Summary of Safety and Effectivness (SSED)Templateone-piece astigmatism-correcting intraocular lens....

PMA P910056/S027: FDA Summary of Safety and Effectiveness Data

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION

Device Generic Name: Toric Posterior Chamber Intraocular Lens (IOL)

Device Trade Name: enVista® One-Piece Hydrophobic Acrylic Toric Intraocular Lens; Model MX60T

Device Procode: MJP

Applicant’s Name and Address: Bausch + Lomb, Inc.

400 Somerset Corporate Blvd. Bridgewater, NJ 08807

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P910056/S027

Date of FDA Notice of Approval: June 8, 2018

The original PMA P910056 was approved on January 17, 1992 and incorporated by reference here. TheenVista® One-Piece Hydrophobic Acrylic Toric Intraocular Lens; Model MX60T is a modified version of the enVista® One-Piece Acrylic Intraocular Lens, Model MX60 approved under PMA P910056/S010 on April 30, 2012 and incorporated by reference here. . The current supplement was submitted to expand the indication for the enVista® Posterior Chamber Intraocular Lens to include correction of aphakia and astigmatism.

II. INDICATIONS FOR USE

The enVista® One-Piece Hydrophobic Acrylic Toric IOL (Model MX60T) is indicated for primary implantation in the capsular bag of the eye in adult patients for visual correction of aphakia and corneal astigmatism following removal of a cataractous lens for improved uncorrected distance vision.

III. CONTRAINDICATIONS

There are no known contraindications. IV. WARNINGS AND PRECAUTIONS


The warnings and precautions can be found in the enVista® Toric IOL labeling packaged with the device.

V. DEVICE DESCRIPTION

The enVista® One-Piece Hydrophobic Acrylic Toric Intraocular Lens, Model MX60T (see Figure 1, below), is an ultraviolet-absorbing, posterior chamber, hydrophobic acrylic one-piece astigmatism-correcting intraocular lens. It has an overall diameter of 12.5 mm, and an optic body diameter of 6.0 mm. The enVista® Toric IOL has an aspheric optic that is designed to be free of spherical aberration through the incorporation of a proprietary spherical aberration-neutral optic design that does not influence the pre-surgical corneal spherical aberration profile. The optic is designed with the SureEdge™, posterior squared step edge to provide a 360 degree posterior capsule opacification (PCO) barrier. The enVista® Toric IOL employs an Accuset™ haptic with a broad, modified C-loop design and optic-haptic offset to facilitate improved contact and stability within the capsular bag. The posterior located cylinder axis marks denote the meridian with the lowest power. The enVista® material that makes up the TruSight™ optic has been assessed for glistening-free capacity and scratch resistance. The enVista® One-Piece Hydrophobic Acrylic Toric Intraocular Lens, Model MX60T, is a modification to the B+L enVista® One-Piece Hydrophobic Acrylic Intraocular Lens, Model MX60. The only difference between the enVista® Toric IOL and the currently approved enVista® IOL is the incorporation of a toric optic surface and axis marks on the posterior optic surface of the lens. The lens toricity results in a periodic change in refractive power between the flat and steep lens meridians. When the flat meridian of the toric IOL is correctly aligned with the steep corneal meridian, the toric IOL corrects the corneal astigmatism. The enVista® Toric Intraocular Lens is available in seven different cylinder powers (+1.25 D, +2.00 D, +2.75 D, +3.50 D, +4.25 D, +5.00 D and +5.75 D) and in spherical equivalent powers of +6.0 D to +30.0 D, in 0.5 D increments. To facilitate IOL selection and axis parameters, B+L provides a web-based proprietary tool, the enVista Toric calculator.

Figure 1: Schematic of MX60T IOL


The physical characteristics of the enVista® Toric Intraocular Lens are shown in Table 1.

Table 1: PHYSICAL CHARACTERISTICS OF ENVISTA TORIC INTRAOCULAR LENS

Characteristic Model MX60T

Optic Body Diameter 6.0 mm

Overall Diameter 12.5 mm

Haptic Angle 0° Lens Configuration One-Piece

Modified C-loop Haptics; Zero Angulation; Step-Vaulted 360⁰ square posterior edge

Anterior Surface Aspheric Optic

Posterior Surface Toric Optic with Cylinder Axis Marks 360° Square Edge

Lens / Haptic Material Hydrophobic Acrylic (hydroxyethyl methacrylate (HEMA)-polyethylene glycol phenyl ether acrylate (poly(EG)PEA)-styrene copolymer, cross-linked with ethylene glycol dimethacrylate)

Spherical Equivalent Power +6.0 D to +30.0 D, in 0.5 D Increments.

Cylinder Power (Diopter, D)

(+1.25 D, +2.00 D, +2.75 D, +3.50 D, +4.25 D, +5.00 D and +5.75 D)

Refractive Index 1.54 @ 35ºC

UV Transmittance

363 nm

Suggested A-Constant 119.1 (Optical Biometry)

VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of restoring functional vision of the aphakic eye. Non-surgical options include special cataract glasses or contact lenses. Surgical options such as monofocal, multifocal, simultaneous vision or accommodative IOLs are also available. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.


VII. MARKETING HISTORY

The enVista® One-Piece Hydrophobic Acrylic Toric IOL has not been marketed in the United States or any foreign country although it has been available in the European Union since receiving the CE Mark in April, 2012. Subsequently, the product has been marketed in Canada, Latin America, and in the Asia Pacific region. The enVista® One-Piece Hydrophobic Acrylic Toric IOL has not been withdrawn from marketing in any country for any reason.

VIII. PROBABLE ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the probable adverse effects (e.g., complications) associated with the use of the device. Potential adverse events and complications accompanying cataract or implant surgery may include, but are not limited to the following: corneal endothelial damage, infection (endophthalmitis), retinal detachment, vitritis, cystoid macular edema, corneal edema, pupillary block, cyclitic membrane, iris prolapsed, hypopyon, transient or persistent glaucoma, acute corneal decompensation, toxic anterior segment syndrome (TASS), and secondary surgical intervention.

