1. State-of-the-Science: Treatment of Neovascular Age-Related Macular Degeneration (AMD) Ivan J. Suñer, MD Associate Professor of Ophthalmology Duke University Medical Center (Duke Eye Center) Chief of Ophthalmology Service Durham Veteran Affairs Medical Center Durham, NC

2. Presentation Outline Overview of age-related macular degeneration (AMD) Overview of age-related macular degeneration (AMD) Current therapies in the treatment of neovascular AMD Current therapies in the treatment of neovascular AMD –Thermal laser photocoagulation –Ocular photodynamic therapy Verteporfin Verteporfin –Vascular endothelial growth factor (VEGF) inhibitors FDA approved FDA approved –Pegaptanib –Ranibizumab Off label Off label –Bevacizumab Summary Summary

3. Overview of Age-Related Macular Degeneration (AMD)

4. Definition Late onset (age > 50 years) Late onset (age > 50 years) Some degree of vision loss Some degree of vision loss Lipid deposits (drusen) under retina Lipid deposits (drusen) under retina

5. Epidemiology 15 million affected in the United States 15 million affected in the United States Leading cause of vision loss age > 50 years Leading cause of vision loss age > 50 years Distribution (age) Distribution (age) –55–64: 17% –65–74: 26% –>75: 42% Congdon N, et al. Arch Ophthalmol. 2004;122:477.

6. Projected Prevalence of Advanced AMD* in the United States 0 1 2 3 20002020 Number of Cases (millions) Year *Defined as neovascular AMD and/or geographic atrophy in at least 1 eye. Prevalence figures were calculated using 2000 US census data. Friedman DS, et al. Arch Ophthalmol. 2004;122:564. 1.75 2.95

7. Photoreceptors Choroid RPE Genentech, Inc. Data on file. Normal Retina Fovea Macula

8. Normal retina Bruch’s membrane thickens and drusen develop Photoreceptors Choroid RPE Fovea Macula Genentech, Inc. Data on file. Progression of AMD Development of Drusen

9. New abnormal blood vessels proliferate and penetrate Bruch’s membrane New blood vessels leak blood and fluid Progression of AMD Formation and Leakage from Choroidal Neovascularization (CNV) Genentech, Inc. Data on file.

10. Advanced Wet AMD Fibrovascular Scar Genentech, Inc. Data on file.

11. Current Therapies in the Treatment of Neovascular AMD

12. Thermal effects of laser destroys CNV, low recurrence rate Thermal effects of laser destroys CNV, low recurrence rate Causes damage to surrounding healthy tissue Causes damage to surrounding healthy tissue Not for use on CNV located beneath fovea (subfoveal) Not for use on CNV located beneath fovea (subfoveal) – Immediate, permanent decrease in central vision Laser beam aimed at CNV Immediate damage to RPE and photoreceptors overlying CNV Thermal Laser Photocoagulation CNV = choroidal neovascularization RPE = retinal pigment epithelium Genentech, Inc. Data on file.

13. Verteporfin Intravenously administered photosensitizing drug Intravenously administered photosensitizing drug Attaches to the inner surface of abnormal proliferating blood vessels Attaches to the inner surface of abnormal proliferating blood vessels Activated by nonthermal laser light at 689 nm Activated by nonthermal laser light at 689 nm Generates highly reactive, short-lived oxygen radicals, which damage vessel walls Generates highly reactive, short-lived oxygen radicals, which damage vessel walls Minimal effects on the surrounding tissue structures Minimal effects on the surrounding tissue structures

14. Forms of Subfoveal Neovascular AMD Minimally classicOccult with no classicPredominantly classic 18%–24%6%–19%60%–75% Olsen T, et al. Ophthalmology. 2004;111:250. Zawinka C, et al. Retina. 2005;25:324. Margherio RR, et al. Retina. 2000;20:325. Ng E, Adamis AP. Can J Ophthalmol. 2005;40:352.

