)	-5.5 ± 5.24 mm Hg (mean ± SD) with a 95% CI of (-6.9, -4.2).
Safety:	(Implicit criteria that adverse event rates and types should be comparable to or better than predicate devices and acceptable for the intended use.)	No intraoperative adverse events. Most common AEs included ocular surface disease (11.5%), substantial IOP increase vs. baseline (8.2%), and loss of BSCVA >= 2 lines (11.5%). Stent obstruction occurred in 3.3%. Stent migration in 1.6%. Secondary surgical intervention in 4.9%. No reports of: corneal decompensation, choroidal effusion/hemorrhage, hypotony maculopathy, deep stents not visible, stent explantation, stent dislocation (overall), or stent repositioning.
Bench Testing
Surface & Edge Quality	Stent had smooth edges and was free from surface defects.	Pass: SEM photos demonstrated smooth edges and no surface defects.
Dimensions	Production meets tolerances to appropriate statistical levels.	Pass: Validated that stent production meets tolerances.
Physical Stability	Dimensional measurements remain the same before and after incubation; surface finish maintained quality; coating intact after incubation.	Pass: Dimensional measurements and visual inspection confirmed stability after 14 days incubation. Coating remained intact.
Pressure/Flow Characteristics	Negligible flow resistance.	Pass: Numerical modeling and CFD showed negligible flow resistance.
Structural Integrity	Safety factors at lowest and highest implant velocities support structural integrity (e.g., 41x and 14x respectively).	Pass: FEA modeling showed safety factors of 41x and 14x, confirming structural integrity.
Insertion Testing	All specified requirements met (stent delivery, singulation, implantation, trocar penetration).	Pass: All tested injectors successfully passed predetermined acceptance criteria for stent delivery.
Stability of Coating	Coating stability demonstrated for shelf life.	Pass: Demonstrated for the shelf life period.
MRI Compatibility	MR Conditional.	Pass: Device is MR Conditional under specified conditions.
Corrosion Resistance	Acceptable corrosion resistance to pitting and crevice corrosion.	Pass: Test lab concluded acceptable corrosion resistance per ASTM F2129-15.
Sterilization SAL	10^-6 sterility assurance level (SAL).	Pass: Gamma ray validation (25 kGy) substantiated 10^-6 SAL.
Bacterial Endotoxin	Meets recommendations for single-use intraocular ophthalmic devices.	Pass: LAL testing performed as recommended.
Packaging & Shelf Life	Functional performance of stent/injector, and packaging integrity maintained after simulated distribution and aging for 1 year.	Pass: Meets functional requirements and sterile barrier remains intact after simulated distribution and aging for 1 year.
Biocompatibility (Stent)	Non-toxic, non-mutagenic, non-irritating, non-sensitizing, no significant reaction after implantation, non-pyrogenic.	Pass for all tests: Cytotoxicity (Cell growth inhibition < 30%, No cell lysis or toxicity), Genotoxicity (No mutagenic changes, No toxicity or mutagenic effects, No chromosomal aberrations induced), Intraocular Irritation (No evidence of irritation), Sensitization (No evidence of sensitization), Implantation (No significant reaction), Systemic Toxicity (No evidence of systemic toxicity), Pyrogenicity (Non-pyrogenic).
Biocompatibility (Injector)	Non-toxic, non-irritating, non-sensitizing, non-pyrogenic.	Pass for all tests: Cytotoxicity (No cell lysis or toxicity), Intraocular Irritation (No evidence of irritation), Sensitization (No evidence of sensitization), Irritation (Non-irritating), Systemic Toxicity (No evidence of systemic toxicity), Pyrogenicity (Non-pyrogenic).

2. Sample size used for the test set and the data provenance

Sample Size (Clinical Test Set): 61 participants (implanted with iStent infinite).
Data Provenance:
- Country of Origin: 14 sites in the US and one OUS site.
- Retrospective/Prospective: Prospective, multi-center, single-arm, open-label clinical trial.
- Follow-up: 12 months post-operatively.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The document describes a clinical trial for an implantable medical device, not an AI or diagnostic imaging device where "experts" would be establishing a ground truth for a test set of images or readings. The "ground truth" here is the clinical outcomes (IOP reduction, adverse events) observed directly in patients treated with the device, which are objective measurements or clinically assessed by the participating investigators. Therefore, this question is not directly applicable in the context of this device's clinical performance study, as 'ground truth' in this case refers to direct patient data and outcomes rather than expert labeled data for AI model validation. The study was conducted by medical professionals at clinical sites, implicitly assuming their expertise in ophthalmology and glaucoma management.

