ACRYSOF IQ RESTOR +3.0 D MULTIFOCAL TORIC INTRAOCULAR LENS

P040020S049 · Alcon Research, Ltd. · MFK · Dec 22, 2016 · Ophthalmic

Device Facts

Record IDP040020S049
Device NameACRYSOF IQ RESTOR +3.0 D MULTIFOCAL TORIC INTRAOCULAR LENS
ApplicantAlcon Research, Ltd.
Product CodeMFK · Ophthalmic
Decision DateDec 22, 2016
DecisionAPPR
Regulation21 CFR 886.3600
Device ClassClass 3
AttributesSoftware as a Medical Device, Real-World Evidence

Real-World Evidence

SubmissionDeviceSponsorRWD SourcesRWE Use SummaryKey Tags
P040020S049 · Dec 22, 2016ACRYSOF IQ RESTOR +3.0 D MULTIFOCAL TORIC INTRAOCULAR LENSAlcon Research, Ltd.2011-2013 Medicare Beneficiary Encrypted Files (BEF)Retrospective analysis of Medicare claims data to establish a background rate of post-surgical intraocular inflammation for comparison with the investigational device in a post-approval study.Medicare claims; Post-approval study; Background rate estimation

Clinical Evidence

Study DesignPopulationComparatorKey Endpoints
Post-Approval Study Phase B; Retrospective secondary data analysis; Follow-up/Duration: 180 days post-surgical period; Study Period: 2011-2013Cataract surgery patients in the 2011-2013 Medicare Beneficiary Encrypted Files; Sample Size: Approximately 180,000 surgeriesNot applicable for this studyBackground rate of post-surgical intraocular inflammation

Indications for Use

The AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric Posterior Chamber Intraocular Lens (IOL) is indicated for primary implantation in the capsular bag of the eye for the visual correction of aphakia and pre-existing corneal astigmatism secondary to removal of a cataractous lens in adult patients with and without presbyopia, who desire near, intermediate and distance vision, reduction of residual refractive cylinder and increased spectacle independence. The lens is intended to be placed in the capsular bag.

Device Story

The AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL is a foldable, UV and blue light-filtering posterior chamber lens; implanted in the capsular bag during cataract surgery. It features an apodized diffractive aspheric optic to provide multifocal vision and a toric component to correct pre-existing corneal astigmatism. The lens is biconvex with negative spherical aberration to compensate for corneal aberration. An Alcon web-based calculator is used by the surgeon to determine the appropriate cylinder power and alignment axis. The device provides near, intermediate, and distance vision, reducing the need for spectacles. It benefits patients by correcting both aphakia and astigmatism in a single procedure.

Clinical Evidence

Prospective, nonrandomized, parallel-group study (IDE #G100262) of 574 subjects (386 investigational, 188 control). Primary endpoints: mean monocular UCDVA and UCNVA at 12 months. Results: met non-inferiority targets (0.1 logMAR). Investigational group showed superior intermediate visual acuity (approx. 1 line improvement) compared to control. Safety: rate of secondary surgical interventions (SSI) due to optical properties was 1.04% (1st eye) and 0.52% (2nd eye). Rotational stability: >97% of subjects had <10° rotation at 12 months.

Technological Characteristics

Material: UV/blue light-filtering acrylate/methacrylate copolymer. Design: Biconvex, apodized diffractive aspheric toric. Optic diameter: 6.0 mm. Overall length: 13.0 mm. Refractive index: 1.55. Haptic: STABLEFORCE®. Sterilization: Ethylene oxide (EO) per ANSI/AAMI/ISO 11135. Standards: ISO 11979-2 (optical), ISO 11979-3 (mechanical), ISO 11979-5 (biocompatibility).

Indications for Use

Indicated for adult patients (21+) with bilateral cataracts undergoing phacoemulsification who desire near, intermediate, and distance vision, reduction of residual refractive cylinder, and increased spectacle independence. Contraindications: None known.

Regulatory Classification

Identification

An intraocular lens is a device made of materials such as glass or plastic intended to be implanted to replace the natural lens of an eye.

Predicate Devices

Reference Devices

Submission Summary (Full Text)