Secondary surgical interventions include, but are not limited to, lens repositioning, lens replacement, vitreous aspiration or iridectomy for pupillary block, wound leak repair, and retinal detachment repair.

For the specific adverse events that occurred in the clinical studies, please see Section 10.

IX. SUMMARY OF NONCLINICAL STUDIES

The enVista® Toric IOL is composed of identical materials to the currently approved enVista® One-Piece Hydrophobic Acrylic IOL, MX60 (material parent, P910056/S010). Preclinical studies were performed on the material parent device and are incorporated by referenced. These tests are as follows: physicochemical and biocompatibility testing (with the exception of inorganic insolubility testing), sterilization, packaging, shelf-life, and transport stability testing. Insoluble inorganics testing and results are shown in Table 2.

Table 2: PHYSICAL-CHEMICAL AND BIOLOGICAL TESTING


Optical and Mechanical Testing

The optical properties of the Model MX60T were tested per “ISO 11979-2: Ophthalmic implants – Intraocular lenses: Optical properties and test methods and ANSI Z80.30: Toric intraocular lenses.” The mechanical properties were tested per “ISO 11979-3: Ophthalmic implants – Intraocular lenses: mechanical properties and test methods.”

The lens testing was performed using fully processed and sterilized Model MX60T lenses supplied from product manufactured at the B+L Clearwater, Florida manufacturing facility as part of the process validation of the Model MX60T.

Testing was performed on lenses representing the low, medium and the high diopter ranges: (spherical equivalent power (SE) = +6.0 D with cylinder = 1.25 D; SE = +20.0 D with cylinder = 2.0 D; SE = +30.0 D with cylinder = 2.75 D; SE=+6.0 D with cylinder = 3.50; SE = + 21.0 with cylinder 4.25 and SE = + 30.0 D with cylinder = 5.75D.). The results of the testing demonstrate that the Model MX60T meets the ISO and ANSI standards for optical and mechanical properties and qualifies as a Level A modification to the approved enVista® Model MX60 per ISO/TR 22979. The results of the testing demonstrate that the Model MX60T meets all of the ISO and ANSI standards for optical and mechanical properties, as summarized in Table 3 and Table 4.

Table 3: SUMMARY OF OPTICAL TESTING FOR MODEL MX60T - ISO 11979-2 & ANSI Z80.30

SUMMARY OF OPTICAL TESTING FOR MODEL MX60T - ISO 11979-2 & ANSI Z80.30

Optical Property (Design criteria)

Requirement (Design Input)

Results (Design Output)

Dioptric Power (SE)

+6.0 ≤ SE ≤ + 15.0D: ± 0.3D + 15.0 < SE ≤ + 25.0D: ± 0.4D + 25.0 < SE ≤ + 30.0D: ± 0.5D

Passed

ISO 11979-5

Insoluble Inorganics

Aluminum Assay Extraction

Passed

Using ICP-MS or ICP-OES on digested material to detect material on and in the lens

Passed


SUMMARY OF OPTICAL TESTING FOR MODEL MX60T - ISO 11979-2 & ANSI Z80.30

Optical Property (Design criteria)



Cylinder Power

Cylinder SKU range (D) Cylinder Acceptance Criteria

+1.25 and +2.00 Cylinders SE +6.0 to < +25.0 ± 0.3D SE ≥+25.0 to ≤ +30.0 ± 0.4D

Passed

+2.75, +3.50, and +4.25 Cylinders

SE +6.0 to < +25.0 ± 0.4D SE +≥25.0 to ≤ +30.0 ± 0.4D

Passed

+5.00 and +5.75 Cylinders SE +6.0 to < +25.0 ± 0.5D SE ≥ +25.0 to ≤ +30.0 ± 0.5D

Passed

Axis Orientation Marks ± 5.0 Degrees from Toric Meridian

Passed

Imaging Quality

MTF ≥ 0.08 @ 70.0% cut-off freq. MTF ≥ 0.36 @ 36.9% cut-off freq. (Equivalent to 0.43 @

100 lp/mm per ISO 11979-2)

Passed

Spherical Aberration 0 ± 0.05 µm Passed


Table 4: SUMMARY OF MECHANICAL TESTING FOR MODEL MX60T - ISO 11979-3

SUMMARY OF MECHANICAL TESTING FOR MODEL MX60T - ISO 11979-3

Mechanical Property (Design Criteria)



Clear Optic Diameter ≥ 4.25 mm Passed

Dimensions:

• Overall Diameter • Optic Diameter • Vault Height • Sagitta

• 12.5 mm ± 0.2 mm • 6.0 mm ± 0.1 mm • Satisfy dimension criteria • Satisfy dimension criteria

Passed

Surface and Bulk

Homogeneity

Free of surface and bulk defects at 10x magnification

Passed

Optic Decentration

Sum of mean and two standard deviations must not exceed 10% of

clear optic

Passed

Optic Tilt Sum of mean and two standard

deviations must not exceed 5°

Passed

Axial Displacement in Compression

Measured and reported at same diameters used for compression force

Complete

Haptic Pull Withstand a force of ≥0.25 N Passed

Contact Angle

Informational only

56°

56° (post decay)

Compression Force

Informational only

0.125 g

0.119 g (post decay)

Mechanical Characterization

Contact Angle within 40% of parent at 10 mm compressed diameter

Passed

UFB/AC and LFB/AC overlaps with parent model

Passed

Dynamic Fatigue Durability Testing

Withstand 250,000 cycles (± 0.25 mm; 1 Hz and 10 Hz)

Passed

Fold & Recovery After release from deformed state,

return to specifications within 24 hrs.