4. Adjudication method for the test set

Similarly to question 3, this question pertains more to diagnostic studies where readings or classifications need to be adjudicated. For an interventional device clinical trial like this, adjudication methods would typically apply to subjective endpoints (e.g., adverse event classification or severity), usually by an independent Clinical Events Committee (CEC) or Data Monitoring Committee (DMC). The document does not explicitly state an independent adjudication method for clinical outcomes or adverse events in the manner of "2+1" or "3+1" for image interpretation. However:

The study design was "open-label," meaning participants and investigators knew the treatment.
The safety section mentions that "participants with hypotony (IOP < 6 mmHg) associated with clinically significant findings, loss of light perception, IOP-related SSIs, cyclodialysis cleft, and/or no stents visible were treated as non-responders," which implies predefined rules for classifying certain safety events as failures or non-responders in the effectiveness analysis. This is a form of pre-specified adjudication criterion regarding outcomes but not expert consensus on ground truth data.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, an MRMC comparative effectiveness study was not done. This device is an implantable medical device, not a diagnostic imaging or AI-assisted interpretation tool. Therefore, human readers or AI assistance in reading cases are not relevant to this study.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

No, a standalone algorithm performance study was not done. Again, this device is a physical implant, not a software algorithm.

7. The type of ground truth used

The "ground truth" for this study is primarily clinical outcomes data directly measured from human patients after the device implantation. This includes:

Intraocular Pressure (IOP) measurements (mean diurnal IOP, reduction percentages).
Medication usage.
Adverse events (ocular and systemic).
Visual acuity (BSCVA) measurements.
Ocular findings from various examinations (slit-lamp, fundus, gonioscopy, pachymetry, visual field).

For the bench testing, the "ground truth" (or acceptance criteria) was based on established engineering standards, material science principles, and functional requirements verified through laboratory tests.

8. The sample size for the training set

This question is not applicable. The study describes a clinical trial and bench testing for an implantable medical device, not the development or training of an AI algorithm on a "training set."

9. How the ground truth for the training set was established

This question is not applicable, as there was no "training set" in the context of AI algorithm development for this device. The clinical study collected real-world patient data post-implantation to assess safety and effectiveness.

Summary

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August 2, 2022

Glaukos Corporation Mr. David Fernquist Vice President Regulatory Affairs 229 Avenida Fabricante San Clemente, California 92672

Re: K220032

Trade/Device Name: iStent infinite Trabecular Micro-Bypass System, Model iS3 Regulation Number: 21 CFR 886.3920 Regulation Name: Aqueous Shunt Regulatory Class: Class II Product Code: KYF Dated: June 21, 2022 Received: June 24, 2022

Dear Mr. David Fernquist:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's

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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Anjana Jain, PhD Assistant Director DHT1A: Division of Ophthalmic Devices OHT1: Office of Ophthalmic, Anesthesia, Respiratory, ENT and Dental Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K220032

Device Name iStent infinite® Trabecular Micro-Bypass System Model iS3

Indications for Use (Describe)

Type of Use (Select one or both, as applicable)
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X Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) SUMMARY

This 510(k) summary is being submitted in accordance with the requirements of 21 CFR 807.92.

SUBMITTERI.	Glaukos Corporation229 Avenida FabricanteSan Clemente, CA 92672
Contact Person:	David S. FernquistVice President, Regulatory AffairsGlaukos Corporation(949) 367-9600
Date Summary Prepared:	August 2, 2022
II.DEVICE
Trade Name:	iStent infinite Trabecular Micro-Bypass System Model iS3
Common Name:	Glaucoma Implant
Classification Name:	Aqueous shunt (21 CFR 886.3920)
Device Class:	Class II (special controls)
Device Product Code:	KYF ("Implant, Eye Valve")

III. PREDICATE DEVICE

XEN Glaucoma Treatment System (K161457), 21 CFR 886.3920, Product Code KYF

IV. DEVICE DESCRIPTION

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four side outlets that each have a diameter of 50 um.