15. 67% 56% 49% 39% 55% 45% 0 10 20 30 40 50 60 70 80 90 100 Predominantly Classic 12-Month Results of PDT Trials TAP-VIP Study Populations % Patients Losing <15 Letters PDT = photodynamic therapy. TAP Study Group. Arch Ophthalmol. 1999;117:1329. VIP Study Group. Am J Ophthalmol. 2001;131:541. *Azab M, et al. Arch Ophthalmol. 2005. Minimally ClassicOccult No Classic PDT Placebo PDT benefit has been demonstrated for small lesions (<4 disc areas) of all compositions*

16. Endothelial cell activation, proliferation, migration 4 VEGF-A Is a Key Mediator of Angiogenesis ANGIOGENESIS 3 VASCULAR LEAKAGE 3 Environmental factors 1 (hypoxia, 2 pH) Growth factors, hormones 1 (EGF, bFGF, PDGF, IGF-1, IL-1 , IL-6, estrogen) VEGF-A binding and activation of VEGF receptor 3 Endothelial cell activation 3 VEGF-A = vascular endothelial growth factor A; EGF = epidermal growth factor; bFGF = basic fibroblast growth factor; PDGF = platelet-derived growth factor; lGF = insulin-like growth factor; IL= interleukin. 1. Dvorak HF. J Clin Oncol. 2002;20:4368. 2. Aiello LP, et al. Arch Ophthalmol. 1995;113:1538. 3. Ferrara N, et al. Nat Med. 2003;9:669. 4. Griffioen AW and Molema G. Pharmacol Rev. 2000;52:237.

17. Multiple Isoforms of VEGF-A Are Generated from Exon Splicing Adapted from Ferrara N, et al. Nat Med. 2003;9:669. Highly diffusible isoform 1 121 VEGF-A 121 1 206 Highest molecular weight isoform bound to extracellular matrix VEGFR-binding domain Heparin-binding domain VEGF-A 206 Sequestered in the extracellular matrix 1 189 VEGF-A 189 165 1 Most abundant isoform expressed in humans VEGF-A 165

18. VEGF Inhibition in AMD FDA approved Pegaptanib Pegaptanib –Aptamer –Specific for VEGF-A isoform 165 1 Ranibizumab Ranibizumab –Recombinant, humanized antibody fragment –Blocks all VEGF-A isoforms Off label Bevacizumab Bevacizumab –Recombinant humanized monoclonal antibody –Blocks all VEGF-A isoforms 1 Gragoudas ES, et al. N Engl J Med. 2004;351:2805.

19. Pegaptanib for Neovascular AMD The VISION Study Concurrent, randomized, double-blind, controlled, dose-ranging studies Concurrent, randomized, double-blind, controlled, dose-ranging studies –Prespecified combined data analysis 1190 patients at 117 centers worldwide 1190 patients at 117 centers worldwide –295 received Pegaptanib0.3 mg –295 received Pegaptanib 0.3 mg –298 received usual care with sham injections every 6 weeks Photodynamic therapy with verteporfin was allowed per FDA-approved label at physician discretion for predominantly classic lesions in all treatment arms VISION = VEGF Inhibition Study in Ocular Neovascularization Gragoudas ES, et al. N Eng J Med. 2004;351:2805. Pegaptanib 1.0 mg IVT injection every 6 weeks Pegaptanib 0.3 mg Pegaptanib 3.0 mg Usual Care Every 6 weeks

20. 68% 75% 66% 57% 53% 56% 0 10 20 30 40 50 60 70 80 90 100 Predominantly ClassicMinimally ClassicOccult No Classic Pegaptanib 0.3 mg Usual Care 12-Month Results of Pegaptanib Trials % Patients Losing <15 Letters VISION Study: post-hoc analysis Adapted from Gragoudas ES, et al. N Eng J Med. 2004;351:2805.

21. Two Pivotal Phase III Ranibizumab Trials in Neovascular AMD MARINA = Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovasular AMD; ANCHOR = ANti-VEFG Antibody for the Treatment of Predominantly Classic CHORidal Neovascularization in AMD; VA visual acuity. Presented at ARVO; April 30–May 4, 2006. MARINA ANCHOR N716423 Lesion typesMinimally classic Predominantly or occultclassic DosesPlaceboPlacebo ranibizumab 0.3 mg / ranibizumab 0.5 mg Primary endpoint % patients losing <15 letters at month 12 Key secondary Mean change from baseline in VA Endpoints over time up to month 12 ≥15-letter gainers in VA at month 12 compared to baseline Mean change in leakage at month 12 compared to baseline

22. MARINA Trial: Primary Endpoint Patients Losing <15 Letters from Baseline at Month 12 *P <.0001 vs Sham Presented at ARVO; April 30–May 4, 2006. 0 10 20 30 40 50 60 70 80 90 100 Sham (n = 238) Ranibizumab 0.3 mg (n = 238) Ranibizumab 0.5 mg (n = 240) 94.6%*94.5%* % of Subjects 62.2% Maintains Vision