Passed

Spectral Transmittance Record Range 300 nm to 1100 nm Complete


Standards

Standards used to conduct the testing presented in this section were conducted in accordance with the standards cited in Table 3 as well as:

• EN ISO 11137-1: 2012-Sterilization of health care products – Radiation – Part

1: Requirements for development, validation, and routine control of a sterilization process for medical devices

• EN ISO 11137-2: 2015-Sterilization of health care products – Radiation – Part 2: Establishing a sterilization dose

• EN11607-1: 2009+A1:2014-Packaging for terminally sterilized medical devices – Part 1: Requirements for materials, sterile barrier systems and packaging systems

• EN 11607-2:2006+A1:2014-Packaging for terminally sterilized medical devices – Part 2: Validation requirements for forming, sealing and assembly processes

• DIN EN 11737-1: 2016-Sterilization of medical devices – Microbiological methods – Part 1: Determination of a population of microorganisms on products

• EN 11737-2:2015-Sterilization of medical devices – Microbiological methods – Part 2: Tests of sterility performed in the definition, validation and maintenance of a sterilization process

A. Additional Studies

Software Validation

A software validation was performed for the B+L Toric Calculator per the procedures described in FDA’s Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, Software Level of Concern: MAJOR. The software for this device was developed under an appropriate software development program. A hazard analysis was performed from both the patient's and user's standpoint and all identified


hazards were addressed. These procedures provide the foundation for assuring, to the extent possible, that the software will operate in a manner described in the specifications, and in no other way. In addition, software standard, ISO 63204:2006 - Medical device software – Software Lifecycle Processes was followed.

X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of subjects undergoing cataract extraction and IOL implantation with the enVista® Toric IOL, Model MX60T for primary implantation in the capsular bag of the eye in adult subjects for visual correction of aphakia and corneal astigmatism following removal of a cataractous lens for improved uncorrected distance vision in the US under IDE # G120193. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

A. Study Design Subjects were treated between March 6, 2013 and June 2, 2016. The database for this Panel Track Supplement (PTS) reflected data collected through February 3, 2017 and included 191 subjects. There were 9 investigational sites.

The study was a prospective, multicenter, parallel, partially randomized, partially controlled, double-masked, monocular clinical trial. The study was designed to evaluate the safety and effectiveness of the enVista® Toric IOL (Model MX60T) in reducing postoperative refractive astigmatism in subjects undergoing cataract extraction. IOL implantations were conducted in the US with study duration of 6 months for subjects. Subjects in the lowest astigmatic power (1.25 D) cohort were randomized to undergo implantation of either the toric test lens or the non-toric spherical control lens (enVista® One-Piece Hydrophobic IOL Model MX60) in one eye. Subjects in the non-randomized higher astigmatic power cohorts (2.00 D, 2.75 D) were implanted with the test lens in one eye.

The control group were fellow aphakic subjects that only had spherical corrective lenses implanted (one-piece monofocal IOL; Model MX60).


1. Clinical Inclusion and Exclusion Criteria Enrollment in the enVista® Toric IOL study was limited to subjects who met the following inclusion criteria:

• Clinically documented diagnosis of age-related cataract (cortical, nuclear, subcapsular, or a combination) considered amenable to treatment with standard phacoemulsification / extracapsular cataract extraction,

• 18 years of age or older and met any applicable local minimum age requirements for IOL implantation following cataract surgery,

• Clear intraocular media other than cataract in study eye,

• BCVA equal to or worse than 20/40, with or without a glare source,

• Ability to return for scheduled follow-up examinations and had mental capacity to cooperate when undergoing a detailed postoperative exam,

• Contact lens wearers demonstrate stable refraction (within ± 0.50 D) in operative eye, determined by manifest refraction spherical equivalent (MRSE) on 2 consecutive exam dates, under the following conditions:

• Lenses not worn for at least 2 weeks (rigid or toric contact lenses) or 3 days (soft contact lenses),

• The 2 refractions were performed at least 7 days apart,

• Preoperative dilated pupil size greater than or equal to 5.0 mm,

• Underwent primary IOL implantation for correction of aphakia following continuous curvilinear anterior capsulotomy and phacoemulsification cataract extraction,

• Required spherical lens power of 16.00 D to 27.00 D,

• Minimum preoperative corneal astigmatism of 0.90 D in operated eye,

• Predicted postoperative corneal astigmatism between 0.90 D and 2.40 D, as determined by the toric calculator, and

• Potential for BCDVA of 20/30 or better in the operated eye (determined by medical judgment or measured by retinal acuity meter / potential acuity meter testing).

Subjects were not permitted to enroll in the enVista® Toric IOL study if they met any of the following exclusion criteria:


• Anterior segment pathology for which extracapsular phacoemulsification cataract surgery would be contraindicated (e.g., chronic uveitis, iritis, iridocyclitis, rubeosis, iridis, clinically significant corneal dystrophy, clinically significant Fuch’s dystrophy, clinically significant anterior membrane dystrophy)

• Corneal pathology potentially affecting topography

• Diagnoses of degenerative visual disorders (e.g., macular degeneration or other retinal disorders) predicted to cause future acuity losses to a level of 20/30 or worse

• Conditions associated with increased risk of zonular rupture (zonule rupture during cataract extraction procedure that may affect postoperative rotation, centration, or tilt of the lens)

• Inability to achieve pupil dilation of 5.0 mm

• Any inflammation or edema (swelling) of the cornea, including but not limited to keratitis, keratoconjunctivitis and keratouveitis

• Any ocular condition (e.g., amblyopia) that could prevent the possibility of a visual outcome better than 20/30 in the operative eye

• Presence of rubella, bilateral congenital, traumatic or complicated cataract

• Previous intraocular or corneal surgery

• Uncontrolled glaucoma

• Prior retinal detachment

• Irregular corneal astigmatism

• Diabetic retinopathy (proliferative or nonproliferative)

• Marked microphthalmos or aniridia

• Clinically significant retinal pigment or epithelium/macular changes

• Iris or chorioretinal neovascularization

• Presence of optic atrophy

• Chronic use of systemic steroids or immunosuppressive medications


• Concurrent participation in another clinical trial or participation in another clinical trial within 30 days prior to enrollment in this study