V. INTENDED USE

The iStent infinite Trabecular Micro-Bypass System Model iS3 has the same intended use as the predicate device and all other devices regulated within the generic type of device known as aqueous shunts in accordance with 21 CFR 886.3920. The iStent infinite is a prescription (Rx) device that is intended to be permanently implanted to reduce intraocular pressure for the management of glaucoma. Both the subject device and predicate device (XEN® Glaucoma Treatment System) have the same intended use for the treatment, namely, "to be permanently implanted to reduce intraocular pressure for the management of glaucoma", as stated above. The iStent infinite will bear the following indications for use statement:

The iStent infinite Trabecular Micro-Bypass System Model iS3 is an implantable device intended to reduce the intraocular pressure (IOP) of the eye. It is indicated for use in adult patients with primary open-angle glaucoma in whom previous medical and surgical treatment has failed.

The indications for use statement for iStent infinite is not substantially different from that of the XEN implant predicate device. The non-substantial difference in the indications for use statement for the iStent infinite vs. the predicate device is that the iStent infinite indication is narrower. Compared to the XEN indications for use statement (shown below), the iStent infinite indications for use statement does not include patients with pseudoexfolative glaucoma or pigmentary glaucoma who have failed maximally tolerated medical therapy. It should be noted that both the pivotal study for XEN and the pivotal study for iStent infinite comprised a substantial majority of primary open-angle glaucoma patients with prior failed surgical intervention and similar baseline characteristics.

The XEN® Glaucoma Treatment System is indicated for the management of refractory glaucomas, including cases where previous surgical treatment has failed, cases of primary open angle glaucoma, and pseudoexfoliative or pigmentary glaucoma with open angles that are unresponsive to maximum tolerated medical therapy.

VI. COMPARISON OF TECHNOLOGICAL CHARACTERISTICS WITH THE SUBJECT DEVICE AND PREDICATE DEVICE

Although the iStent infinite and the XEN do not share identical technological characteristics, those differences do not raise different questions of safety and effectiveness.

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Characteristics	Allergan XEN GlaucomaTreatment SystemK161457PREDICATE DEVICE	iStent infiniteSUBJECT DEVICE
Intended use	To be permanently implanted toreduce intraocular pressure for themanagement of glaucoma	To be permanently implanted toreduce intraocular pressure for themanagement of glaucoma
RegulationNumber/ProductCode	886.3920, KYF	886.3920, KYF
Indication	The XEN Glaucoma TreatmentSystem is indicated for themanagement of refractoryglaucomas, including cases whereprevious surgical treatment hasfailed, cases of primary open angleglaucoma, and pseudoexfoliative orpigmentary glaucoma with openangles that are unresponsive tomaximum tolerated medical therapy.	The iStent infinite Trabecular Micro-Bypass System Model iS3 is animplantable device intended toreduce the intraocular pressure (IOP)of the eye. It is indicated for use inadult patients with primary open-angle glaucoma in whom previousmedical and surgical treatment hasfailed.
Rx or OTC	Rx	Rx
Permanent Implant	Yes	Yes
Design	Monolithic, round tube design with acentral inlet and outlet lumen	Monolithic round tube design with acentral inlet and outlet lumen
Material	Gelatin derived from porcine dermis,formed into a tube, and then cross-linked with glutaraldehyde; nocoating	Implant grade titanium (Ti6Al4VELI) with a stearalkonium heparincoating
Size (nominaldimensions)	Dry dimensions:6 mm length0.045 mm inner diameter0.15 mm outside diameter	0.36 mm length0.36 mm flange diameter0.23 mm head diameter0.08 mm central outlet diameter0.05 mm flow outlet diameter
Sterilization	Terminal gamma ray radiation	Terminal gamma ray radiation
Single-Use	Yes	Yes
Anatomical site	Angle-based implant	Angle-based implant
Mechanism of action	Outflow of aqueous fluid via asubconjunctival bleb	Outflow of aqueous fluid viatrabecular bypass
Method of Insertion	Via a preloaded XEN injector	Via a preloaded injector

Table 1. Comparison of the iStent infinite System and XEN Glaucoma Treatment System (Predicate Device)

VII. PERFORMANCE DATA

The following performance data were provided in support of the substantial equivalence determination.

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Bench Testing A.

The nonclinical bench testing conducted on the iStent infinite Trabecular Micro-Bypass System Model iS3 included design verification and functional product testing, sterilization validation, packaging and shelf life testing, and biocompatibility testing. Results of the nonclinical testing demonstrate that theiStent infinite Trabecular Micro-Bypass System Model iS3 functions as intended.