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION | Device Generic Name: | Intraocular Lens (IOL) | | --- | --- | | Device Trade Name: | AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric Intraocular Lens (IOL) Models SND1T3, SND1T4, SND1T5, and SND1T6 | | Device Procode: | MFK | | Applicant's Name and Address: | Alcon Laboratories, Inc. 6201 South Freeway Fort Worth, TX 76134 | Date of Panel Recommendation: November 14, 2014 Premarket Approval Application (PMA) Number: P040020/S049 Date of FDA Notice of Approval: December 22, 2016 The original PMA (PMA #P040020) for the multifocal optical design parent IOL was approved on March 21, 2005 and is indicated for the visual correction of aphakia secondary to removal of a cataractous lens in adult patients with and without presbyopia, who desire near, intermediate and distance vision with increased spectacle independence. The lens is intended to be placed in the capsular bag. The SSED to support the indication is available on the CDRH website at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P040020 and is incorporated by reference here. The current supplement was submitted to expand the indication for the AcrySof® ReSTOR® IOLs. This device is considered a first-of-a-kind device because it in the first multifocal IOL that also corrects corneal astigmatism. ## II. INDICATIONS FOR USE The AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric Posterior Chamber Intraocular Lens (IOL) is indicated for primary implantation in the capsular bag of the eye for the visual correction of aphakia and pre-existing corneal astigmatism secondary to removal of a cataractous lens in adult patients with and without presbyopia, who desire near, intermediate and distance vision, reduction of residual refractive cylinder and increased spectacle independence. The lens is intended to be placed in the capsular bag. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 1 {1} ### III. CONTRAINDICATIONS There are no known contraindications. ### IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric Intraocular Lens labeling. ### V. DEVICE DESCRIPTION The AcrySof® IQ ReSTOR® +3.0 D Apodized Diffractive Aspheric Multifocal Toric Posterior Chamber IOL is an ultraviolet (UV) and blue light filtering foldable multifocal IOL. The optical portion is biconvex and consists of a soft acrylic material capable of being folded prior to insertion, allowing placement through an incision smaller than the optic diameter of the lens. See Figure 1. The anterior surface of the AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL is designed with negative spherical aberration to compensate for the positive spherical aberration of the cornea. The posterior surface of the optic of the AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL is marked with 6 indentations (3 on either side) on the flatter meridian of the optic. Figure 1: AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric Drawing ![img-0.jpeg](img-0.jpeg) The AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOLs studied in the current PMA will be available in four different cylinder powers (1.50 D, 2.25 D, 3.00 D, and 3.75 D) and in spherical equivalent powers of +6 D to +30 D. The four model designations and the associated cylinder powers available are provided in Table 1. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 2 {2} Table 1: Model Designation and the Associated Cylinder Powers of the AcrySof® IQ ReStor® Multifocal Toric Intraocular Lens (IOL) | | Cylinder Power (D) | | Recommend Corneal Astigmatism Range (D)* | | | --- | --- | --- | --- | --- | | Lens Model | IOL Plane | Corneal Plane* | Lower | Upper | | SND1T3 | 1.50 | 1.03 | 0.75 | 1.28 | | SND1T4 | 2.25 | 1.55 | 1.29 | 1.80 | | SND1T5 | 3.00 | 2.06 | 1.81 | 2.32 | | SND1T6 | 3.75 | 2.57 | 2.33 | 2.82 | *Based on an average pseudophakic human eye The physical characteristics of the AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL are shown in Table 2. Table 2: Physical Characteristics of the AcrySof® IQ ReStor® +3.0 D Multifocal Toric IOL | Characteristics | Model | | | | | --- | --- | --- | --- | --- | | | SND1T3 | SND1T4 | SND1T5 | SND1T6 | | Optic Type | Biconvex Apodized Diffractive Aspheric Toric | | | | | Optics/Haptics Material | Ultraviolet and blue light filtering Acrylate/Methacrylate Copolymer | | | | | UV Cutoff at 10% T | 401 nm for 21.0 D | | | | | Index Of Refraction | 1.55 | | | | | Optic Powers (spherical equivalent diopters) | +6.0 to +30.0 (0.5 D increments) (+3.0 Diopters of add power for near vision) | | | | | IOL Cylinder Power (Diopters) | 1.50 | 2.25 | 3.00 | 3.75 | | Haptic Configuration | STABLEFORCE® Haptic | | | | | Optics/Haptic Color | Yellow | | | | | Optic Diameter (mm) | 6.0 | | | | | Overall Length (mm) | 13.0 | | | | | Haptic Angle | 0° | | | | An Alcon web-based calculator is used in conjunction with the AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric to determine the appropriate intraocular alignment and cylinder power for the patient. The AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL is a combination of the previously approved AcrySof® IQ ReSTOR® +3.0 D Multifocal IOL (P040020/S012) and the previously approved AcrySof® IQ Toric IOL (P930014/S15, S016 and S045). Except for the addition of the toric component, ReSTOR® Toric Multifocal IOLs are identical to ReSTOR® Multifocal IOL in material composition (AcrySof Natural PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 3 {3} material) and asphericity. The AcrySof® Natural IOL material has also been used in the FDA-approved AcrySof® Toric IOLs (SN60T3, SN60T4 and SN60T5; P930014/S016). ## **VI. ALTERNATIVE PRACTICES AND PROCEDURES** Patients who undergo cataract extraction presently have several non-surgical and surgical alternatives for restoring functional vision of the aphakic eye. Non-surgical options include special cataract glasses or contact lenses. Surgical options such as monofocal, toric, 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 AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOLs are currently commercially available in the European Union, Australia, Canada, multiple countries within Central and South America, the Middle East and the Far East. The lenses have been withdrawn from the market in Japan because of reasons related to safety. An investigation of safety issues with the Japanese lenses indicates that they are related to manufacturing processes unique to lenses manufactured for the Japanese market. ## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH** Below is a list of the potential 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 prolapse, hypopyon, transient or persistent glaucoma, and secondary surgical intervention. Potential 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 study, please see the safety results section for the pivotal study (Section X.D.1). PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 4 {4} ## **IX. SUMMARY OF PRECLINICAL STUDIES** ### **A. Laboratory Studies** #### **Biocompatibility** The AcrySof® IQ ReSTOR® Multifocal Toric lenses are made of AcrySof® Natural IOL material (AL-37884), the same material that was used with other previously approved IOL designs. The Applicant referenced biocompatibility testing performed on AcrySof® Natural IOL material submitted in P930014/S006. The biocompatibility testing met the requirements of International Standard Organization (ISO) 10993, Biological Evaluation of Medical Devices, and ISO 11979-5, Ophthalmic Implants- Intraocular Lenses- Part 5: Biocompatibility, and demonstrated that the AcrySof® Natural IOL material does not induce cytotoxicity, sensitization, genotoxicity, or inflammation to muscular and ocular tissue. Studies were conducted in accordance with Good Laboratory Practices. #### **Sterilization, Packaging and Shelf Life** The AcrySof® IQ ReSTOR® Multifocal Toric lenses are sterilized using 100% ethylene oxide (EO). The sterilization validation was performed according to ANSI/AAMI/ISO 11135 (Sterilization of health care products – Ethylene oxide) using the overkill method. Sterilization validation parameters were designed to achieve a Sterility Assurance Level (SAL) of 10⁻⁶. The Multifocal Toric lenses are supplied in a polypropylene “wagon wheel” case inside of a polyester/TYVEK pouch. The pouch is enclosed in a paper box with appropriate labels. Packaging, shipping, and shelf life studies were conducted to verify that the packaging for the Multifocal Toric lenses maintains a sterile barrier and that device performance meets product specifications through a 5 year shelf life. The Applicant performed a microbial aerosol challenge and dye penetration testing on samples aged to an equivalent of 5 years. The shelf life studies conducted were performed in accordance with ISO 11979-6 (Ophthalmic implants – Intraocular lenses – Part 6: Shelf-life and transport stability). #### **Material/ Chemical Characterization** Alcon performed material/ chemical characterization testing of the AcrySof® IQ ReSTOR® Multifocal Toric lenses. The material/ chemical characterization tests meet the requirements of ISO 11979-5, Ophthalmic Implants – Intraocular Lenses – Part 5: Biocompatibility and FDA Guidance Document for Multifocal Intraocular Lenses, May 29, 1997, when present. The material/ chemical tests are listed in Table 3. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 5 {5} **Table 3: Summary of Material/Chemical Characterization Tests** | Test: | Acceptance Criteria | Results | | --- | --- | --- | | Material Stability – aging and leachability | No relevant surface or optical changes | Passed | | Material Extraction | None | N/A | | Process Extractable Analysis | None | N/A | | Heavy Metal Analysis | None | N/A | | Fourier Transform/Infrared Spectroscopy | None | N/A | | Contact Angle | None | N/A | | X-ray photoelectron Spectroscopy | None | N/A | ### **Optical/ Mechanical characterization** Alcon performed optical/ mechanical characterization of the AcrySof® IQ ReSTOR® Multifocal Toric lenses. The optical / mechanical tests were conducted and evaluated in accordance with ISO 11979-2 Ophthalmic Implants – Intraocular Lenses – Part 2: Optical Properties and Test Methods and ISO 11979-3 Ophthalmic Implants – Intraocular Lenses – Part 3:Mechanical Properties and Test Methods and ISO 11979-5, Ophthalmic Implants – Intraocular Lenses – Part 5: Biocompatibility. The material/ chemical tests are listed in Table 4. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 6 {6} **Table 4: Summary of Optical / Mechanical Characterization Tests** | Test: | Acceptance Criteria | Results | | --- | --- | --- | | Haptic Compression Force | None | N/A | | Haptic Compression Force Decay | None | N/A | | Axial Displacement | None | N/A | | Optic Decentration | < 10% of clear optic | Pass | | Optic Tilt | < 5° | Pass | | Angle of Contact | None | N/A | | Fatigue Testing | > 250,000 cycles | Pass | | Haptic Strength | > 0.25 N | Pass | | Spectral Transmittance | None | N/A | | Modulation Transfer Function | MTF specifications at distance and near image planes | Pass | | Optical Evaluation after Multiple Folds | Optical specifications | Pass | | Test Photostability | Material stability in terms of optical properties and polymer breakdown compounds | Pass | | Nd: YAG Laser Exposure Test | No release of cytotoxic compounds | Pass | | Refractive Index | None | N/A | # **B. Animal Studies** No animal studies were conducted. # **X. SUMMARY OF PRIMARY CLINICAL STUDY** The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL Models SND1T3, SND1T4, SND1T5, or SND1T6 for primary implantation in the capsular bag for the visual correction of aphakia and pre-existing astigmatism secondary to removal of a cataractous lens in adult patients with and without presbyopia, who desire near, intermediate and distance vision, reduction of residual refractive cylinder and increased spectacle independence. This study was conducted in the US under IDE #G100262. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 7 {7} # A. Study Design A prospective, nonrandomized, unmasked, parallel-group study was designed for bilateral implantation of a minimum of 510 (maximum of 600 subjects) subjects in total, with a minimum of 340 subjects implanted with the investigational AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL Models SND1T3-SND1T6 (referred to as the ReSTOR® Toric +3.0 D IOL below), and a minimum of 170 subjects implanted with the previously FDA approved AcrySof® ReSTOR® (+4.0 D Add) Multifocal IOL Model SA60D3 (referred to as the ReSTOR® +4.0 D IOL below), at up to 25 investigational sites in the United States (US). The investigational ReSTOR® Toric +3.0 D IOL was designed with a near reading distance of 40 cm and the control ReSTOR® +4.0 D IOL was designed with a near reading distance of 33 cm. The parameters expected to be impacted by the near add power difference included intermediate visual acuity and binocular defocus, in favor of the ReSTOR® Toric +3.0 D IOL. The rate of severe visual disturbances (e.g., glare and halos) between the ReSTOR® Toric +3.0 D IOL and the ReSTOR® +4.0 D IOL was also expected to favor the ReSTOR® Toric +3.0 D IOL based on the add power difference. This study included a concurrent, active control arm. The AcrySof® ReSTOR® Multifocal IOL (Model SA60D3) is an FDA approved posterior chamber IOL. This IOL is intended to be placed in the capsular bag and has no toric component to correct pre-existing corneal astigmatism and does not incorporate asphericity to compensate for corneal spherical aberration. The add power at the IOL plane is +4.0 D. The investigational and control IOL models were available in IOL powers ranging from 10.0 D to 30.0 D in 0.5 D increments. According to the study protocol, the primary driver of sample size for the study was the precision of the confidence interval on the rate of actual or potential secondary surgical interventions related to optical properties of the IOL. The study was designed such that the event rate in the ReSTOR® Toric IOL group could be estimated to as low as approximately 1% with 95% confidence. Therefore, a minimum of 340 subjects would be enrolled for the ReSTOR® Toric IOL group in order to ensure at least 300 eligible subjects to complete the study. An additional 170 subjects were planned for enrollment in the ReSTOR® IOL control group. The study was non-randomized and not masked due to the difference between the control and investigational populations (with regard to the amount of astigmatism that could be present for enrollment) The control group were required to have ≤ 0.74 D of preoperative keratometric astigmatism in both eyes. The investigational group included subjects with preoperative astigmatism ≥ 0.75 D # 1. Clinical Inclusion and Exclusion Criteria PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 8 {8} Enrollment in the study was limited to patients who met the following inclusion criteria: - Adults, 21 years of age or older at the time of surgery, of either gender or any race, diagnosed with bilateral cataracts - Able to comprehend and sign a statement of informed consent - Calculated lens power and astigmatism within the available range - Willing and able to complete all required postoperative visits - Planned cataract removal by phacoemulsification - Potential postoperative visual acuity of 0.2 logMAR (logarithm of the minimum angle of resolution) or better in both eyes - Clear intraocular media other than cataract in study eyes - Preoperative Best Corrected Distance Visual Acuity (BCDVA) worse than 0.2 logMAR in each eye - Pupil size greater than or equal to 6 mm after dilation - Able to undergo second eye surgery within 30 days of the first eye surgery. Patients were not permitted to enroll in the study if they met any of the following exclusion criteria: - Significant irregular corneal aberration as demonstrated by corneal topography; - Keratopathy/Kerectasia - any corneal abnormality, other than regular corneal astigmatism, including, but not limited to the following: keratoconus, keratoglobus, keratolysis, keratomalacia, keratomycosis, and corneal plana; - Any inflammation or edema (swelling) of the cornea, including but not limited to the following: keratitis, keratoconjunctivitis, and keratouveitis; - Subjects with diagnosed degenerative visual disorders (e.g., macular degeneration or other retinal disorders) that are predicted (by subjective assessment of the retina) to cause future acuity losses to a level worse than 0.2 logMAR; - Subjects who may have reasonably been expected to require a secondary surgical intervention at any time during the study (other than YAG capsulotomy); - Previous corneal refractive surgery; - Amblyopia; - Clinically severe corneal dystrophy (e.g., epithelial, stromal, or endothelial dystrophy); - Diabetic retinopathy; - Extremely shallow anterior chamber, not due to swollen cataract; - Microphthalmos; - Previous retinal detachment; - Previous corneal transplant; PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 9 {9} - Recurrent severe anterior or posterior segment inflammation of unknown etiology; - Rubella or traumatic cataract; - Iris neovascularization; - Glaucoma (uncontrolled or controlled with medication); - Aniridia; - Optic nerve atrophy; - Pregnancy; - Any subject participating in another investigational drug or device study; - Other planned ocular surgery procedures, including, but not limited to LASIK, astigmatic keratotomy and limbal relaxing incisions, for the duration of the study; The following were intraoperative criteria for not implanting the device: - Any incision site other than temporal (±15° from the horizontal meridian); - Other ocular surgery procedures, including, but not limited to LASIK, astigmatic keratotomy and limbal relaxing incisions, for the duration of the study; - Mechanical or surgical manipulation required to enlarge the pupil; pupil size was required to be at least 4.5 mm or larger just prior to IOL implantation; - Significant vitreous loss; - Significant anterior chamber hyphema; - Uncontrollable intraocular pressure; - Zonular or capsular rupture; - Bag-sulcus, sulcus-sulcus or unknown placement of the haptics. In the event of zonular damage or capsulorhexis tear during surgery, the subject was to be excluded from the study, the study IOL was not to be implanted, and the surgeon was to make arrangements to implant an alternative non-study IOL. 2. Follow-up Schedule The follow-up visit schedule is presented in Table 5. Specific examinations and scheduled clinical assessments are presented in Table 6. Note that IOL axis orientation was determined using Photographic Assessment of Lens Orientation (PALO) methodology. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 10 {10} **Table 5: Follow-up schedule** | Time From Implantation | 1st Implant | 2nd Implant | | --- | --- | --- | | Preoperative | Visit 0 (monocular and binocular) | - | | Operative | Visit 00 | Visit 00A | | 1 – 2 days | Visit 1 | Visit 1A | | 7 - 14 days | Visit 2 | Visit 2A | | 30 - 60 days | Visit 3 (monocular-1st eye) | Visit 3A (monocular-2nd eye) | | 120 - 180 days (after 2nd eye implant) | - | Visit 4A (monocular and binocular) | | 330 - 420 days (after 2nd eye implant) | - | Visit 5A (monocular and binocular) | **Table 6: Study plan** | PROCEDURES/ MEASUREMENTS/ STATUS | Visit 0 (Preop) | Visit 00 (Op) | Visit 1 (d1-2) | Visit 2 (d7-14) | Visit 3 (d30-60) | Visit 00A (Op) | Visit 1A (d1-2) | Visit 2A (d7-14) | Visit 3A (d30-60) | Visit 4A (d120-180) | Visit 5A (d330-420) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Screening | X | | | | | | | | | | | | Informed Consent | X | | | | | | | | | | | | Demographics | X | | | | | | | | | | | | Ocular and Non-Ocular Medical History | X | | | | | | | | | | | | Manifest Refraction | X | | X | X | X | | X | X | X | X | X | | Inclusion/Exclusion Criteria | X | X | | | | X | | | | | | | Urine Pregnancy Test | X | | | | | | | | | | | | Device Deficiencies | X | X | X | X | X | X | X | X | X | X | X | | Adverse Events | X | X | X | X | X | X | X | X | X | X | X | | Lighting Measurements | X | | X | X | X | | X | X | X | X | X | | Photopic and Mesopic Pupil Size at Distance | | | | | | | | | | | X | | Photopic and Mesopic Pupil Size at Near (40 cm) | | | | | | | | | | | X | | Distance Visual Acuity | | | | | | | | | | | | | Uncorrected | X^{b} | | X | X | X | | X | X | X | X X^{b} | X X^{b} | | Best Corrected | X | | X | X | X | | X | X | X | X X^{b} | X X^{b} | | Intermediate Visual Acuity- 50 cm | | | | | | | | | | | | | Uncorrected | | | | | | | | | | | X^{b} | | Distance Corrected | | | | | | | | | | | X^{b} | | Intermediate Visual Acuity-60 cm | | | | | | | | | | | | | Uncorrected | X^{b} | | | | | | | | | | X^{b} | | Distance Corrected | | | | | | | | | | | X^{b} | | Intermediate Visual Acuity-70 cm | | | | | | | | | | | | | Uncorrected | | | | | | | | | | | X^{b} | | Distance Corrected | | | | | | | | | | | X^{b} | PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 11 {11} **Table 6: Study plan (continued)** | PROCEDURES/ MEASUREMENTS/ STATUS | Visit 0 (Preop) | Visit 00 (Op) | Visit 1 (d1-2) | Visit 2 (d7-14) | Visit 3 (d30-60) | Visit 00A (Op) | Visit 1A (d1-2) | Visit 2A (d7-14) | Visit 3A (d30-60) | Visit 4A (d120-180) | Visit 5A (d330-420) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | **Near Visual Acuity- Fixed Distance** | | | | | | | | | | | | | Uncorrected | X^{a} | | | | X | | | | X | X.X^{a} | X.X^{a} | | Distance Corrected | | | | | X | | | | X | X.X^{a} | X.X^{a} | | Best Corrected | | | | | X | | | | X | X.X^{a} | X.X^{a} | | **Near Visual Acuity- Best Distance** | | | | | | | | | | | | | Uncorrected | | | | | X | | | | X | X.X^{a} | X.X^{a} | | Distance Corrected | | | | | X | | | | X | X.X^{a} | X.X^{a} | | **Mesopic Near Visual Acuity- Best Distance** | | | | | | | | | | | | | Distance Corrected | | | | | X | | | | X | X | X.X^{a} | | Corneal Topography | X | | | | | | | | | | | | Contrast Sensitivity | | | | | | | | | | X^{a} | X^{a} | | Defocus Curve | | | | | | | | | | X^{a} | | | Anterior Chamber Depth | X | | | | | | | | | | | | Axial Length | X | | | | | | | | | | | | ReSTOR Toric Calculator^{b} | X | | | | | | | | | | | | Automated Keratometry | X | | | X | X | | | X | X | X | X | | Intended Axis Placement^{c} | X | | | | | X | | | | | | | Current Orientation of Lens Axis^{c} | | X | X | X | X | X | X | X | X | X | X | | Target Residual Refractive Error | X | | | | | | | | | | | | Intraocular Pressure | X | | X | X | X | | X | X | X | X | X | | APPLES Questionnaire^{c} | X^{a} | | | | | | | | | X^{a} | X^{a} | | VISTAS Questionnaire | X^{a} | | | | | | | | | X^{a} | | | SILVER Questionnaire^{c} | X^{a} | | | | | | | | | X^{a} | X^{a} | | Ocular and Non-Ocular Concomitant Medications | X | X | X | X | X | X | X | X | X | X | X | | Operative Eye | | X | | | | X | | | | | | | Problems During Surgery | | X | | | | X | | | | | | | Other Procedures at Surgery | | X | | | | X | | | | | | | Folding Instrument | | X | | | | X | | | | | | | Insertion Instrument | | X | | | | X | | | | | | | Incision Site | | X | | | | X | | | | | | | Final Incision Size | | X | | | | X | | | | | | | Lens Information | | X | | | | X | | | | | | | Slit-Lamp Examination | X | | X | X | X | | X | X | X | X | X | | Dilated Fundus Examination | X | | | | X | | | | X | X | X | | Retinal Detail | | | | | X | | | | X | | | | Secondary Surgical Interventions | | | X | X | X | | X | X | X | X | X | | IOL Observations | | | X | X | X | | X | X | X | X | X | | IOL Position Change | | | X | X | X | | X | X | X | X | X | | Subjective Posterior Capsule Opacification | | | X | X | X | | X | X | X | X | X | | Posterior Capsulotomy | | | X | X | X | | X | X | X | X | X | $^{a}$ Investigational Lens Only $^{b}$ Binocular Testing $^{c}$ APPLES and SILVER prior to any SSI $^{d}$ Contrast testing was repeated at Visit 5A for those subjects that had a posterior capsulotomy after Visit 4A. If the patient was scheduled a posterior capsulotomy at Visit 4A, contrast testing was deferred to Visit 5A. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 12 {12} ### 3. Clinical Endpoints The primary effectiveness outcomes were mean monocular Uncorrected Distance Visual Acuity (UCDVA) and mean monocular Uncorrected Near Visual Acuity (UCNVA) at fixed distance for the first operative eye at 12 months (Visit 5A). The two primary effectiveness endpoints are evaluated by comparing the two treatment groups using a non-inferiority test. Results would be considered successful if the upper limit for each co-primary parameter was less than the clinical performance target. The clinical performance target was set at 0.1 logMAR (logarithm of the minimum angle of resolution) unit. The supportive effectiveness variables were: - • Monocular (Best Corrected) and Binocular (Uncorrected and Best Corrected) Distance Visual Acuity - • Monocular (Distance Corrected for optical infinity and Best Corrected) and Binocular (Uncorrected, Distance Corrected for optical infinity and Best Corrected) Near Visual Acuity at Fixed Distance - • Monocular and Binocular Near Visual Acuity at Best Distance: Uncorrected and Distance Corrected for optical infinity - • Monocular and Binocular Mesopic Near Visual Acuity at Best Distance: Distance Corrected for optical infinity - • Binocular Intermediate Visual Acuity (50 cm, 60 cm, and 70 cm): Uncorrected and Distance Corrected for optical infinity - • Orientation of Lens Axis determined by Photographic Assessment of Lens Orientation, PALO (Investigational Lens only) - • Reduction of Cylinder (Investigational Lens only) - • Binocular Defocus (+2.0 D to -5.0 D in 0.5 D increments) - • Contrast Sensitivity (Photopic and Mesopic with and without glare) - • Pupil Size (Photopic Distance and Near and Mesopic Distance and Near) - • Intended Lens Placement (Investigational Lens only) - • Spectacle Independence Lens Vision Evaluation And Repurchase (SILVER) Questionnaire - • Visual Tasks (VISTAS) Questionnaire The primary safety endpoint is the rate of actual and potential secondary surgical interventions (SSIs) related to the optical properties of the IOL for first and second operative eyes separately at Visit 5A (12 months) for both the investigational and control groups. If an ocular surgical intervention was performed on a subject, it qualified as an actual SSI; however, if a subject met the criteria that would warrant an SSI, but did not actually undergo the SSI during the course of the study, it qualified as a potential SSI. Therefore, subjects were required to answer the following item on the Assessment of Photic Phenomena and Lens Effects (APPLES) questionnaire—“Are you experiencing any symptoms bothersome enough that you would want to have PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 13 {13} another surgery to reposition or remove the IOL(s), if the lens is determined to be the cause of your symptoms?" This question was administered to subjects in the "Other Concern Section" of the APPLES questionnaire at 6 months, 12 months and at any unscheduled visit. If the subject answered the question in the affirmative, the site was required to fill out the SSI Notification Form and evaluate the subject's symptoms including the need to perform an ocular intervention. If it was determined that the optical properties of the lens were not the cause of the subject's symptoms, then alternative etiology was required to be documented. The predefined SSIs related to the optical properties of the IOL included, but were not limited to the following: - IOL repositioning due to IOL misalignment - Toric component of the IOL - IOL repositioning due to IOL instability (e.g., decentration, tilt or rotation) - IOL explantation/replacement due to incorrect IOL power that is not a result of inaccurate preoperative planning or surgical error - IOL explantation/replacement due to subject intolerance of visual symptoms or functional impairment No formal statistical hypotheses were specified for the primary safety endpoints. The secondary safety endpoint is the rate of severe visual disturbances/distortions as reported by the subjects on the APPLES questionnaire at 12 months (Visit 5A). Supportive Safety Variables were: - AEs including SSI - Slit-Lamp Examination - Dilated Fundus Examination - Subjective Posterior Capsule Opacification (PCO) - Posterior Capsulotomy - IOL Observations - IOL Position Change - IOP - Retinal Detail - Surgical Problems - Device Deficiencies Additional safety data is incorporated by reference to the parent lens, the ACRYSOF® ReSTOR® Apodized Diffractive Optic Posterior Chamber IOL, Models MA60D3 and SA60D3, including results from a driving sub-study. ## **B. Accountability of PMA Cohort** All subjects with successful IOL implantation in at least one eye were considered evaluable for the "All Implanted" analyses. All subjects with attempted IOL PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 14 {14} implantation (successful or aborted after contact with the eye) were considered evaluable for the “Safety” analyses. In addition, all eyes successfully implanted, that had at least one postoperative visit and had no preoperative ocular pathology or macular degeneration at any time, were evaluable for “Best Case” analyses. The “Best Case” data set was the primary data set of analysis for the supportive effectiveness parameters of Defocus Curve and Contrast Sensitivity. As summarized in the Figure 2 and Table 7, 677 subjects provided informed consent and were enrolled in the clinical study, which began with the first preoperative examination (Form 0) conducted on 28 July 2011. Study enrollment involved consenting the subject and then performing the preoperative (Form 0) study testing, in order to determine the subject’s eligibility for implantation and further participation in the study. Of these, 103 subjects were not implanted (screening failures), while the remaining 574 subjects were implanted with either the ReSTOR Toric +3.0 D IOL (120 – Model SND1T3, 179 – SND1T4, 76 – Model SND1T5, and 41 – Model SND1T6) (386 subjects) or the control ReSTOR +4.0 D IOL (188 subjects). Of these 574 subjects, all but 3 were implanted, or had an attempted implantation, in the second eye. The first implantation occurred on 01 August 2011, and the implantation of the last study subject in the first eye occurred on 22 December 2011. Second eye implantations began on 08 August 2011 and the last second eye implantation was on 29 December 2011. The primary reasons for the 103 screening failures were due to the inclusion/exclusion criteria. These criteria included: preoperative BCDVA was not worse than 0.2 logMAR in each eye (n = 34); did not meet astigmatism ranges for first and/or second eye (n = 15); consent withdrawn prior to surgery (n = 8); significant irregular corneal aberration as demonstrated by corneal topography (n = 6); calculated lens power and astigmatism not within the available range (n = 4); amblyopia (n = 4); the primary investigator withdrew from the study (n=4); for all other individual criteria leading to screening failures, n ≤ 3. Among the 574 subjects implanted with an intraocular lens in this clinical study, 19 subjects were discontinued before completion of the study. Four subjects were discontinued due to deaths from causes unrelated to the study IOLs. One subject experienced a stroke. Five subjects were lost to follow-up. Eight subjects no longer wished to participate and one subject moved prior to visit 5A. Percent accountability at Visit 5 was 96.6% (373/386) in the first eyes of the investigational arm, 95.7% (180/188) in the first eyes of the control arm, 97.1% (371/386) in the second eyes of the investigational arm, and 96.8% (180/188) in the second eyes of the control arm. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 15 {15} **Figure 2: Subject Accountability Flowchart, All Lens Models, First Eye, All Implanted** ![img-1.jpeg](img-1.jpeg) **Table 7: Subject Disposition (All Implanted)** | | ReSTOR Toric +3.0 D (N=386) | | ReSTOR +4.0 D (N=188) | | Combined (N=574) | | | --- | --- | --- | --- | --- | --- | --- | | | n | (%) | n | (%) | n | (%) | | Completed | 373 | (96.6) | 182 | (96.8) | 555 | (96.7) | | Discontinued | 13 | (3.4) | 6 | (3.2) | 19 | (3.3) | | Adverse Event | 1 | (0.3) | 0 | (0.0) | 1 | (0.2) | | Lost to Follow-up | 4 | (1.0) | 1 | (0.5) | 5 | (0.9) | | No Longer Wished Participation | 4 | (1.0) | 4 | (2.1) | 8 | (1.4) | | Unable to Make Office Visit/Moved | 1 | (0.3) | 0 | (0.0) | 1 | (0.2) | | Subject Died | 3 | (0.8) | 1 | (0.5) | 4 | (0.7) | ReSTOR Toric +3.0 D = ACRYSOF IQ ReSTOR +3.0 D Multifocal Toric Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR +4.0 D = ACRYSOF* ReSTOR Multifocal Lens (+4.0 D Add) Model SN60D3 PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 16 {16} ### C. Study Population Demographics and Baseline Parameters The study population demographics are reported in Table 8. Baseline characteristics for BCDVA, axial length, and anterior chamber depth were similar between the ReSTOR Toric IOL and the control ReSTOR IOL arms. Table 8: Demographic Statistics (All Implanted) | | ReSTOR Toric +3.0 D (N=386) n (%) | ReSTOR +4.0 D (N=188) n (%) | Overall (N=574) n (%) | | --- | --- | --- | --- | | Age(Years) | | | | | 21-29 | 2 (0.5) | 0 (0.0) | 2 (0.3) | | 30-39 | 3 (0.8) | 0 (0.0) | 3 (0.5) | | 40-49 | 10 (2.6) | 3 (1.6) | 13 (2.3) | | 50-59 | 57 (14.8) | 24 (12.8) | 81 (15.1) | | 60-69 | 155 (40.2) | 73 (38.8) | 228 (39.7) | | 70-79 | 135 (35.0) | 76 (40.4) | 211 (36.8) | | ≥80 | 24 (6.2) | 12 (6.4) | 36 (6.3) | | Gender | | | | | Male | 146 (37.8) | 52 (27.7) | 198 (34.5) | | Female | 240 (62.2) | 136 (72.3) | 376 (65.5) | | Race | | | | | White | 362 (93.8) | 176 (93.6) | 538 (93.7) | | Black or African American | 14 (3.6) | 12 (6.4) | 26 (4.5) | | Asian | 5 (1.3) | 0 (0.0) | 5 (0.9) | | Other | 5 (1.3) | 0 (0.0) | 5 (0.9) | | Ethnicity | | | | | Hispanic, Latino or Spanish | 6 (1.6) | 3 (1.6) | 9 (1.6) | | Not Hispanic, Latino or Spanish | 380 (98.4) | 185 (98.4) | 565 (98.4) | ReSTOR Toric +3.0 D = ACRYSOF® IQ ReSTOR® +3.0 D Multifocal Toric Intraocular Lens Models SN61T3/SND1T4/SND1T5/SND1T6 ReSTOR +4.0 D = ACRYSOF® ReSTOR Multifocal Lens (+4.0 Add) Model SN60D3 PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 17 {17} ## D. Safety and Effectiveness Results ### 1. Safety Results Primary safety endpoint: Rate of actual and potential secondary surgical interventions (SSIs) due to the optical properties of the IOL The rate of actual and potential SSIs due to optical properties for ReSTOR® Toric IOL subjects was 1.04% [90% CI:(0.35, 2.36)] in the first eye and 0.52% [90% CI:(0.09, 1.63)] in the second eye. The rate of actual and potential SSIs due to optical properties for the control ReSTOR® IOL subjects was 2.13% [90% CI:(0.73, 4.80)] in the first eye and 2.13% [90% CI:(0.73, 4.80)] in the second eye. See Table 9. **Table 9: Incidence and Confidence Limits of Actual and Potential SSIs Due to Optical Properties (assuming discontinued subjects having no incidents) Safety Set** | | ReSTOR Toric IOL | | | | ReSTOR IOL | | | | Difference | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | N | n | (%) | 90% CI | N | n | (%) | 90% CI | (%) | 90% CI | | First Implanted Eye | 386 | 4 | (1.04) | (0.00, 0.02) | 188 | 4 | (2.13) | (0.01, 0.05) | (-1.09) | (-0.08, 0.06) | | Second Implanted Eye | 383 | 2 | (0.52) | (0.00, 0.02) | 188 | 4 | (2.13) | (0.01, 0.05) | (-1.61) | (-0.09, 0.06) | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 CI = Confidence interval SSI = Actual and Potential Secondary Surgical Interventions Due to Optical Properties Difference = ReSTOR Toric IOL Rate - ReSTOR IOL Rate If an SSI was reported as due to both optical and non-optical properties, Alcon has reported the SSI such that the event was included in the analyses as related to the optical properties of the lens. The most frequently reported reason for an SSI due to optical properties in both arms was visual disturbances. No subjects implanted with the ReSTOR® Toric IOL experienced an actual SSI due to the optical properties of the IOL. In the control ReSTOR® IOL group, 2 subjects experienced an actual SSI in both their first and second eyes. Four subjects in the ReSTOR® Toric group experienced potential SSIs of which two subjects experienced potential SSIs in their first and second eyes. Two subjects in the control ReSTOR® group experienced potential SSIs in both their first and second eyes. In the ReSTOR® Toric IOL investigational arm, there were no actual SSIs and six potential SSIs. One subject had a potential SSI reported for visual symptoms related to aberrations in the first operative eye. Another subject had a potential SSI reported in the first operative eye at Visit 5A (12 months) for residual astigmatism (manifest refraction - 0.75+0.75x021). The investigator recommended that a PRK procedure be performed if the subject was dissatisfied with his vision. At the conclusion of the study, the subject had not yet scheduled the procedure. A third subject had 2 potential SSIs reported for the first and second operative eyes at Visit 5A (12 months) for complaints of visual disturbances on the APPLES questionnaire that were related to the optical PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 18 {18} properties of the IOL. Additionally, the investigator reported an inaccurate preoperative measurement error for the axial length. The investigator recommended that a LASIK procedure be performed; however, the subject decided to postpone treatment. Finally, a fourth subject had 2 potential SSIs reported for the first and second operative eyes at Visit 4A (6 months) for complaints of visual disturbances. In the ReSTOR® IOL control arm, there were four actual SSIs and four potential SSIs. One subject had bilateral SSIs due to severe visual disturbances and answered “yes” to the “Are you experiencing any symptoms bothersome enough that you would want to have another surgery to repositions or remove the IOL(s), if the lens is determined to be the cause of your symptoms?” APPLES question at Visit 4A (6 months). Another subject had bilateral SSIs due to severe visual disturbances and stated that the reading distance with the IOL was too close. Additionally, this subject reported “yes” to the “Are you experiencing any symptoms bothersome enough that you would want to have another surgery to repositions or remove the IOL(s), if the lens is determined to be the cause of your symptoms?” APPLES question. Two subjects in the control ReSTOR® group experienced potential SSIs. One subject had 2 potential SSIs reported for the first and second operative eyes at Visit 4A (6 months) for visual disturbances. Another subject had two potential SSIs reported for the first operative eye and two potential SSIs reported for the second operative eye at Visits 4A and 5A (6 months and 12 months, respectively). The Investigator completed the SSI Notification Form twice for each eye for this subject; however, for accounting purposes (i.e., in the tables), this subject was only counted once. At Visits 4A and 5A, the subject reported visual disturbances and answered “yes” to the “Are you experiencing any symptoms bothersome enough that you would want to have another surgery to repositions or remove the IOL(s), if the lens is determined to be the cause of your symptoms?” APPLES question. # Secondary safety endpoint: rate of severe visual disturbances/distortions as reported by the subjects on the APPLES questionnaire at 12 months (Visit 5A). A Patient-Reported Outcomes instrument (APPLES) was developed and used in this clinical study to assess visual disturbances and distortions. Psychometric evaluation did not support this instrument being fit for its purpose of measuring the concept of visual disturbances and distortions in this intended use population. Interpretation of the results from this questionnaire should be made with caution. The frequency of patients reporting specific visual symptoms were similar between the ReSTOR® Toric +3.0 D IOL and the control ReSTOR® +4.0 D IOL groups at 1 year. The highest rate of “severe” reports at 1 year was for halos at 7.5 % for ReSTOR® Toric +3.0 D IOL and 11.0 % for the control ReSTOR® +4.0 D IOL. See Table 10. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 19 {19} **Table 10: Reported Frequencies (Percentage) of Visual Disturbances for ReSTOR Toric +3.0 D and ReSTOR +4.0 D 1 year Postoperative (following second eye implantation)** | Visual Disturbance | ReSTOR® Toric +3.0 D | | | | | ReSTOR® +4.0 D | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | N | None % | Mild % | Mod^{®} % | Severe % | N | None % | Mild % | Mod^{®} % | Severe % | | Glare | 372 | 40.6 | 36.3 | 19.6 | 3.5 | 182 | 35.2 | 36.8 | 25.3 | 2.7 | | Halos | 372 | 22.6 | 38.4 | 31.5 | 7.5 | 182 | 20.9 | 40.7 | 27.5 | 11.0 | | Starbursts | 372 | 37.4 | 39.0 | 19.4 | 4.3 | 182 | 34.6 | 37.4 | 19.2 | 8.8 | | Hazy vision | 372 | 55.1 | 33.1 | 10.5 | 1.3 | 182 | 51.6 | 30.8 | 17.0 | 0.5 | | Blurred vision | 372 | 70.7 | 19.1 | 9.4 | 0.8 | 182 | 69.2 | 23.6 | 7.1 | 0.0 | | Distortion where straight lines look tilted | 372 | 96.8 | 2.2 | 1.1 | 0.0 | 182 | 92.9 | 4.9 | 2.2 | 0.0 | | Distortion where flat lines look curved | 372 | 96.5 | 3.2 | 0.3 | 0.0 | 182 | 94.0 | 4.9 | 1.1 | 0.0 | | Double vision | 372 | 89.8 | 7.5 | 1.9 | 0.8 | 182 | 91.2 | 6.6 | 2.2 | 0.0 | | Color distortion | 371 | 94.3 | 5.1 | 0.5 | 0.0 | 182 | 95.1 | 3.8 | 1.1 | 0.0 | | Feeling sick due to visual distortion | 371 | 98.4 | 1.3 | 0.3 | 0.0 | 182 | 97.8 | 1.6 | 0.0 | 0.5 | $^{®}$ Mod = Moderate ReSTOR® Toric +3.0 D = AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric IOL Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR® +4.0 D = AcrySof® ReSTOR® Multifocal IOL (+4.0 D Add) Model SA60D3 ### Supportive Safety Variables: - AEs including SSI During the clinical study, 39 SSIs actual (excluding potential) were performed across all eyes. Some eyes experienced multiple SSIs. Of these, 20 SSIs occurred in 16 primary eyes (15 in the investigational arm and 5 SSIs in the control arm). In the first implanted eye, the observed rate of secondary surgical interventions exceeded the Safety and Performance Endpoints (SPE) rates for serious and persistent adverse events listed in ISO 11979-7 in the ReSTOR® Toric group (Table 11). This indicates that the observed rate of SSIs was statistically significantly greater than the SPE rate for SSIs (0.8%). In addition, 19 SSIs occurred in 17 second implanted eyes (13 SSIs in the investigational arm and 6 SSIs in the control arm). In the second implanted eye, the