• Difference in corneal astigmatism measured with the IOL Master and the topographer greater than 0.50 D using vector analysis

2. Follow-up Schedule

All subjects were scheduled to return for follow-up examinations at:

• Postoperative Visit 1 (Form 1) Day 1 to 2

• Postoperative Visit 2 (Form 2) Day 7 to14

• Postoperative Visit 3 (Form 3) Day 30 to 60

• Postoperative Visit 4 (Form 4) Day 120 to180

Preoperatively, subjects were evaluated to obtain a medical history and to establish a baseline for their ocular condition. Subjects in the lowest astigmatic power group were randomized to undergo implantation of either the test or control lens. No corneal or refractive procedures (such as limbal relaxing incisions or astigmatic keratotomies) were permitted at any time during the course of the study. Postoperatively, the objective parameters measured during the study included the following:

• Analysis of IOL axial stability included continuous summary statistics, 95% confidence intervals (CIs) around the mean, and the proportion of lenses with axial rotation ≤ to 5° for cylindrical powers of 1.25 D, 2.00 D and 2.75 D.

• Analysis of the dioptric reduction in cylinder included continuous summary statistics. Additionally, a statistical model including the effects of treatment and site was constructed to test the null hypothesis that the dioptric reduction in cylinder of the eyes implanted with IOL cylinder power 1.25 D was less than or equal to the dioptric reduction in cylinder of the eyes implanted with the control IOL.

• Analysis of the percent reduction in absolute cylinder included continuous summary statistics and 95% confidence intervals (CIs) around the mean. For the endpoint of the percent of eyes with reduction of cylinder within 0.50 D and 1.00 D of target, categorical summary statistics were provided, including exact 95% binomial CIs around the percent of eyes within 0.50


D and 1.00 D.

• Analysis of lens axis misalignment included continuous summaries of the absolute value of the misalignment, the signed value of the misalignment (including a 2-sided 95% tolerance interval, which contains at least 90% of the population), and the proportion of lenses with axis misalignment in the following categories: ≤ 5, ≥ 10, ≤ 20, ≤ 30, and > 30 degrees.

• Analysis of the best corrected distance visual acuity (BCDVA) includes a comparison to historical controls to test the null hypothesis that the true rate of cases with BCDVA 0.3 logMAR or better is greater than or equal to the historical control rate.

• Analysis of uncorrected distance visual acuity (UCDVA), expressed as the logarithm of the minimum angle of resolution, logMAR, includes a comparison of the Toric 1.25 D arm to the spherical control group to test the null hypothesis that the true UCDVA of the Toric 1.25 D eyes is equivalent to the mean logMAR UCDVA of the spherical control group.

Adverse events and complications were recorded at all visits.

The key timepoints are shown below in the tables summarizing safety and effectiveness.

3. Clinical Endpoints

With regards to safety, the study endpoints were the incidence of cumulative and persistent adverse events for eyes implanted with toric IOLs.

With regards to effectiveness, primary endpoints were:

• IOL axial stability, expressed as the degree of rotation between consecutive visits,

• Dioptric reduction in cylinder,

• Percent reduction in absolute cylinder, expressed as a percentage of the intended reduction in cylinder, calculated as:

(⃓Postoperative Manifest Refractive Cylinder⃓ − ⃓Preoperative Keratometric Cylinder⃓)

(⃓Intended Postoperative Manifest Refractive Cylinder⃓ − ⃓Preoperative Keratometric Cylinder⃓)) ∗ 100

• Percent of eyes with “reduction of cylinder” within 0.50 D and within 1.00 D of intended,


• Lens axis misalignment as determined by a direct measurement method; and

• Best corrected distance visual acuity (BCDVA).

A secondary effectiveness endpoint was:

• Uncorrected distance visual acuity (UCDVA).

B. Accountability of PMA Cohort At the time of database lock, of 191 subjects enrolled in the PMA study, 98.4% (188/191) subjects are available for analysis at the completion of the study, the 6 month post-operative visit. Refer to Table 5 below for subject accountability by each scheduled visit.

Table 5: ACCOUNTABILITY OF SUBJECTS AT EACH FORM VISIT (ALL

ENROLLED)

Subject Status

Op Visit n (%)

Form 1 n (%)

Form 2 n (%)

Form 3 n (%)

Form 4 n (%)

Available for Analysis

191 (100.0)

190 (99.5)

189 (99.0)

188 (98.4)

188 (98.4)

Discontinued 0 0 0 0 1 (0.5)

Missing at scheduled visit but seen later

0

1

(0.5)

2

(1.0)

3

(1.6)

1

(0.5)

Lost to follow-up 0 0 0 0

1 (0.5)

Active 0 0 0 0 0 Percent

Accountability - 190/191 (99.5) 189/191 (99.0) 188/191 (98.4)

188/190 (98.9) Abbreviations: Op = Operative; n = number of subjects at a study visit in a stated category

Figure 2: summarizies the analysis of the various populations used in this study: All Enrolled Cohort, Safety Cohort, Repositioned Lens Cohort, Effectiveness ITT Cohort, Best Case Cohort; Not Best Case Cohort; and Per Protocol Cohort.


Figure 2: STUDY POPULATIONS ANALYSIS FLOW CHART

*A total of 4 subject eyes (1 toric, 3 control) reporting 4 ocular pathologies were included in the Not Best Case Cohort. Note: n=Control/Toric 1.25 D/Toric 2.00 D/Toric 2.75 D IOL

C. Study Population Demographics and Baseline Parameters The demographics (Table 6) of the study population are typical for an IOL study performed in the US. In total, 89 subjects were male, and 102 subjects were female. The mean age for subjects in the Control Cohort was 69.5 years and the mean age for subjects in the All Toric Cohort was 70.5 years. The age range for all subjects was 40 to 89 years. With regard to gender, the majority for the Control Cohort were male at 54.4% (43/79) while the majority for the All Toric Cohort was female at 58.9% (66/112).