Design Verification and Functional Product Testing:

The iStent infinite Trabecular Micro-Bypass System Model iS3 Stent and injector were evaluated to verify that the design output met the original design input and intent. This testing was based on tests described in ANSI Z80.27, Implantable Glaucoma Devices, the FDA guidance document "Aqueous Shunts - 510(k) Submissions", and the FDA guidance document "Premarket Studies of Implantable Minimally Invasive Glaucoma Surgical (MIGS) Devices". All physical and mechanical testing demonstrated that the stent and injector function as intended.

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Table 2. Physical & Mechanical Testing
Test	Results
Surface & EdgeQuality	High magnification SEM photos of the G2-W stent demonstrated that the stenthad smooth edges and was free from surface defects.
Dimensions	Glaukos has validated that stent production meets tolerances to appropriatestatistical levels.
Physical Stability	An in-vivo test to evaluate the physical stability of the titanium stent wasperformed per ANSI Z80.27 Section 5.5. A total of 10 etched and coatedstents were pulled from a production lot for the validation, inspected, and wereplaced into BSS for 14 days at a temperature 35 $\pm$ 2 °C. Visual inspection (atleast 10x) and dimensional measurements were performed at baseline and after14 days. The results of the dimensional inspection showed that the fourcritical dimension measurements remained the same before and afterincubation. The results of the visual inspection demonstrated that the surfacefinish on the incubated stents maintained the same quality as prior toincubation. The data also show that the coating on the stents remains intactafter incubation.
Pressure/FlowCharacteristics	Numerical modeling, including computational fluid dynamics, was used toevaluate the flow through the stents over physiologically relevant boundaryconditions. The stents were found to have negligible flow resistance.
Structural Integrity	A study was undertaken to evaluate the stress levels during the highestanticipated load conditions for the stent by Finite Element Analysis (FEA).Based on the modeling data, it was determined that the safety factors at thelowest and highest implant velocities were 41x and 14x, respectively. Theresults confirm that the stent will maintain its structural integrity afterimplantation with the velocity range seen clinically.
Insertion Testing	As part of the shelf life testing for the iS3 injector, functional testing wasperformed at baseline and after 1 year of aging to demonstrate that all specifiedrequirements were met e.g. stent delivery, stent singulation, stent implantationand trocar penetration in synthetic tissue. All tested injectors successfullypassed all predetermined acceptance criteria for stent delivery.
Stability of Coating	Stability of the stearalkonium heparin coating on the stent was demonstratedfor the shelf life period of the finished, sterile device.
MRI Compatibility	Non-clinical testing has demonstrated that the iStent infinite Trabecular Micro-Bypass System (Model iS3) is MR Conditional. A patient with this device canbe safely scanned in an MR system meeting conditions specified in the IFUand patient implant card.
Corrosion Resistance	Glaukos submitted samples that were representative of the finished, steriletitanium stent to a contract laboratory for electrochemical evaluation inaccordance with ASTM (American Society For Testing and Materials) F2129-15, Standard Test Method for Conducting Cyclic Potentiodynamic PolarizationMeasurements to Determine the Corrosion Susceptibility of Small ImplantDevices". The test lab concluded that test samples displayed acceptablecorrosion resistance to pitting and crevice corrosion in the ASTM F2129 test inthe received condition.

Sterilization Validation:

The gamma irradiation sterilization method was validated using the VDmx 35 method described in ISO 11137-1:2015 and ISO 11137-2:2015. Validation results demonstrate that a minimum

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exposure dose of 25 kGy has been substantiated for the routine sterilization of the iStent infinite Trabecular Micro-Bypass System Model iS3 to provide a 10-6 sterility assurance level (SAL).

Bacterial Endotoxin

Endotoxin Limulus amebocyte lysate (LAL) testing has been performed as recommended in the FDA guidance document "Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices."

Packaging and Shelf Life Testing:

The iStent infinite Trabecular Micro-Bypass System Model iS3 is labeled with an expiration date of 1 year. The shelf life study evaluated the functional performance of the G2-W Stent and the iS3 injector, as well as the packaging integrity of the tray sealed with the Tyvek lid. Additional testing was completed to evaluate the impact of environmental conditioning and distribution factors. Test results confirm that the G2-W Stent and the iS3 injector meet their functional requirements and the sterile barrier (package integrity) remains intact after simulated distributionand aging. This testing provides the justification for the 1-year shelf life and the maintenance of the sterile barrier.

