Appendix Table 1. Ophthalmic drugs approved by the US Food and Drug Administration,

SUPPLEMENTARY DATA Appendix Table 1. Ophthalmic drugs approved by the US Food and Drug Administration, 2002-2012 Approval Year Name Indication Pivotal Trial Design Randomized Comparator Masked Post-Approval Study 2003 epinastine hydrochloride Prevention of itching associated with allergic conjunctivitis Yes Standard of care Double No 2004 pegaptanib Neovascular (wet) age-related macular degeneration Yes Sham injections Double Yes 2004 trypan blue Aid in ophthalmic surgery by staining the anterior capsule of the lens No Literature n.a. No 2006 ranibizumab Neovascular (wet) age-related macular degeneration Yes Sham injections Double Yes 2008 difluprednate Inflammation and pain associated with ocular surgery Yes Vehicle Double No 2009 bepotastine besilate ophthalmic solution Ocular itching associated with allergic conjunctivitis Yes Vehicle Double No 2009 besifloxacin ophthalmic suspension Bacterial conjunctivitis Yes Vehicle Double Yes 2010 alcaftadine Prevention of itching associated with allergic conjunctivitis Yes Vehicle Double No 2011 aflibercept Neovascular (wet) age-related macular degeneration Yes Standard of care Double Yes 2012 ocriplasmin Symptomatic vitreomacular adhesion Yes Placebo Double Yes 2012 tafluprost ophthalmic solution Reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension Yes Standard of care Double No

Appendix Table 2. High-risk (class III) ophthalmic devices approved by the US Food and Drug Administration, 2002-2012 Approval Year Name Indication 2012 HEALON ENDOCOAT OPVISCOSURGICAL OPHTHALMIC DEVICE (OVD) (3% SODIUM HYALURONATE) Surgical aid in patients undergoing ophthalmic anterior segment surgical procedures including, cataract surgery with an intraocular lens, cataract surgery without an intraocular lens, and secondary intraocular lens implantation Pivotal Trial Design Post-Approval Study Randomized Comparator Masked Yes Standard of care Single No 2012 GLAUKOS ISTENT TRABECULAR BYPASS STENT MODEL GTS100R/L 2010 EC-3 INTRAOCULAR LENS (IOL) AND EC-3 PRECISION ASPHERIC LENS (PAL) IOL 2010 IMPLANTABLE MINIATURE TELESCOPE (IMT) 2010 LENSTEC SOFTEC HD POSTERIOR CHAMBER INTRAOCULAR LENS 2009 XACT FOLDABLE HYDROPHOBIC ACRYLIC ULTRAVIOLET LIGHT- ABSORBING POSTERIOR LENS (IOL) 2009 TECNIS MULTIFOCAL FOLDABLE POSTERIOR LENS (IOL) Use in conjunction with cataract surgery for the reduction of intraocular pressure in adult patients with mild to moderate open-angle glaucoma currently treated with ocular hypotensive medication in whom a cataractous lens has been removed Indicated for monocular implantation to improve vision in patients greater than or equal to 75 years of age with stable severe to profound vision impairment (best corrected distance visual acuity 20/160 to 20/800) caused by bilateral central scotomas associated with end-stage age-related macular degeneration Indicated for the replacement of the human crystalline lens following phacoemulsification cataract removal in adults over the age of 21. The lens is indicated for capsular bag placement of aphakia in adult patients in whom the cataractous lens has been removed by an extracapsular cataract extraction method. The lens is intended for placement in the capsular bag of aphakia adult patients with and without presbyopia in whom a cataractous lens has been removed by phacoemulsification and who desire near, intermediate, Yes Standard of care No Yes No Literature No No No Standard of care Single No

and distance vision with increased spectacle independence 2008 BIOFINITY (COMFILCON A) Correction of ametropia (myopia and hyperopia) in aphakic and non-aphakic persons with non-diseased eyes in powers from -20. 00 to +20. 00 diopters Yes Standard of care No No 2008 HOYA ISPHERIC MODEL YA-60BB INTRAOCULAR LENS 2008 AKREOS POSTERIOR LENSMODEL ADAPT 2007 C-FLEX MODEL 570C INTRAOCULAR LENS (IOL) 2006 PARAGON Z CRT (TISILFOCON A) RIGID GAS PERMEABLE CONTACT LENSES FOR CONTACT LENS CORNEAL REFRACTIVE THERAPY 2006 MEL 80 EXCIMER LASER 2005 VISIAN ICL (IMPLANTABLE COLLAMER LENS) in whom a cataractous lens has been removed of aphakia in adult patients where a cataractous lens has been removed by phacoemulsifi-cation. The lens is intended to be placed in the capsular bag of aphakia in adults in whom a cataractous lens has been removed by phacoemulsification. The lens is intended to be place in the capsular bag Indicated for use in the reduction of myopic refractive error in non-diseased eyes Indicated for primary laser assisted in situ keratomileusis (lasik) treatments for: 1) the reduction or elimination of myopia of less than or equal to -7. 0 d, with or without refractive astigmatism of less than or equal to -3. 0 d, with a maximum mrse of -7. 00 d; 2) in patients who are 21 years of age or older; 3) with documentation of stable manifest refraction over the past year as demonstrated by change in sphere and cylinder of <=0. 5d Indicated for adults 21-45 years of age: 1) to correct myopia ranging from -3. 0 diopters to <=-15. 0 diopters with less than or equal to 2. 5 diopters of astigmatism at the spectacle plane; 2) to reduce myopia ranging from greater than -15. 0 diopters to -20. 0 diopters with less than or equal to 2. 5 diopters of astigmatism at the spectacle plane; and 3) with an anterior chamber depth (acd) 3. 00 No Literature No No