Safety Cohort N=191

(n=79/80/20/12)

All Enrolled Cohort N=191

(n=79/80/20/12)

ITT Cohort N=191

(n=79/80/20/12)

Not Best Case Cohort* N=4 (n=3/1/0/0) Reasons: Mild Drusen (ARMD), CME ongoing, Glaucoma, or Moderate Macular Edema

Best Case Cohort N=184

(n=76/76/20/12)

Implanted N=191

(n=79/80/20/12)

Discontinued N=2

(n=0/0/2/0)

PP Cohort N=188

(n=79/77/20/12)

Repositioned Lens Cohort

N=0


Table 6: DEMOGRAPHICS (ALL ENROLLED)

Control IOL

(N=79)

Toric IOL 1.25 D

(N=80)

Toric IOL 2.00 D

(N=20)

Toric IOL 2.75 D

(N=12)

All Toric IOL (N=112)

Age (years)

Total Non-Missing 79 80 20 12 112

Mean (SD) 69.5 (8.6) 71.1 (8.8) 68.7 (9.1) 69.6 (8.8) 70.5 (8.9)

Median 69.0 71.0 67.0 67.5 70.0 Min, Max 52, 87 40, 89 58, 86 56, 85 40, 89

Age Category, n (%) < 60 11 (13.9%) 7 (8.8%) 3 (15.0%) 1 (8.3%) 11 (9.8%) 60 to 69 29 (36.7%) 24 (30.0%) 10 (50.0%) 6 (50.0%) 40 (35.7%)

70 to 79 28 (35.4%) 35 (43.8%) 4 (20.0%) 3 (25.0%) 42 (37.5%)

≥ 80 11 (13.9%) 14 (17.5%) 3 (15.0%) 2 (16.7%) 19 (17.0%)

Gender, n (%) Total Non-Missing 79 80 20 12 112

Male 43 (54.4%) 31 (38.8%) 12 (60.0%) 3 (25.0%) 46 (41.1%)

Female 36 (45.6%) 49 (61.3%) 8 (40.0%) 9 (75.0%) 66 (58.9%)

Operative Eye, n (%) Total Non-Missing 79 80 20 12 112 Oculus Dexter (OD) 40 (50.6%) 48 (60.0%) 12 (60.0%) 8 (66.7%) 68 (60.7%)

Oculus Sinister (OS) 39 (49.4%) 32 (40.0%) 8 (40.0%) 4 (33.3%) 44 (39.3%)

D. Safety and Effectiveness Results

1. Safety Results The analysis of safety was based on the safety cohort of 188 implanted subject eyes available for the 6-month evaluation. The key safety outcomes for this study are presented below in Table 7 and Table 8. Adverse effects are reported in Tables 7 to 9.


Adverse effects that occurred in the PMA clinical study: Table 7: ISO 11979-7 SAFETY AND PERFORMANCE ENDPOINTS (SPE) ADVERSE

EVENTS REPORTED AT EACH POSTOPERATIVE VISIT, IMPLANTED SUBJECTS (SAFETY, ALL TORIC IOL)

Adverse Event Form 1

n/N (%)1 Form 2

n/N (%)1 Form 3

n/N (%)1 Form 4

n/N (%)1 Cumulative

n/N (%)1 ISO

11979-7 SPE rate (%)

p-value

Endophthalmitis 0/112 0/112 0/112 0/112 0/112 0.1 >0.999

Hypopyon 0/112 0/112 0/112 0/112 0/112 0.3 >0.999

Lens Dislocated from Posterior Chamber 0/112 0/112 0/112 0/112 0/112 0.1 >0.999

Cystoid Macular Edema 0/112 1/112

(0.9) 1/112 (0.9) 0/112 2/112 (1.8) 3.0 0.853

Pupillary Block 0/112 0/112 0/112 0/112 0/112 0.1 >0.999

Retinal Detachment 0/112 0/112 0/112 0/112 0/112 0.3 >0.999

Secondary Surgical Intervention 0/112 0/112 0/112 0/112 0/112 0.8 >0.999

Persistent Adverse Events Noted at Form 42

Corneal Stromal Edema 0/112 0.3 >0.999

Iritis 0/112 0.3 >0.999

Cystoid Macular Edema

0/112 0.5 >0.999

Raised IOP Requiring Treatment 0/112 0.4 >0.999

1Only non-zero percent values are shown. 2 Cumulative versus persistent AEs are defined by the FDA SPE Grid and ISO 11979-7 as those occurring at Form 4 in this clinical study.


Table 8: ISO 11979-7 SPE ADVERSE EVENTS REPORTED AT EACH POSTOPERATIVE VISIT, IMPLANTED SUBJECTS (SAFETY, CONTROL IOL)

Adverse Event Form 1 n/N (%)

Form 2 n/N (%)

Form 3 n/N (%)

Form 4 n/N (%)

ISO SPE %

p-Value

Endophthalmitis 0/79 0/79 0/79 0/79 0.1 >0.999

Hypopyon 0/79 0/79 0/79 0/79 0.3 >0.999

Lens Dislocated from Posterior

0/79 0/79 0/79 0/79 0.1 >0.999


0/79 0/79 0/79 2/79 (2.5) 3.0 0.853

Pupillary Block 0/79 0/79 0/79 0/79 0.1 >0.999

Retinal Detachment

0/79 0/79 0/79 0/79 0.3 >0.999

Secondary Surgical Intervention

0/79 0/79 0/79 0/79 0.8 >0.999

Persistent Adverse Events Noted at Form 42

Corneal Stromal Edema

0/79 0.3 >0.999

Iritis 0/79 0.3 >0.999


1/79 (1.3)

0.5 >0.999

Raised IOP Requiring Treatment

0/79 0.4 >0.999

Note: Only non-zero percent values are shown


Table 9: MEAN TORIC LENS AXIS MISALIGNMENT FROM SURGICAL MARKINGS AT FORM 4 (ITT POPULATION)

Axis Misalignment Toric IOL

All Toric IOL (N=112) 1.25 D

(N=80) 2.00 D (N=20)