Biocompatibility Testing

The biocompatibility testing outlined in the tables below (Table 4) was performed on the stent (or representative samples of the finished device) and the patient-contacting portion of the injector in accordance with the relevant parts of International Organization for Standardization (ISO) standard 10993. All testing demonstrated that the device materials have an acceptable biocompatibility profile. With respect to physico-chemical testing of the stent, there is an extensive history of titanium use in medical devices. Therefore, tests for extraction in aqueous and organic solvents and for hydrolytic stability were not performed on the device, since they were considered unnecessary. In addition, the device's titanium material contains no monomers and is not subject to hydrolytic degradation.

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Test	Purpose	AcceptanceCriteria	Results
Cytotoxicity:
ISO Inhibition Of CellGrowth	To determine the potential biological reactivity of amammalian cell culture (L929) in response to the testarticle extract	Cell growthinhibition <30%	Pass
ISO L929 MEMElution Test	To determine the biological reactivity of amammalian cell culture (L929) in response to the testarticle extract	No cell lysis ortoxicity	Pass
Agar Diffusion Test	To determine the biological reactivity of amammalian monolayer cell culture (L929) inresponse to the test article	No cell lysis ortoxicity	Pass
Genotoxicity:
Bacterial ReverseMutation Study	To evaluate the potential of the test article to inducereverse mutations in histidine and tryptophan genesin S. typhimurium and E. coli respectively	No mutagenicchanges	Pass
Mouse Bone MarrowMicronucleus Study	To determine the ability of the test article and/or itsmetabolites to induce micronuclei in maturingerythrocytes of mice	No toxicity ormutageniceffects	Pass
In Vitro ChromosomalAberration Study	To determine the ability of the test article to inducechromosome aberrations, structural or numerical, inCHO cells in the presence or absence of anexogenous mammalian activation system	Nochromosomalaberrationsinduced	Pass
Other:
Intraocular IrritationStudy in the Rabbit	To evaluate the potential of the test article extract tocause intraocular irritation or toxicity following anintracameral injection in rabbits	No evidence ofirritation	Pass
Guinea Pig KligmanMaximization Test	To evaluate the allergenic potential or sensitizingcapacity of the test article	No evidence ofdelayed dermalcontactsensitization	Pass
Muscle Implantationin the Rabbit (2, 4, and13 Weeks)	To evaluate the test article for local tissue responsesand the potential to induce local toxic effects afterimplantation	No significantreaction	Pass
Acute SystemicToxicity in the Mouse	To evaluate the test article extracts for potential toxiceffects following a single-dose systemic injection inmice	No evidence ofsystemictoxicity	Pass
USP Material-Mediated RabbitPyrogen Study	To determine the potential presence of chemicalpyrogens in extracts of the test article	Non-pyrogenic	Pass
Test	Purpose	AcceptanceCriteria	Results
Cytotoxicity:
ISO Medium EluateMethod Test (1x CMEMExtract)	To determine the biological reactivity of a mammaliancell culture (L929) in response to the test article extract	No cell lysis ortoxicity	Pass
ISO Agar Diffusion Test(Solid Sample)	To determine the biological reactivity of a mammalianmonolayer cell culture (L929) in response to the testarticle	No cell lysis ortoxicity	Pass
Other:
Intraocular IrritationTest (PhosphateBalanced Saline Extract)	To evaluate the potential of the test article extract tocause intraocular irritation or toxicity following anintracameral injection in rabbits	No evidence ofirritation	Pass
Guinea Pig KligmanMaximization Test(Saline & Vegetable OilExtracts)	To evaluate the allergenic potential or sensitizingcapacity of the test article	No evidence ofdelayed dermalcontactsensitization	Pass
Rabbit IntracutaneousReactivity/Irritation Test(Saline & Vegetable OilExtracts)	To evaluate the test article for potential irritation effectsas a result of an intracutaneous injection in New ZealandWhite rabbits	Non-irritating	Pass
Acute Systemic Toxicityin the Mouse (Saline &Vegetable Oil Extracts)	To evaluate the test article extracts for potential toxiceffects following a single-dose systemic injection in mice	No evidence ofsystemic toxicity	Pass
Rabbit (Material-Mediated) Pyrogen Test(Normal Saline Extract)	To determine the potential presence of chemical pyrogensin extracts of the injector test article using the ISO RabbitPyrogen Test (Material Mediated) procedure.	Non-pyrogenic	Pass

Table 3. Biocompatibility Testing - Stent

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	Table 4. Biocompatibility Testing - Injector
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B. Clinical Performance Testing