2005 VISTAKON (SENOFILCON A) CONTACT LENS CLEAR AND VISIBILITY TINTED WITH UV BLOCKER 2005 ACRYSOF RESTOR APODIZED DIFFRACTIVE OPTIC POSTERIOR CHAMBER IOL mm or greater, and a stable refractive history within 0. 5 diopter for 1 year prior to implantation Optical correction of refractive ametropia (myopia and hyperopia) in phakic or aphakic persons with non-diseased eyes who have 1. 00d or less of astigmatism; optical correction of distance and near vision in presbyopic, phakic or aphakic persons with non-diseased eyes who may have 0. 75d of astigmatism or less 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 Yes Contralateral Single No No Standard of care No No 2004 JSZ ORTHOKERATOLOGY (OPRIFOCON A) CONTACT LENSES FOR OVERNIGHT WEAR Reduction of myopic refractive error in non-diseased eyes No Historical No Yes 2004 ARTISAN (MODEL 206 AND 204) PHAKIC INTRAOCULAR LENS (PIOL) VERISYSE (VRSM5US AND VRSM6US) PHAKIC INTRAOCULAR LENS (PIOL) Indicated for: 1) the reduction or elimination of myopia in adults with myopia ranging from -5 to -20 diopters with less than or equal to 2. 5 diopters of astigmatism at the spectacle plane and whose eyes have an anterior chamber depth greater than or equal to 3. 2 millimeters; and, 2) patients with documented stability of refraction for the prior 6 months, as demonstrated by spherical equivalent change of less than or equal to 0. 50 diopters 2004 EUCLID S ORTHOKERATOLOGY (OPRIFOCON A) CONTACT LENS FOR OVERNIGHT WEAR Reduction of myopic refractive error in non-diseased eyes No Historical No Yes 2004 OPHTEC CAPSULAR TENSION RING MODELS 276 AND 275 AND STABILEYES MODELS STBL2US AND STBL13US 2003 CRYSTALENS MODEL AT- 45 ACCOMMODATING POSTERIOR CHAMBER Stabilization of weakened, broken or missing zonules that are suspected or observed during cataract extraction using phacoemulsification and continuous curvilinear capsulorhexis techniques in adults in whom a cataractous lens has been removed and is

INTRAOCULAR LENS (IOL) 2003 MORCHER CAPSULAR TENSION RING TYPES 14 14A AND 14C 2003 WAVELIGHT ALLEGRETTO WAVE EXCIMER LASER 2003 WAVELIGHT ALLEGRETTO WAVE EXCIMER LASER 2002 VIEWPOINT(TM) CK intended to provide near, intermediate and distance vision without spectacles Stabilization of the crystalline lens capsule in the presence of weak or partially absent zonules in adult patients undergoing cataract extraction with intraocular lens implantation Indicated for laser assisted in situ keratomileusis (LASIK): 1) for the reduction or elimination of hyperopic refractive errors up to +6. 0 diopters (d) of sphere with and without astigmatic refractive errors up to 5. 0 d at the spectacle plane, with a maximum manifest refraction spherical equivalent (mrse) of +6. 0 d; 2) in patients who are 18 years of age or older; and 3) in patients with documentation of a stable manifest refraction defined as <=0. 50 d of preoperative spherical equivalent shift over one year prior to surgery, exclusive of changes due to unmasking latent hyperopia Indicated for laser assisted in situ keratomileusis (LASIK): 1) for the reduction or elimination of myopia of up to -12. 0 diopters (d) of sphere and up to -6. 0 d of astigmatism at the spectacle plane; 2) in patients who are 18 years of age or older; and 3) in patients with documentation of a stable manifest refraction defined as <=0. 50d of preoperative spherical equivalent shift over one year prior to surgery Indicated for: temporary reduction of spherical hyperopia in patients who have 0. 75 d to 3. 25 d of cycloplegic spherical hyperopia, less than or equal to 0. 75 d of refractive astigmatism (minus cylinder format), a cycloplegic spherical equivalent of 0. 75 d to 3. 00 d, and are 40 years of age or greater with a documented stability of refraction for the prior 12 month, as demonstrated by a change of less than 0. 50 d in spherical and cylindrical components of the manifest refraction.