2.75 D (N=12)

Form 4 signed axis misalignment, degrees

n 77 16 11 104 Mean ±SD 1.11±8.69 3.08±10.51 2.52±3.03 1.56±8.57 95% tolerance interval for 90% of the population -15.51 to 17.73 -22.54 to 28.70 -5.78 to 10.82 -14.45 to 17.57

Form 4 absolute misalignment, degrees n 77 16 11 104 Mean ±SD 4.77±7.33 5.15±9.61 3.32±2.01 4.68±7.33 95% tolerance interval for 90% of the population -9.25 to 18.79 -18.28 to 28.58 -2.19 to 8.83 -9.02 to 18.38

Form 4 signed axis misalignment category, n (%) ≤ 5 degrees 56 (72.7%) 13 (81.3%) 9 (81.8%) 78 (75.0%) ≤ 10 degrees 71 (92.2%) 15 (93.8%) 11 (100.0%) 97 (93.3%)

Form 4 signed axis misalignment category, n (%) -10.00 to -5.01 degrees 4 (5.2%) 2 (12.5%) 0 (0.0%) 6 (5.8%) -5.00 to -0.01 degrees 31 (40.3%) 3 (18.8%) 2 (18.2%) 36 (34.6%) 0.00 degrees 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) +0.001 to +5.00 degrees 25 (32.5%) 10 (62.5%) 7 (63.6%) 42 (40.4%)

+5.01 to 10.00 degrees 11 (14.3%) 0 (0.0%) 2 (18.2%) 13 (12.5%)

2. Effectiveness Results

The analysis of effectiveness was based on the 188 evaluable subjects at the 6-month time point. Key effectiveness outcomes are presented in Tables 11 to 14.

The primary analysis of effectiveness was based on the 191 intent-to-treat (ITT) subjects who were allocated to a randomly assigned treatment IOL or the non-randomized cohort, and for whom phacoemulsification was successfully completed. Effectiveness analyses were also conducted using the 188 subjects in the per protocol (PP) population who were implanted with a study lens and who had no major protocol deviations. The effective corneal powers for each of the test lens plane cylindrical powers of the test IOLs are shown in Table 10. Key effectiveness outcomes are presented in Table 11, Table 12, Table 13, Table 14, and Table 15. The results achieved for 191 subject eyes followed


postoperatively for six months provide data to support the conclusion that eyes implanted with an enVista® Toric IOL following cataract extraction achieve adequate visual correction of aphakia and astigmatism.

The data for subject eyes specifically support a significant dioptric reduction in cylinder and reduction in absolute cylinder, rotational stability of the lens, and improvement of both best corrected and uncorrected visual acuity at distance following implantation of an enVista® Toric IOL.

A primary effectiveness endpoint was mean Toric IOL axial stability from Form 3 to Form 4. Table 12 shows the absolute axial stability from Form 3 to Form 4 for subjects who received an enVista® Toric IOL in the ITT population, with 95% confidence intervals and notation of the percent of subjects in each Toric IOL treatment group who demonstrated ≤ 5 degrees rotation during this interval. All subjects in the Toric IOL treatment groups demonstrated ≤ 5 degrees rotation from Form 3, including those subjects with missing data for which 5 rounds of multiple data imputation were used to simulate the entire Toric IOL ITT population.

The percent of eyes within 0.50 D and 1.00 D of intended correction for the enVista® Toric Posterior Chamber Intraocular Lens (All Toric Cohort) at Form 4 was 57.3% (63/112) and 90.9% (100/112), respectively. The minimum preoperative keratometric cylinder treated with a toric IOL was 1.24 D. The results for percent of non-missing eyes in the ITT population with reduction in cylinder within 0.50 D and 1.00 D of intended cylinder are shown in Table 11.

Table 10: ENVISTA TORIC IOL CYLINDER POWER

Cylinder Power at IOL Plane (D) Cylinder Power at Corneal Plane (D) Range of Predicted

Postoperative Corneal Cylinder1 (D)

1.25 0.90 0.90-1.39

2.00 1.40 1.40-1.92

2.75 1.93 1.93-2.40 1 Each Surgeon’s individual surgically-induced astigmatism (SIA) was added to the recommended preoperative correction range to determine eligibility based on preoperative corneal cylinder. Once the SIA was estimated, this value stayed constant during the study for each investigator.


Table 11: MEAN PERCENT OF EYES WITH REDUCTION IN CYLINDER WITHIN 0.50

D AND 1.00 D OF INTENDED – FORM 4 (ITT POPULATION)

Control IOL (N=79) n (%)

Toric IOL

1.25 D (N=80) n (%)

Toric IOL

2.00 D (N=20) n (%)

Toric IOL

2.75 D (N=12) n (%)

All Toric IOL

(N=112) n (%)

Total Non- Missing, n

78

80

18

12

110

Within 0.50 D of Intended, n(%)

27 (34.6%)

43 (53.8%)

12 (66.7%)

8 (66.7%)

63 (57.3%)

Within 1.00 D of Intended, n (%)

45 (57.7%)

71 (88.8%)

17 (94.4%)

12 (100.0%)

100 (90.9%)

Table 12: MEAN TORIC IOL AXIAL STABILITY FROM FORM 3 TO FORM 4 (ITT POPULATION)

Absolute rotation (degrees)

Toric IOL All Toric IOL

(N=112) 1.25 D (N=80)

2.00 D (N=20)

2.75 D (N=12)

Absolute rotation from Form 3 to Form 4 n 74 15 12 101 Mean ± SD 1.15 ± 1.08 0.92 ± 1.09 1.08 ± 0.73 1.11 ± 1.04 ≤ 5 degrees rotation 74 (100.0%) 15 (100.0%) 12 (100.0%) 101 (100.0%) 95% exact CI 95.1% to 100.0% 78.2% to 100.0% 73.5% to 100.0% 96.4% to 100.0% Five multiple imputations of absolute rotation from Form 3 to Form 4 for missing data ≤ 5 degrees rotation 560 (100.0%) Abbreviations: CI = confidence interval; D = diopter; IOL = intraocular lens; Max = maximum; Min = minimum; SD = standard deviation.