A prospective, multi-center, single-arm, open-label, clinical trial was conducted at 14 sites in the US and one OUS site to evaluate the safety and effectiveness of the iStent infinite in adult patients with primary open-angle glaucoma, pseudoexfoliative or pigmentary glaucoma with open angles, and in whom previous medical and surgical treatment has failed. 61 participants were implanted with the iStent infinite and followed post-operatively for 12 months. The two effectiveness endpoints were 1) the proportion of participants achieving a 20% or greater mean diurnal IOP (MDIOP) reduction from baseline at 12 months on the same or fewer number of medication classes and 2) the change from baseline in MDIOP at 12 months. No washout of IOP-lowering medications was performed before implantation. Safety outcomes included adverse events (AEs), surgical complications, best spectacle corrected visual acuity (BSCVA), and ocular findings from slit-lamp biomicroscopy, fundus examination, gonioscopy, pachymetry, and visual field testing.

Demographics and Preoperative Characteristics

61 participants were implanted. The mean age of participants was 71.7 years (median 71.0, range 49 to 88) and there were 28 men (28/61 or 45.9%) and 33 women (33/61 or 54.1%). 37 of 61 (60.7%) participants were White, 15 of 61 (24.6%) were Black, six of 61 (9.8%) were Asian: race

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was not reported for three of 61 (4.9%) subjects. 11 of 61 participants (18.0%) had ethnicity reported as Hispanic or Latino. 55 participants (90.1%) were diagnosed with primary open angle glaucoma (POAG), three (4.9%) had pseudoexfoliative glaucoma, and three (4.9%) had pigmentary glaucoma. All 61 participants had undergone prior filtering or cilioablative glaucoma procedures. Preoperatively, the mean visual field mean deviation (MD) score was -15.1 (SD 8.56) dB (median -13.7 dB, range -31.82 to -1.79 dB). The mean baseline medicated MDIOP was 23.5±2.82 mm Hg (median 22.7 mm Hg, range 20-35 mm Hg). At baseline, participants were using a mean of 3.0 (± 0.9) ocular hypotensive medications, with 19 of 61 (31.1%) on two or fewer medications and 42 of 61 (68.9%) on three or more medications.

Effectiveness Results

Tables 5 and 6 summarize the primary effectiveness analyses based on 12-month diurnal IOP data.

Analysis Population/Imputation Method for Missing Data	iStent infiniten/N (%)(95% CI)N= 61
ITT Population/Worst Postoperative IOP & Last AvailableMedication Classes1	44/61 (72.1%)(59.2%, 82.9%)
ITT Population/Failure Assumption2	44/61 (72.1%)(59.2%, 82.9%)
PP Population	43/59 (72.9%)(59.7%, 83.6%)
ITT Population/Exclusion from Cohort3	44/60 (73.3%)(60.3%, 83.9%)
ITT Population/Multiple Imputation4	73.4%(62.2%, 84.6%)

Table 5. Analyses of Responder Effectiveness Endpoint Proportion of Responders at Month 12

Participants with hypotony (IOP < 6 mmHg) associated with clinically significant findings, loss of light perception, IOP-related SSIs, cyclodialysis cleft, and/or no stents visible were treated as non-responders.

1. Responder status for the single participant with missing data at Month 12 was determined using the worst postoperative IOP and the last available number of medication classes.
1. The single participant who missed the 12-month evaluation was treated as a non-responder.
1. The single participant who missed the 12-month evaluation was excluded.
1. Multiple imputation was used for the single participant with missing data at Month 12.

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Analysis Population/Imputation Method for Missing Data	iStent infiniteNMean ± SD(95% CI)
ITT Population/Worst Postoperative IOP1	61$-5.5 \pm 5.24$(-6.9, -4.2)
PP Population	59$-5.5 \pm 5.29$(-6.9, -4.1)
ITT Population/Exclusion from Cohort2	60$-5.6 \pm 5.27$(-6.9, -4.2)
ITT Population/Multiple Imputation3	61$-5.5 \pm 0.67$ 4(-6.9, -4.2)

Table 6. Analyses of MDIOP Change from Baseline Effectiveness Endpoint 12-Month Diurnal IOP Change from Baseline

The worst postoperative IOP was used as the 12-month MDIOP for the single participant who missed the 12-month evaluation.
The single participant who missed the 12-month evaluation was excluded.
Multiple imputation was used for the single participant with missing data at Month 12.
Mean ± SE for this value.