23. Secondary Endpoint: Mean Change in Visual Acuity Over Time Improves Vision ETDRS Letters 17.7-letter difference* 17.0-letter difference* *P <.0001 vs Sham Sham (n = 238) Ranibizumab 0.3 mg (n = 238)Ranibizumab 0.5 mg (n = 240) 123456789101112 -15 -10 -5 0 5 10 15 0 -10.5 +6.5 +7.2 Presented at ARVO; April 30–May 4, 2006. Months

24. ANCHOR Trial: Primary Endpoint Subjects Losing <15 Letters from Baseline at Month 12 *P <.0001 vs PDT 0 10 20 30 40 50 60 70 80 90 100 PDT (n = 143) Ranibizumab 0.3 mg (n = 140) Ranibizumab 0.5 mg (n = 139) 96.4%* 94.3%* % of Subjects 64.3% Maintains Vision Presented at ARVO; April 30–May 4, 2006.

25. ETDRS Letters Improves Vision Secondary Endpoint: Mean Change in Visual Acuity Over Time Note: Vertical bars are ± one standard error of the mean. *P <.0001 vs Sham +11.3 +8.5 –9.5 20.8-letter difference* 18.0-letter difference* PDT (n = 143) Ranibizumab 0.3 mg (n = 140)Ranibizumab 0.5 mg (n = 139) Month -15 -10 -5 0 5 10 15 123456789101112 Presented at ARVO; April 30–May 4, 2006.

26. Investigational Bevacizumab Trials California Retina Consultants Study. Avery RL et al. Ophthalmology. 2006 Mar. Vitreous Retina Macula Consultants of New York. Spaide RF et al. Retina. 2006 Apr. Preliminary data from 2 trials show promising decrease in central macular thickness Preliminary data from 2 trials show promising decrease in central macular thickness Both trials reported a mean improvement in visual acuity with bevacizumab Both trials reported a mean improvement in visual acuity with bevacizumab Follow-up too short to make treatment recommendations Follow-up too short to make treatment recommendations Further study needed Further study needed

27. Summary Neovascular AMD is leading cause of legal blindness in patients > 50 years old in the United States Neovascular AMD is leading cause of legal blindness in patients > 50 years old in the United States Thermal laser photocoagulation effective in juxta- and extra-foveal lesions (<10%) Thermal laser photocoagulation effective in juxta- and extra-foveal lesions (<10%) Ocular photodynamic therapy (OPT) approved for predominantly classic choroidal neovascularization (~20% of subfoveal) Ocular photodynamic therapy (OPT) approved for predominantly classic choroidal neovascularization (~20% of subfoveal)

28. Summary Vascular endothelial growth factor (VEGF) inhibition is effective in all forms of subfoveal choroidal neovascularization Vascular endothelial growth factor (VEGF) inhibition is effective in all forms of subfoveal choroidal neovascularization –FDA approved Pegaptanib Pegaptanib Ranibizumab Ranibizumab –Off label Bevacizumab Bevacizumab VEGF inhibition therapy with ranibizumab VEGF inhibition therapy with ranibizumab –95% response rate –On average, visual acuity improves

29. Implications of Anti-VEGF Therapies in Managed Care: Avoiding Billing Pitfalls Alexander M. Stockdale, MBA Chief Executive Officer Southeastern Retina Associates Knoxville, TN

30. Avoiding Billing Pitfalls Understand Medicare competitive acquisition program (CAP) versus “buy and bill” 1,2 Understand Medicare competitive acquisition program (CAP) versus “buy and bill” 1,2 Analyze past performance/problems Analyze past performance/problems Know your specific carrier rules, advance beneficiary notices (ABNs) 3 Know your specific carrier rules, advance beneficiary notices (ABNs) 3 Educate and update MDs, staff, patients Educate and update MDs, staff, patients Use programs and resources of manufacturers when appropriate Use programs and resources of manufacturers when appropriate Work cooperatively with carriers for coverage and flexibility Work cooperatively with carriers for coverage and flexibility 1. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/Competitive AcquisforBios/Downloads/303d.pdf 2. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/CompetitiveAcquisforBios/02_infophys.asp. Accessed June 27, 2006. 3. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/BNI. Accessed June 27, 2006.