Another primary effectiveness endpoint was the mean (dioptric) cylinder reduction achieved at Form 4. Dioptric cylinder reduction (preoperative keratometric cylinder magnitude – postoperative manifest refraction cylinder magnitude referenced to the corneal plane) was determined at Form 4. At Form 4, mean cylinder reduction from preoperative keratometric cylinder measurements in the randomized ITT population was 0.479 ± 0.665 D among those subjects with control IOLs and 0.865 ± 0.487 D among those subjects with 1.25 D toric IOLs (Table 13), showing a statistically significant improvement favoring the 1.25 D toric IOLs (P < 0.001). Similar results were seen for the PP population. The dioptric cylinder reduction treatment effect (1.25 D IOL minus control IOL) in the ITT population was 0.39 D (95% CI: 0.228 to 0.545 D). Covariate


analyses of dioptric cylinder reduction across age, gender, race, and site showed there were no statistically significant inconsistent results between the randomized treatment groups. dditional sensitivity analyses with best case and worst case imputation methods showed a significant benefit in the 1.25 D toric IOL arm (P < 0.001 for both imputation methods).


Table 13: MEAN DIOPTRIC CYLINDER REDUCTION FROM PREOPERATIVE MEASUREMENTS, (ITT POPULATION)

Cylinder reduction (D) Control IOL

(N=79)

Toric IOL All Toric IOL

(N=112) 1.25 D (N=80)

2.00 D (N=20)

2.75 D (N=12)

Form 2 n 77 80 20 12 112

Mean reduction ± SD 0.640 ± 0.591 0.966 ± 0.466 1.486 ± 0.498 2.115 ± 0.328 1.182 ± 0.594

Form 3 n 79 79 18 12 109


Form 4 n 78 80 18 12 110


Treatment effect at Form 4 0.39 95% CI of effect 0.228 to 0.545

Multiple imputation p-valuea < 0.001 Abbreviations: CI = confidence interval; D = diopter; IOL = intraocular lens; Max = maximum; Min = minimum; SD = standard deviation. a P-values and treatment effects are from a linear model Type II analysis, which include an effect for investigator and compare the control and 1.25 D toric IOLs at Form 4. Note: Dioptric change in cylinder = preoperative keratometric cylinder- postoperative manifest cylinder

At Form 4, no eyes in any treatment arm lost ≥ 10 letters from baseline. However, as required by the study statistical analysis plan, an analysis of eyes that lost ≥ 10 letters between an evaluation and a later postoperative evaluation (Form 2 through Form 4) identified 3 such eyes (2.7%; 3/112) in the overall population. One subject (1.2%; 1/112) in the control IOL group lost 14 letters from Form 3 to Form 4, and two subjects in the 1.25 D toric IOL group transiently lost 10 and 11 letters from Form 2 to Form 3, respectively. Preservation of best-corrected distance visual acuity showed 99.1% (111/112) of eyes in the ITT population implanted with a Toric IOL reported a VA of 20/40 or better at Form 4. Best-corrected distance visual acuity (BCDVA) results for the all Toric IOL treatment group are presented in Table 14 and Table 15. Uncorrected distance visual acuity (UCDVA) results for all Toric IOL treatment groups are presented in Table 16. The data provided in these tables are summaries for all subject eyes enrolled in the study, including 79 eyes with the control lens MX60 and 112 eyes with the test lens (MX60T).


Table 14: PRESERVATION OF BCDVA AT EACH EXAMINATION (ALL TORIC IOLS, ITT POPULATION)

Preoperative N=112

Form 2 N=112

Form 3 N=112

Form 4 N=112

20/40 or

Better, n(%)

27 (24.1%)

108 (96.4%)

109 (100%)

109 (99.1%)

Worse than 20/40, n(%)

85 (75.9%)

4 (3.6%)

0 (0.0%)

1 (0.9%)

Table 15: BCDVA WITHOUT GLARE AT FORM 4 (ITT POPULATION)

Control

IOL (N=79)

Toric IOL 1.25 D (N=80)




BCDVA (logMAR) Total Non- Missing, (n) 78 80 18 12 110

Mean (±SD) 0.01 (±0.09) 0.00 (±0.09) 0.05 (±0.10) -0.01 (±0.09) 0.01 (±0.09)

BCDVA (Snellen)

20/40 or Better, n (%) 78 (100.0%) 79 (98.8%) 18 (100.0%) 12 (100%) 109 (99.1%)

Worse than 20/40, n (%) 0 1 (1.3%) 0 0 1 (0.9%)


Table 16: UCDVA AT FORM 4 (ITT POPULATION)

Control

IOL (N=79)





UCDA (logMAR) Total Non- Missing, n 78 80 18 12 110

Mean (±SD) 0.19 (±0.16) 0.11 (±0.14) 0.12 (±0.11) 0.13 (±0.18) 0.11 (±0.14)

UCDVA (Snellen)

20/40 or Better, n (%) 65 (83.3%) 76 (95.0%) 18 (100.0%) 10 (83.3%) 104 (94.5%)

Worse than 20/40, n (%) 13 (16.7%) 4 (5.0%) 0 2 (16.7%) 6 (5.5%)

3. Subgroup Analyses

The following preoperative characteristics were evaluated for potential association with outcomes: The reduction in cylinder and UCDVA (in LogMAR units) following preoperative characteristics were evaluated for potential association with device effectiveness in subgroups prospectively defined across the range of preoperative corneal astigmatism values (Table 18) and (Table 19). Table 17 shows the dioptric change in cylinder (D) in the ITT population at Form 4 by intended preoperative IOL cylinder power for the randomized control and 1.25 D toric IOL treatment groups, where change in cylinder is preoperative keratometric cylinder minus postoperative manifest refraction cylinder.