Safety Results

Ocular adverse events (AEs) are summarized in Table 7. There were no intraoperative adverse events (AEs). Five of 61 participants (8.2%) needed the use of a second injector due to nondeployment of the second or third stent, and there was also head movement in one of these 5 participants. There were no reports of corneal decompensation, choroidal effusion, choroidal hemorrhage, hypotony maculopathy, deep stents ("buried" in the trabecular meshwork) that were not visible at the last three scheduled visits of the study, stent explantation, stent dislocation, or stent repositioning. The most common AEs reported were ocular surface disease, substantial increase in IOP vs. baseline, and loss of BSCVA ≥ 2 lines. Stent obstruction occurred in two of 61 participants (3.3%). Two instances of stent migration occurred in one participant (1.6%). Three of 61 participants (4.9%) required secondary surgical intervention (implantation of aqueous shunt) to lower IOP.

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	iStent infinite N = 61Number (Percent) ofSubjects with Event
Postoperative Adverse Event
A significant increase in crystalline lens opacity from baseline defined as achange of ARLNS grade of three half-step increments of 0.5 per increment orgreater for nuclear opalescence, cortical or posterior subcapsular opacities (asapplicable to phakic eyes)	0 (0.0%)
Age-related macular degeneration	0 (0.0%)
Allergic reaction	0 (0.0%)
Anterior chamber fill	0 (0.0%)
Anterior chamber tap	0 (0.0%)
An increase of three half-step increments of 0.5 per increment or greater inanterior subcapsular opacities or a clinically significant cataract eligible forphacoemulsification with BCVA loss (ETDRS) of greater than 10 letters frombaseline (as applicable to phakic eyes)	0 (0.0%)
Aqueous misdirection	0 (0.0%)
Atrophy/phthisis	0 (0.0%)
Bleb leak	0 (0.0%)
Blepharitis	3 (4.9%)
Chalazion	0 (0.0%)
Choroidal effusion	0 (0.0%)
Choroidal hemorrhage	0 (0.0%)
Chronic pain in the study eye present greater than 3 months postoperative	0 (0.0%)
Clinically significant cystoid macular edema	0 (0.0%)
Conjunctival erosion due to tube shunt	1 (1.6%)
Conjunctivitis	1 (1.6%)
Corneal abrasion	0 (0.0%)
Deep stents ("buried" in the trabecular meshwork) that are not visible at the lastthree scheduled visits of the study	0 (0.0%)
Dellen	0 (0.0%)
Disc hemorrhage	1 (1.6%)
Dysesthetic bleb	NA
Elevated IOP¹	1 (1.6%)
Endophthalmitis	0 (0.0%)
Fixed dilated pupil	0 (0.0%)
Flat or shallow anterior chamber (e.g., shallowing of the anterior chamber thatcauses any amount of iris-cornea touch)	0 (0.0%)
Hyperemia	2 (3.3%)
Hypotony (IOP < 6 mmHg) associated with clinically significant findings	1 (1.6%)
Implant exposure	0 (0.0%)
Implant migration	0 (0.0%)
IOP increase >= 10 mmHg vs. baseline IOP¹	5 (8.2%)
IOP increase requiring oral medication¹	2 (3.3%)
IOP increase requiring surgical intervention¹	3 (4.9%)
Increase in C/D ratio of > 0.3 units on ophthalmoscopic examination	0 (0.0%)
Intraocular inflammation arising after the protocol's specified medication regimenis complete	1 (1.6%)
Intraocular inflammation following tube shunt surgery	2 (3.3%)
Iridodialysis	0 (0.0%)
Lens/IOL dislocation	0 (0.0%)
Loss of best spectacle corrected visual acuity (BSCVA) of 2 lines or more	7 (11.5%)
<= 30 days	1 (1.6%)
> 30 days²	6 (9.8%)
Loss of eye	0 (0.0%)
Macular edema	2 (3.3%)
Macular puckering	0 (0.0%)
Nd:YAG capsulotomy	0 (0.0%)
Needling procedure	NA
iStent infinite N = 61
	Number (Percent) ofSubjects with Event
Postoperative Adverse Event
Ocular hypotensive medication intolerance	3 (4.9%)
Ocular pain	1 (1.6%)
Ocular surface disease	7 (11.5%)
Perioperative inflammation	4 (6.6%)
Posterior vitreous detachment	1 (1.6%)
Proliferative vitreoretinopathy	0 (0.0%)
Ptosis	0 (0.0%)
Pupillary block	0 (0.0%)
Retinal detachment	0 (0.0%)
Retinal dialysis	0 (0.0%)
Retinal flap tears	0 (0.0%)
Secondary surgical intervention	3 (4.9%)
Significant corneal complications including opacification and decompensation	0 (0.0%)
Significant corneal edema	0 (0.0%)
Significant corneal injury	0 (0.0%)
Significant damage to trabecular meshwork	0 (0.0%)
Significant hyphema (i.e, >= 10% of anterior chamber)	2 (3.3%)
Significant iris damage	0 (0.0%)
Stent dislocation	0 (0.0%)
Stent explant	0 (0.0%)
Stent migration3	1 (1.6%)
Stent obstruction4	2 (3.3%)
Stent-cornea touch	0 (0.0%)
Stye	1 (1.6%)
Subconjunctival hemorrhage	1 (1.6%)
Toxic Anterior Segment Syndrome (TASS)	0 (0.0%)
Transient hypotony	1 (1.6%)
Visual field loss < 2.5 dB	1 (1.6%)
Visual field loss >= 2.5 dB	4 (6.6%)
Vitreous hemorrhage	0 (0.0%)
Vitreous loss	0 (0.0%)
Wound leak/dehiscence	0 (0.0%)
Wound repair	0 (0.0%)