observed rate of secondary surgical interventions exceeded the Safety and Performance Endpoints (SPE) rates in both the ReSTOR® Toric IOL and the control ReSTOR® IOL groups. In the investigational ReSTOR® Toric group, twelve first eyes and eleven second eyes experienced a secondary surgical intervention. In the control ReSTOR IOL group, four first eyes and six second eyes experienced a SSI. Five cases of IOL repositioning were reported in four ReSTOR® Toric subjects. One subject underwent two separate lens repositioning procedures due to floppy iris syndrome. The IOL was still misaligned by 8.141 degrees at the final study visit (Visit 5A) in this subject. No unanticipated serious adverse device effects were reported. In the first implanted eye, 28 ocular serious AEs (SAE) and ocular adverse device effects were reported among the 386 subjects implanted with the ReSTOR® Toric IOL. Eight ocular SAEs and adverse device effects were reported among the 188 subjects implanted with the control ReSTOR® IOL. The observed rates for all ocular SAEs and ocular adverse device effects were less than or equal to 1.1% in either group. In the second implanted eye, 32 ocular SAEs and adverse device effects were reported among the 383 subjects implanted PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 20 {20} with the ReSTOR® Toric IOL. Fifteen ocular SAEs and adverse device effects were reported among the 188 subjects implanted with the control ReSTOR® IOL. The observed rates for all ocular SAEs and adverse device effects were less than or equal to 1.6% in either group. Persistent adverse events are observed at the final 12 month postoperative visit. See Tables 11-16. Table 11: Serious and Persistent Adverse Events and SPE Rates (Safety) | | First implanted eye | | | | | | Second implanted eye | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | ReSTOR® Toric +3.0 D (N = 386) | | | ReSTOR® +4.0 D (N = 188) | | | ReSTOR® Toric +3.0 D (N = 383) | | | ReSTOR® +4.0 D (N = 188) | | | | | n | % | SPE % | n | % | SPE % | n | % | SPE % | n | % | SPE % | | **Serious Adverse Events** | | | | | | | | | | | | | | Cystoid macular edema | 1 | (0.3) | 3.0 | 0 | (0.0) | 3.0 | 3 | (0.8) | 3.0 | 1 | (0.5) | 3.0 | | Endophthalmitis | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | | Hypopyon | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | | Lens dislocated from posterior chamber | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | | Pupillary block | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | 0 | (0.0) | 0.1 | | Retinal detachment | 1 | (0.3) | 0.3 | 0 | (0.0) | 0.3 | 2 | (0.5) | 0.3 | 1 | (0.5) | 0.3 | | Secondary surgical intervention | 12 | (3.1) | 0.8 | 4 | (2.1) | 0.8 | 11 | (2.9) | 0.8 | 6 | (3.2) | 0.8 | | **Persistent Serious Adverse Events** | | | | | | | | | | | | | | Corneal oedema | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | | Cystoid macular oedema | 1 | (0.3) | 0.5 | 0 | (0.0) | 0.5 | 1 | (0.3) | 0.5 | 0 | (0.0) | 0.5 | | Iritis | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | 0 | (0.0) | 0.3 | | Raised IOP requiring treatment | 0 | (0.0) | 0.4 | 0 | (0.0) | 0.4 | 0 | (0.0) | 0.4 | 0 | (0.0) | 0.4 | ReSTOR® Toric +3.0 D = AcrySof® IQ ReSTOR® +3.0 D Multifocal Toric Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR® +4.0 D = AcrySof® ReSTOR® Multifocal Lens (+4.0 D Add) Model SA60D3 PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 21 {21} **Table 12: Summaries of Ocular SAEs and Adverse Device Effects by Preferred Term- First Implanted Eye (Safety Set)** | | ReSTOR Toric IOL (N = 386) | | | | ReSTOR IOL (N = 188) | | | | Overall (N = 574) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | n | (%) | UCL | E | n | (%) | UCL | E | n | (%) | UCL | E | | Eye disorder | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Halo vision | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.3) | 1.1 | 2 | | Iris atrophy | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Keratotomy | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Photopsia | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Retinal detachment | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Surgical procedure repeated | 3 | (0.8) | 2.0 | 3 | 2 | (1.1) | 3.3 | 2 | 5 | (0.9) | 1.8 | 5 | | Vision blurred | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Visual impairment | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.3) | 1.1 | 2 | | Vitrectomy | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Vitreous prolapse | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Glare | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Intraocular lens repositioning | 4 | (1.0) | 2.4 | 5 | 0 | (0.0) | 1.6 | 0 | 4 | (0.7) | 1.6 | 5 | | Intra-ocular injection | 0 | (0.0) | 0.8 | 0 | 1 | (0.5) | 2.5 | 2 | 1 | (0.2) | 0.8 | 2 | | Eye laser surgery | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Cataract operation complication | 2 | (0.5) | 1.6 | 2 | 0 | (0.0) | 1.6 | 0 | 2 | (0.3) | 1.1 | 2 | | Cystoid macular oedema | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Corneal operation | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.3) | 1.1 | 2 | | Device dislocation | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Age-related macular degeneration | 0 | (0.0) | 0.8 | 0 | 1 | (0.5) | 2.5 | 1 | 1 | (0.2) | 0.8 | 1 | | Retinopexy | 2 | (0.5) | 1.6 | 2 | 0 | (0.0) | 1.6 | 0 | 2 | (0.3) | 1.1 | 2 | | Keratomileusis | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 Adverse Events coded using MedDRA UCL - 95% one-sided upper confidence limit using Clopper-Pearson exact test If an eye has multiple occurrences of an AE, the eye was presented only once in the respective eye count (n). Events are counted each time in the event (E) column. Events recorded as OU (both eyes) were counted once for the first eye and second eye. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 22 {22} **Table 13: Summaries of Ocular SAEs and Adverse Device Effects by Preferred Term – Second Implanted Eye (Safety Set)** | | ReSTOR Toric IOL (N = 383) | | | | ReSTOR IOL (N = 188) | | | | Overall (N = 571) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | n | (%) | UCL | E | n | (%) | UCL | E | n | (%) | UCL | E | | Eye disorder | 3 | (0.8) | 2.0 | 3 | 0 | (0.0) | 1.6 | 0 | 3 | (0.5) | 1.4 | 3 | | Halo vision | 1 | (0.3) | 1.2 | 1 | 2 | (1.1) | 3.3 | 2 | 3 | (0.5) | 1.4 | 3 | | Iris atrophy | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Macular oedema | 0 | (0.0) | 0.8 | 0 | 1 | (0.5) | 2.5 | 1 | 1 | (0.2) | 0.8 | 1 | | Photopsia | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Retinal detachment | 2 | (0.5) | 1.6 | 3 | 1 | (0.5) | 2.5 | 1 | 3 | (0.5) | 1.4 | 4 | | Retinal tear | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Surgical procedure repeated | 1 | (0.3) | 1.2 | 1 | 3 | (1.6) | 4.1 | 3 | 4 | (0.7) | 1.6 | 4 | | Vision blurred | 0 | (0.0) | 0.8 | 0 | 1 | (0.5) | 2.5 | 1 | 1 | (0.2) | 0.8 | 1 | | Visual impairment | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.4) | 1.1 | 2 | | Macular hole | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Glare | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Suture insertion | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.4) | 1.1 | 2 | | Wound complication | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.4) | 1.1 | 2 | | Eye laser surgery | 3 | (0.8) | 2.0 | 3 | 0 | (0.0) | 1.6 | 0 | 3 | (0.5) | 1.4 | 3 | | Cataract operation complication | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.4) | 1.1 | 2 | | Cystoid macular oedema | 3 | (0.8) | 2.0 | 3 | 1 | (0.5) | 2.5 | 1 | 4 | (0.7) | 1.6 | 4 | | Eye injury | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Corneal operation | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.4) | 1.1 | 2 | | Retinal operation | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Retinopexy | 3 | (0.8) | 2.0 | 5 | 1 | (0.5) | 2.5 | 1 | 4 | (0.7) | 1.6 | 6 | | Keratomileusis | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 Adverse Events coded using MedDRA UCL - 95% one-sided upper confidence limit using Clopper-Pearson exact test If an eye has multiple occurrences of an AE, the eye was presented only once in the respective eye count (n). Events are counted each time in the event (E) column. Events recorded as OU (both eyes) were counted once for the first eye and second eye. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 23 {23} **Table 14: Secondary Surgical Interventions – First and Second Eyes** | | First Eye | | Second eye | | | --- | --- | --- | --- | --- | | | ReSTOR^{a} Toric +3.0 D (N=386) | ReSTOR^{b} +4.0 D (N=188) | ReSTOR^{a} Toric +3.0 D (N=383) | ReSTOR^{b} +4.0 D (N=188) | | **Secondary Surgical Intervention** | **15** | **5** | **13** | **6** | | IOL repositioning due to IOL misalignment | 1^{a} | 0 | 0 | 0 | | IOL repositioning due to inaccurate IOL placement | 4^{b,c} | 0 | 0 | 0 | | IOL repositioning due to haptic outside of the bag | 1 | 0 | 0 | 0 | | IOL replacement due to visual disturbances | 0 | 2 | 0 | 2 | | LASIK to correct residual refractive error | 1 | 0 | 1 | 0 | | Astigmatic keratotomy to correct residual refractive error (astigmatism) | 1 | 0 | 0 | 0 | | Limbal relaxing incision to correct surgically induced astigmatism | 1 | 0 | 1 | 0 | | Limbal relaxing incision to correct pre-existing astigmatism | 0 | 1 | 0 | 1 | | Macular hole repair | 0 | 0 | 1 | 0 | | YAG laser capsulotomy for wrinkles, folds or strands in capsule | 1^{b} | 0 | 3 | 0 | | Intraocular injection for wet age related macular degeneration | 0 | 2^{d} | 0 | 0 | | Retinal detachment repair and prophylactic retinopexy | 2 | 0 | 5^{e} | 1 | | Retained lens removal | 2 | 0 | 1 | 1 | | Corneal wound leak repair | 0 | 0 | 1 | 1 | | Anterior vitrectomy | 1 | 0 | 0 | 0 | $^{a}$ One subject required an IOL repositioning surgery at the 6 month visit. The Investigator considered the event related to the patient's eye anatomy and the IOL rotation was assumed to have occurred within the first 24 hours following surgery. $^{b}$ One subject experienced floppy iris during surgery and required two repositioning procedures. The same subject also experienced a YAG laser capsulotomy for wrinkled capsule in the first eye. $^{c}$ The IOL was implanted at the incorrect axis in two subjects. $^{d}$ One subject was administered two intraocular injections for wet age related macular degeneration in the first eye. $^{e}$ One subject had one prophylactic retinopexy procedure performed in the first eye and three retinopexy procedures performed in the second eye. **Table 15: Summaries of Ocular SAEs by Preferred Term where Surgical Intervention was Performed - First Implanted Eye (Safety Set)** | | ReSTOR Toric IOL (N = 386) | | | | ReSTOR IOL (N = 188) | | | | Overall (N = 574) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | n | (%) | UCL | E | n | (%) | UCL | E | n | (%) | UCL | E | | Keratotomy | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Surgical procedure repeated | 3 | (0.8) | 2.0 | 3 | 2 | (1.1) | 3.3 | 2 | 5 | (0.9) | 1.8 | 5 | | Vitrectomy | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Intraocular lens repositioning | 4 | (1.0) | 2.4 | 5 | 0 | (0.0) | 1.6 | 0 | 4 | (0.7) | 1.6 | 5 | | Intra-ocular injection | 0 | (0.0) | 0.8 | 0 | 1 | (0.5) | 2.5 | 2 | 1 | (0.2) | 0.8 | 2 | | Eye laser surgery | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Corneal operation | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.3) | 1.1 | 2 | | Retinopexy | 2 | (0.5) | 1.6 | 2 | 0 | (0.0) | 1.6 | 0 | 2 | (0.3) | 1.1 | 2 | | Keratomileusis | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 Adverse Events coded using MedDRA UCL - 95% one-sided upper confidence limit using Clopper-Pearson exact test If an eye has multiple occurrences of an AE, the eye was presented only once in the respective eye count (n). Events are counted each time in the event (E) column. Events recorded as OU (both eyes) were counted once for the first eye and second eye. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 24 {24} **Table 16: Summaries of Ocular SAEs by Preferred Term where Surgical Intervention was Performed - Second Implanted Eye (Safety Set)** | | ReSTOR Toric IOL (N = 383) | | | | ReSTOR IOL (N = 188) | | | | Overall (N = 571) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | n | (%) | UCL | E | n | (%) | UCL | E | n | (%) | UCL | E | | Surgical procedure repeated | 1 | (0.3) | 1.2 | 1 | 3 | (1.6) | 4.1 | 3 | 4 | (0.7) | 1.6 | 4 | | Suture insertion | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.4) | 1.1 | 2 | | Eye laser surgery | 3 | (0.8) | 2.0 | 3 | 0 | (0.0) | 1.6 | 0 | 3 | (0.5) | 1.4 | 3 | | Corneal operation | 1 | (0.3) | 1.2 | 1 | 1 | (0.5) | 2.5 | 1 | 2 | (0.4) | 1.1 | 2 | | Retinal operation | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | | Retinopexy | 3 | (0.8) | 2.0 | 5 | 1 | (0.5) | 2.5 | 1 | 4 | (0.7) | 1.6 | 6 | | Keratomileusis | 1 | (0.3) | 1.2 | 1 | 0 | (0.0) | 1.6 | 0 | 1 | (0.2) | 0.8 | 1 | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 Adverse Events coded using MedDRA UCL - 95% one-sided upper confidence limit using Clopper-Pearson exact test If an eye has multiple occurrences of an AE, the eye was presented only once in the respective eye count (n). Events are counted each time in the event (E) column. Events recorded as OU (both eyes) were counted once for the first eye and second eye. # - • Slit-Lamp Examination and Dilated Fundus Examination The incidences of slit-lamp and dilated fundus examination findings were similar between the ACRYSOF® IQ ReSTOR® Multifocal Toric IOL Models SND1T3/SND1T4/SND1T5/SND1T6 and the control ACRYSOF® ReSTOR® Multifocal IOL Model SA60D3 groups. The most frequent slit-lamp observation was posterior capsule opacification in both the ReSTOR® Toric IOL (1$^{st}$ eye – 52.3%) and the control ReSTOR® IOL (1$^{st}$ eye - 42.9%) groups at Visit 5 (12 months). The most frequent dilated fundus finding was clinically non-significant vitreous detachment observed in both the ReSTOR® Toric IOL and the control ReSTOR® IOL. Overall, no untoward safety issues were identified for subjects implanted with the ReSTOR Toric IOL or the control ReSTOR IOL based on an evaluation of slit lamp and dilated fundus observations. # - • Subjective Posterior Capsule Opacification (PCO) The development of clinically significant PCO requiring a posterior capsulotomy (YAG) was reported in less than 10% of eyes from each IOL group at any scheduled postoperative visit. The incidence of PCO of any grade at the early postoperative visits (Visits 1 and 2) was < 6% in either group. All reports of PCO at Visits 1 and 2 were assessed as clinically non-significant with the exceptions of 1 subject (both eyes) in the ReSTOR® Toric IOL group, in whom PCO was assessed as clinically non-significant prior to 1 month postoperative (Visit 3). At subsequent visits, the PCO was graded as clinically significant without a need for YAG, and the BCDVA improved. The first eye did not require posterior capsulotomy during the study, despite the early findings of clinically significant PCO. In the second eye of the same subject, clinically significant PCO was noted at the 1 day postoperative (Visit 1A) with a BCDVA of 0.02 logMAR. At subsequent visits, the PCO was graded as clinically significant (except for the 1 week postoperative visit where it was graded clinically non-significant). The second eye also did not require posterior capsulotomy during the study. See Table 17. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 25 {25} Table 17: Number and Percentage of Eyes with Subjective PCO by Visit (Safety Set) | | First Implanted Eye | | | | Second Implanted Eye | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | ReSTOR Toric IOL | | ReSTOR IOL | | ReSTOR Toric IOL | | ReSTOR IOL | | | | | n | (%) | n | (%) | n | (%) | n | (%) | | Visit 1 | Total | 386 | | 188 | | 382 | | 188 | | | | None | 376 | (97.4) | 187 | (99.5) | 374 | (97.9) | 188 | (100.0) | | | Clinically non-significant | 9 | (2.3) | 1 | (0.5) | 7 | (1.8) | 0 | (0.0) | | | Clinically significant | 0 | (0.0) | 0 | (0.0) | 1 | (0.3) | 0 | (0.0) | | | Clinically significant requiring a YAG | 1 | (0.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | Visit 2 | Total | 386 | | 188 | | 382 | | 188 | | | | None | 373 | (96.6) | 182 | (96.8) | 362 | (94.8) | 184 | (97.9) | | | Clinically non-significant | 12 | (3.1) | 6 | (3.2) | 20 | (5.2) | 4 | (2.1) | | | Clinically significant | 1 | (0.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | | Clinically significant requiring a YAG | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | Visit 3 | Total | 383 | | 187 | | 382 | | 187 | | | | None | 304 | (79.4) | 154 | (82.4) | 310 | (81.2) | 153 | (81.8) | | | Clinically non-significant | 76 | (19.8) | 30 | (16.0) | 69 | (18.1) | 32 | (17.1) | | | Clinically significant | 1 | (0.3) | 2 | (1.1) | 1 | (0.3) | 2 | (1.1) | | | Clinically significant requiring a YAG | 2 | (0.5) | 1 | (0.5) | 2 | (0.5) | 0 | (0.0) | | Visit 4 | Total | 379 | | 186 | | 378 | | 186 | | | | None | 218 | (57.5) | 114 | (61.3) | 215 | (56.9) | 115 | (61.8) | | | Clinically non-significant | 137 | (36.1) | 59 | (31.7) | 143 | (37.8) | 54 | (29.0) | | | Clinically significant | 11 | (2.9) | 3 | (1.6) | 9 | (2.4) | 3 | (1.6) | | | Clinically significant requiring a YAG | 13 | (3.4) | 10 | (5.4) | 11 | (2.9) | 14 | (7.5) | | Visit 5 | Total | 373 | | 182 | | 372 | | 182 | | | | None | 178 | (47.7) | 104 | (57.1) | 180 | (48.4) | 108 | (59.3) | | | Clinically non-significant | 169 | (45.3) | 72 | (39.6) | 167 | (44.9) | 71 | (39.0) | | | Clinically significant | 9 | (2.4) | 1 | (0.5) | 8 | (2.2) | 1 | (0.5) | | | Clinically significant requiring a YAG | 17 | (4.6) | 5 | (2.7) | 17 | (4.6) | 2 | (1.1) | | Unscheduled | Total | 16 | | 9 | | 17 | | 7 | | | | None | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | | Clinically non-significant | 11 | (68.8) | 7 | (77.8) | 11 | (64.7) | 5 | (71.4) | | | Clinically significant | 3 | (18.8) | 0 | (0.0) | 2 | (11.8) | 0 | (0.0) | | | Clinically significant requiring a YAG | 7 | (43.8) | 3 | (33.3) | 7 | (41.2) | 3 | (42.9) | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 - Posterior Capsulotomy Posterior capsulotomy for the treatment of a posterior capsule opacification was performed at a similar incidence in each of the IOL groups. A review of the individual PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 26 {26} patient data revealed that none of the eyes experienced clinically significant raised IOP or an IOL position change following posterior capsulotomy. One eye in the ReSTOR® Toric IOL group experienced a retinal detachment and one eye in the control ReSTOR® IOL group experienced cystoid macular edema following posterior capsulotomy. See Table 18. Table 18: Number and Percentage of Eyes with Posterior Capsulotomy (Safety Set) | | First Implanted Eye | | | | | | Second Implanted Eye | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | ReSTOR Toric IOL | | | ReSTOR IOL | | | ReSTOR Toric IOL | | | ReSTOR IOL | | | | | N | n | (%) | N | n | (%) | N | n | (%) | N | n | (%) | | Visit 1 | 386 | 0 | (0.0) | 188 | 0 | (0.0) | 382 | 0 | (0.0) | 188 | 0 | (0.0) | | Visit 2 | 386 | 0 | (0.0) | 188 | 0 | (0.0) | 382 | 0 | (0.0) | 188 | 0 | (0.0) | | Visit 3 | 386 | 1 | (0.3) | 188 | 1 | (0.5) | 382 | 2 | (0.5) | 188 | 0 | (0.0) | | Visit 4 | 386 | 7 | (1.8) | 188 | 2 | (1.1) | 383 | 5 | (1.3) | 188 | 3 | (1.6) | | Visit 5 | 386 | 42 | (10.9) | 188 | 21 | (11.2) | 383 | 39 | (10.2) | 188 | 21 | (11.2) | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3-SND1T4-SND1T5-SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 Surgeries occurring after Visit 5 were mapped to Visit 5. - IOL Observations Overall, no unexpected safety issues were identified for subjects implanted with the ReSTOR® Toric IOL or the control ReSTOR® IOL based on an evaluation of IOL observations. At Visit 5, 95.7% (357/373) of ReSTOR® Toric and 97.3% (177/182) of ReSTOR® subjects had no observation of glistenings in the first implanted eye and 96.0% (357/372) of ReSTOR® Toric and 97.3% (177/182) of ReSTOR® subjects had no observation of glistenings in the second implanted eye. None of the observed glistenings were reported as clinically significant by the implanting surgeons. - IOL Position Change IOL position was stable following IOL implantation. No occurrence of decentration or tilt in either IOL group was observed after the 1 week visit (Visit 2). Decentration of the IOL by > 0.5 mm was observed in 2 eyes, which included 1 eye from each IOL group. These IOL position changes occurred within 1 week after surgery and stabilized at subsequent visits. In one eye, the ReSTOR® Toric IOL (Model SND1T3) was decentered by 0.8 mm at Visit 2 (1 week postoperative). The investigator stated that the IOL decentration was due to the configuration of the capsular bag. In another eye, the control ReSTOR® IOL was decentered by 2 mm at Visit 1 (1 day postoperative). The investigator stated that the IOL decentration occurred due to the absence of nasal zonules in the eye. A capsular tension ring was used during the surgery to correct the decentration. Lens tilt > 10° was observed in 2 eyes in the ReSTOR® Toric IOL group, which occurred at the 1 day visit after surgery. One eye with a tilt of 180 degrees required surgical intervention. In this eye the lens tilt was attributed to surgical error and the subject was noted to have floppy iris syndrome. In another study eye, with IOL tilt of 15 degrees, the IOL position stabilized without intervention. In this case the tilt was believed to have been caused by retained viscoelastic. See Table 19. PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 27 {27} **Table 19: Number and Percentage of Eyes with IOL Position Change since Last Visit (Safety Set)** | | | First Implanted Eye | | Second Implanted Eye | | | --- | --- | --- | --- | --- | --- | | | | ReSTOR Toric IOL | ReSTOR IOL | ReSTOR Toric IOL | ReSTOR IOL | | | | n (%) | n (%) | n (%) | n (%) | | Visit 1 | Total | 386 | 188 | 382 | 188 | | | None | 384 (99.5) | 188 (100.0) | 382 (100.0) | 187 (99.5) | | | Tilted >10 degrees | 2 (0.