Table 17: MEAN REDUCTION IN CYLINDER AT FORM 4 STRATIFIED BY PREOPERATIVE KERATOMETRIC CYLINDER

Preoperative Keratometric Cylinder (D)

Magnitude of Refractive Cylinder Reduction (D)

Toric IOL 1.25 D (n) mean

Sphere IOL (n) mean

1.00 to 1.25 (1) 1.240 (1) 0.550

1.26 to 1.50 (35) 0.890 (25) 0.290

1.51 to 1.75 (33) 0.823 (42) 0.519

1.76 to 2.00 (11) 0.881 (9) 0.708

2.01 to 2.25 (0) --- (1) 1.510

Table 18: MEAN LOGMAR UNCORRECTED DISTANCE VISUAL ACUTITY (UCDVA)

AT FORM 4 STRATIFIED BY PREOPERATIVE KERATOMETRIC CYLINDER

logMAR UCDVA

Preoperative Keratometric Cylinder (D)

Toric IOL 1.25 D (n) mean

Sphere IOL (n) mean

1.00 to 1.25 (1) 0.020 (1) 0.200

1.26 to 1.50 (35) 0.125 (25) 0.193

1.51 to 1.75 (33) 0.103 (42) 0.200

1.76 to 2.00 (11) 0.096 (9) 0.189

A related effectiveness endpoint was the percent reduction in absolute cylinder, defined as the absolute value of the difference between the postoperative magnitude of the subjective Manifest Refractive cylinder (converted to the corneal plane) and the preoperative magnitude of the keratometric cylinder, divided by the intended reduction in in absolute cylinder, with the ratio expressed as a percentage. Table 19 summarizes the mean percent reduction in absolute cylinder at Form 4.


Table 19: MEAN PERCENT REDUCTION IN ABSOLUTE CYLINDER AT FORM 4

Control IOL Mean ± SD

(N=79)

Toric IOL

1.25 D Mean ± SD

(N=80)

Toric IOL

2.00 D Mean ± SD

(N=20)

Toric IOL

2.75 D Mean ± SD

(N=12)

All Toric IOL

Mean ± SD (N=112)

Number of Subjects at Form 4, n

78 80 18 12 110

Mean1 % Reduction in Absolute Cylinder (± SD)

36.8%

±50.49%

64.8%

±36.80%

81.0%

±31.3%

82.8%

±13.0%

69.4%

±34.8% 1Mean of all subject (N) results at Form 4 - n (%)

4. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

E. Financial Disclosure The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 9 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data.

XI. PANEL MEETING RECOMMENDATION AND FDA’S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Ophthalmic Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.


XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES A. Effectiveness Conclusions Significant reduction of astigmatism was achieved for all models of the enVista® Toric IOL. All of the primary effectiveness endpoints of this study were met, including all Toric IOL axial stability, 1.25 D toric IOL dioptric reduction in cylinder compared with control IOL (P< 0.001). The proportion of subjects in the ITT population at Form 4 with BCDVA of 20/40 or better was not statistically inferior (P>0.999) compared to the historical control rate (92.5%). In addition, the secondary effectiveness endpoint of UCDVA was met, also showing a significant advantage for the 1.25 D toric IOL arm compared to the control IOL arm (P < 0.001).

Forty-five percent (50/110) of toric IOL subjects had UCDVA of 20/20 or better, while only 16.7% (13/78) of the non-toric subjects achieved UCDVA of 20/20 or better at Form 4; this difference is highly statistically significant (P<0.01), and supports the expectation astigmatic subjects receiving an enVista® Toric IOL could rely less on glasses for distance vision.

B. Safety Conclusions The risks of the device are based on nonclinical laboratory and animal studies as well as data collected in a clinical study conducted to support PMA approval as described above. The safety of the enVista® One-Piece Hydrophobic Acrylic Toric IOL is highly favorable. All clinical safety endpoints of the clinical trial (G120193) are met. FDA historical controls provided in ISO 11979-7 SPE grids for both cumulative and persistent AEs are also not exceeded in the toric IOL arms of G120193. No secondary surgical interventions (SSIs) occurred during the trial for rotational instability or for any other condition.

Overall, no safety signals were associated with the toric IOLs during G120193. Neither the incidence nor the severity of AEs in the toric IOL arms was increased compared with the control IOL arm, and no SAEs were reported in the study eye. No AEs were related to either the device or the study protocol and no AEs resulted in study discontinuation. Mean IOPs in the toric IOL arms are similar to those in the control IOL arm across time points and no subject in a toric IOL arm had IOP ≥ 22 mmHg at Form 4. It is also true that no subject in the control IOL arm or the All Toric IOL arm have a BCDVA loss > 10 letters (2 lines) from baseline at Form 4. Slit lamp examinations, fundus examinations,


and central posterior capsule assessments did not reveal any clinically meaningful increase in abnormal findings at Form 4.

C. Benefit-Risk Determination The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The clinical benefits of the device are based on data collected in G120193, which demonstrate that the enVista® Toric IOL is a safe and effective option for cataract subjects with astigmatism who, with the counsel of their surgeon, select the enVista® Toric IOL. This can produce excellent vision outcomes for subjects undergoing cataract surgery and may reduce the need for subjects to use glasses, contact lens, or other refractive correction for distance vision. These findings support a favorable risk-benefit ratio for visual correction of aphakia and astigmatism with the enVista® Toric IOL.

The probable risks of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The clinical benefits of the device are based on data collected in the G120193, which demonstrate that the enVista® Toric IOL is a safe and effective option for cataract patients with astigmatism who, with the counsel of their surgeon, select the enVista® Toric IOL.

1. Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

In conclusion, given the available information above, the data support that for primary implantation in the capsular bag of the eye in adult subjects for visual correction of aphakia and corneal astigmatism following removal of a cataractous lens for improved uncorrected distance vision the probable benefits outweigh the probable risks.

D. Overall Conclusions The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use.


XIII. CDRH DECISION

CDRH issued an approval order on June 8, 2018. The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling. Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling. Post-approval Requirements and Restrictions: See approval order.

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