Table 7. Postoperative Ocular Adverse Events in the Study Eye (Sorted Alphabetically)

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1. A total of 8 eyes (8/61 or 13.1%) experienced 12 AEs of increased IOP (consisting of elevated IOP, IOP increase > 10 mmHz vs. baseline IOP, IOP increase requiring oral medication and IOP increase requiring surgical intervention). The 4 eyes with more than one AE of increased IOP are as follows:
- One eye had an AE of IOP increase >= 10 mmHg vs. baseline IOP and an AE of IOP increase requiring secondary surgical intervention
- · One eye had an AE of IOP increase requiring oral medication and an AE of IOP increase requiring surgical intervention
- · One eye had an AE of elevated IOP and an AE of IOP increase requiring secondary surgical intervention
- · One eye had 2 AES of IOP increase >= 10 mmHg vs. baseline IOP
1. Includes persistent BSCVA loss
1. One subject was reported with 2 events of stent migration. The visualization was impaired during implantation of the 1:00 and 4:30 stents due to corneal arcus, striae and external location-marking dye. The stent reported as implanted at 1:00 was identified in the 1:00 position via UBM ("imbedded deep beyond iris insertion"), and the stent reported as implanted at 4:30 was identified in the 7:30 position via both gonioscopy and UBM.
1. The 2 AEs of stent obstruction involved obstruction of 2 stents each. The investigators reported associated findings of significant hyphema in 1 case and pre-existing and postoperative focal goniosynechiae in both cases. One case of stent obstruction resolved following treatment with pilocarpine, and 1 case was not treated and was ongoing at Month 12. Both subjects experienced Month 12 MDIOP reduction on the same medication regimen as preoperative.

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VIII. CONCLUSIONS

The iStent infinite Trabecular Micro-Bypass System Model iS3 has the same intended use as the legally marketed predicate device identified in this 510(k) notification and all other aqueous shunts regulated by FDA under 21 CFR § 886.3920. The indications for use statement differs from those for the predicate device, however, the differences do not alter the intended use of the device.

The iStent infinite Trabecular Micro-Bypass System Model iS3 technological characteristics differ from the predicate device, however, the differences do not raise new or different questions of safety or effectiveness. Results of the nonclinical testing demonstrate that the iStent infinite Trabecular Micro-Bypass System Model iS3 functions as intended. Results of clinical performance testing support a favorable safety and effectiveness profile that supports a determination of substantial equivalence. The non-clinical and clinical performance testing demonstrate that the device is as safe, as effective, and performs as well as or better than the legally marketed device predicate.

Regulation Number and Section

§ 886.3920 Aqueous shunt.

(a)
Identification. An aqueous shunt is an implantable device intended to reduce intraocular pressure in the anterior chamber of the eye in patients with neovascular glaucoma or with glaucoma when medical and conventional surgical treatments have failed.(b)
Classification. Class II. The special controls for this device are FDA's:(1) “Use of International Standard ISO 10993 ‘Biological Evaluation of Medical Devices—Part I: Evaluation and Testing,’ ”
(2) “510(k) Sterility Review Guidance of 2/12/90 (K90-1),” and
(3) “Aqueous Shunts—510(k) Submissions.”