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) | | | Decentered >0.5 mm | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.5) | | Visit 2 | Total | 386 | 188 | 382 | 188 | | | None | 386 (100.0) | 188 (100.0) | 381 (99.7) | 188 (100.0) | | | Tilted >10 degrees | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | | | Decentered >0.5 mm | 0 (0.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) | | Visit 3 | Total | 383 | 187 | 382 | 187 | | | None | 383 (100.0) | 187 (100.0) | 382 (100.0) | 187 (100.0) | | | Tilted >10 degrees | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | | | Decentered >0.5 mm | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | | Visit 4 | Total | 379 | 186 | 377 | 186 | | | None | 379 (100.0) | 186 (100.0) | 377 (100.0) | 186 (100.0) | | | Tilted >10 degrees | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | | | Decentered >0.5 mm | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | | Visit 5 | Total | 373 | 182 | 371 | 182 | | | None | 373 (100.0) | 182 (100.0) | 371 (100.0) | 182 (100.0) | | | Tilted >10 degrees | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | | | Decentered >0.5 mm | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SNDIT3/SNDIT4/SNDIT5/SNDIT6 # - • IOP Transient increases in IOP were observed in both IOL groups following cataract surgery but returned to baseline values by the one week postoperative visit and remained stable at subsequent visits throughout the study for both IOL groups. Among the first and second eyes for each IOL group, the mean IOP increased at Visit 1 (1 day postoperative) by approximately 4 mmHg. The mean IOP returned to near the preoperative baseline by Visit 2 (1 week postoperative) and remained stable at subsequent visits. The mean IOP for eyes with the ReSTOR® Toric IOL was within 1 mmHg of that for eyes with the control ReSTOR® IOL at all scheduled visits. No SAEs for raised IOP requiring treatment were reported, and 9 non-serious AEs of IOP increased were reported. Eight of these AEs occurred in the ReSTOR® Toric IOL, and 1 AE of IOP increased occurred in the control ReSTOR® IOL group. None of the AEs were related to the study device. For 6 cases, the investigator provided an etiology: cataract surgery (n = 1 eye), phacoemulsification during cataract surgery (n = 3 eyes), and steroid response (n = 2 eyes). All of the AEs were reported in the first month postoperative with 6 of the 9 AEs reported on 1 day postoperative. All 9 AEs of PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 28 {28} IOP increased required treatment: medication (n = 7 eyes), a change in medication (n = 1 eye), and wound burping with added medication (n = 1 eye). The AEs of increased IOP resolved with treatment within 1 month of event onset. IOP measurements for these 9 eyes were within 10 mmHg of the preoperative baseline measurement at the final study visit. - Retinal Detail As per the protocol, the investigators were asked to indicate whether the ReSTOR® Toric IOL or the control ReSTOR® IOL caused any loss in retinal detail that would alter a surgeon's ability to administer retinal treatment, as compared to their experience with monofocal IOLs. The postoperative dilated fundus examination utilized for the assessment of retinal detail was performed at Visit 3/3A (1 month). No loss of retinal detail was observed in either IOL group. - Surgical Problems In only one study subject did the Applicant consider a surgical problem to warrant exclusion of the subject's eye from participation in the study (as outlined in the protocol). This subject developed a capsulorhexis tear secondary to breaking of a haptic following implantation of a ReSTOR® Toric IOL. The IOL was explanted at the operative visit and a non-study IOL was implanted. Seven eyes in 6 subjects in the ReSTOR® Toric IOL group experienced a capsulorhexis tear and/or an "other" - anterior radial tear at the operative visit. One subject experienced floppy iris syndrome during surgery and a pupil size less than 2.5 mm at the conclusion of the surgery in the second operative eye. Five subjects implanted with a ReSTOR® Toric IOL experienced pupil constriction in one or both eyes (n = 8 eyes) during surgery. The "Other" types of surgical problems included the following: - In the ReSTOR® Toric group, the "other" types of surgical problems included: floppy iris (n = 4 eyes), wound leak (n = 1 eye), partial zonular dehiscence after IOL was implanted (n = 1 eye), transillumination defect (n = 1 eye), corneal abrasion (n = 1 eye), and an IOL that needed to be reloaded into the C cartridge (n = 1 eye). - In the ReSTOR® control group, the "other" types of surgical problems included: wound leak (n = 1 eye), inadequate zonular support (n = 1 eye), corneal abrasion (n = 1 eye), iris chaffing (n = 1 eye), and enlarged incision (n = 1 eye). While a slightly higher incidence of surgical problems was reported in the ReSTOR® Toric IOL group relative to the control ReSTOR® IOL (1.8% versus 1.6%), overall, surgical problems occurred infrequently in both IOL groups. There is no increased risk associated with the implantation and/or manipulation of the investigational ReSTOR® Toric IOL based on an evaluation of subjects who PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 29 {29} experienced a capsulorhexis tear and/or an anterior capsular tear and zonular damage at the operative visit. Although a numerical increase in the number of subjects who experienced a capsulorhexis tear and anterior radial tear is observed in the investigational arm, a closer inspection into the etiology and timing of these events indicates no relationship to the device being implanted. Of the nine events identified, eight occurred in seven subjects in the investigational arm and one event in one subject in the control arm. See Table 20 – 21. Table 20: Number and Percentage of Eyes with Surgical Problem (Safety Set) Table 9.2.1.10.-1: Number and Percentage of Eyes With Surgical Problems (Safety Set) | | First Implanted Eye | | Second Implanted Eye | | | --- | --- | --- | --- | --- | | | ReSTOR Toric IOL (N = 386) n (%) | ReSTOR IOL (N = 188) n (%) | ReSTOR Toric IOL (N = 383) n (%) | ReSTOR IOL (N = 188) n (%) | | None | 379 (98.2) | 185 (98.4) | 371 (96.9) | 185 (98.4) | | Capsulorhexis tear | 0 (0.0) | 0 (0.0) | 3 (0.8) | 0 (0.0) | | Other | 7 (1.8) | 3 (1.6) | 9 (2.3) | 3 (1.6) | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 Table 21: Number and Percentage of Eyes with Capsulorhexis Tear and Anterior Radial Tear or Zonular Damage (Safety Set) | | First Implanted Eye | | Second Implanted Eye | | | --- | --- | --- | --- | --- | | | ReSTOR Toric IOL (N = 386) n (%) | ReSTOR IOL (N = 188) n (%) | ReSTOR Toric IOL (N = 383) n (%) | ReSTOR IOL (N = 188) n (%) | | Capsulorhexis tear & Anterior radial tear | 3 (0.8) | 1 (0.5) | 5 (1.3) | 0 (0.0) | | Zonular damage | 1 (0.3) | 0 (0.0) | 0 (0.0) | 1 (0.5) | ReSTOR Toric IOL = ACRYSOF IQ ReSTOR Multifocal Lens Models SND1T3/SND1T4/SND1T5/SND1T6 ReSTOR IOL = ACRYSOF ReSTOR Multifocal Lens Model SA60D3 - Device Deficiencies A total of four IOL device deficiencies were reported in this study. Three IOLs (2 ReSTOR® Toric IOLs and 1 control ReSTOR® IOL) scheduled to be used in this clinical study demonstrated a device deficiency due to damage of the haptics from manufacturing or handling of the lens either prior to, during or after the surgical procedure in both IOL groups. One device deficiency was reported for the control ReSTOR® IOL due to a damaged IOL box. Of the damaged IOLs, in only one case did the damage occur following implantation of the IOL (this is the case discussed under “Surgical Problems” above which resulted in exclusion of the subject from the study). In the other two cases, the damage was noted prior to insertion in the eye. # 2. Effectiveness Results PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 30 {30} # Primary effectiveness outcomes: Mean monocular Uncorrected Distance Visual Acuity (UCDVA) and mean monocular Uncorrected Near Visual Acuity (UCNVA) at fixed distance for the first operative eye at 12 months (Visit 5A) The two primary effectiveness endpoints are evaluated by comparing the two treatment groups using a non-inferiority test. Results would be considered successful if the upper limit for each co-primary parameter was less than the clinical performance target. The clinical performance target was set at 0.1 logMAR (logarithm of the minimum angle of resolution) unit. All visual acuity data is presented in logMAR units except in tables 25-26 which use Snellen units. Both primary effectiveness outcomes of mean monocular UCDVA and mean monocular UCNVA at fixed distance for the first operative eye at Visit 5A (12 months) were successfully met. See Tables 22 - 23. **Table 22: Comparison of Monocular UCDVA at Visit 5 Using Least Squares Estimates (All Implanted Population)** | | | ReSTOR Toric IOL (N=386) | ReSTOR IOL (N=186) | Difference (95% UCL) | | --- | --- | --- | --- | --- | | First Implanted Eye | N | 373 | 180 | | | | Mean | 0.126 | 0.125 | 0.001 (0.030) | | | SE | 0.013 | 0.015 | | | Second Implanted Eye | N | 371 | 180 | | | | Mean | 0.113 | 0.102 | 0.011 (0.038) | | | SE | 0.011 | 0.013 | | PMA P040020/S049: FDA Summary of Safety and Effectiveness Data Page 31 {31} **Table 23: Comparison of Monocular UCNVA at Visit 5 at Fixed Distance Using Least Squares Estimates (All Implanted Population)** | | | ReSTOR Toric IOL (N=386) | ReSTOR IOL (N=186) | Difference (95% UCL) | | --- | --- | --- | --- | --- | | **First Implanted Eye** | **N** | 373 | 180 | | | | **Mean** | 0.193 | 0.236 | -0.044 (- 0.017) | | | **SE** | 0.015 | 0.017 | | | **Second Implanted Eye** | **N** | 371 | 180 | | | | **Mean** | 0.181 | 0.234 | -0.052 (- 0.026) | | | **SE** | 0.013 | 0.015 | | ReSTOR Toric…
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