31. CAP For Part B Drugs and Biologicals 1 For Part B Drugs and Biologicals 1 Does not apply to drugs under Medicare Prescription Drug Benefit 1,2 Does not apply to drugs under Medicare Prescription Drug Benefit 1,2 American Academy of Ophthalmology (AAO) pushed to include pegaptanib and verteporfin; ranibizumab will follow in 2007 American Academy of Ophthalmology (AAO) pushed to include pegaptanib and verteporfin; ranibizumab will follow in 2007 Only 1 CAP pharmacy provider signed up Only 1 CAP pharmacy provider signed up Off to bad start Off to bad start 1. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/MedicareGenInfo. Accessed June 27, 2006. 2. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/MMAUpdate/downloads/PL108–173 summary.pdf. Accessed June 27, 2006.

32. Under CAP Physicians can choose to obtain drugs from Medicare-approved pharmacies Physicians can choose to obtain drugs from Medicare-approved pharmacies Drugs are shipped directly from pharmacies to physicians Drugs are shipped directly from pharmacies to physicians Billing is handled by pharmacy but practices may still have to collect copays, etc. Billing is handled by pharmacy but practices may still have to collect copays, etc.

33. Under CAP Physicians charge professional fee only Physicians charge professional fee only Practices do have to cooperate with CAP pharmacies for information 1 Practices do have to cooperate with CAP pharmacies for information 1 Still have buy and bill for non-Medicare patients Still have buy and bill for non-Medicare patients 14-day claim submission deadline – YIKES! 14-day claim submission deadline – YIKES! 1. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/Competitive AcquisforBios/Downloads/303d.pdf. Accessed June 27, 2006.

34. Why Would Physicians Choose CAP? 1 For Medicare patients, eliminates uncertainty of payment For Medicare patients, eliminates uncertainty of payment Not as great a need to provide stock levels or keep track of ordering Not as great a need to provide stock levels or keep track of ordering Fear of large debt for drug, and of collection problems Fear of large debt for drug, and of collection problems Easier? Easier? CAP attractive for some regions (eg, South Carolina tax issue) CAP attractive for some regions (eg, South Carolina tax issue) 1. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/Competitive AcquisforBios/Downloads/303d.pdf. Accessed June 27, 2006.

35. Experience with Commercial CAP Paperwork onerous Paperwork onerous Confusing to patients Confusing to patients Have to loan drug Have to loan drug More difficult and time consuming than buy and bill More difficult and time consuming than buy and bill No payment for handling and paperwork No payment for handling and paperwork

36. Experience with Buy and Bill 1 MDs choose when to treat patient—no delay waiting for drug MDs choose when to treat patient—no delay waiting for drug Medicare billing and payment is smooth and rapid—commercials generally OK in time Medicare billing and payment is smooth and rapid—commercials generally OK in time Drug margin helps cover shipping, handling, and billing costs Drug margin helps cover shipping, handling, and billing costs 1. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/CompetitiveAcquisforBios/02_infophys.asp. Accessed June 27, 2006.

37. Analyze Past Experience FDA-approved therapies FDA-approved therapies –Photodynamic therapy (PDT) –Pegaptanib Non-FDA-approved therapies Non-FDA-approved therapies –Intravitreal triamcinolone –Bevacizumab Combined therapies Combined therapies Payment and billing problems Payment and billing problems –In-office confusion –Insurance coverage –Treatment of associated charges for Evaluation and Management (E/M) 1 and diagnostic tests 1. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/MLNProducts/downloads/ eval_mgmt_serv_guide.pdf. Accessed June 27, 2006.

38. Patient Population for AMD Varies by state, insurance carriers, demographics But: Varies by state, insurance carriers, demographics But: Vast majority of patients are pure Medicare Vast majority of patients are pure MedicareOr: –Medicare HMO patients –Commercial patients –Medicaid/managed Medicaid –Uninsured/underinsured

39. Importance of ABNs Patients need to be fully informed and aware Patients need to be fully informed and aware Staff training and accountability Staff training and accountability MD knowledge MD knowledge Reimbursement Reimbursement Compliance Compliance ABNs = advanced beneficiary notices

40. Sample AMD Coverage Matrix PDT = photodynamic therapy; IVT = intravitreal triamcinolone. Insurance TypePDTPDT/IVTPegaptanibIVTRanibizumabBevacizumabNotes MedicareYesYes/50%YesYesYesYesBevacizumab after failure of therapy Medicare HMO 1YesYes/50%YesYesNoNo2 OCT limit Medicare HMO 2YesNoYesNoYesYesPrecert Commercial Insurance 1YesYes/50%YesYesYesNo Commercial Insurance 2YesNoYesNoNoYesPrecert MedicaidYesYes/50%YesYesYesNo

41. Successful Billing Basics Staff coordination and education Staff coordination and education Report problems centrally Report problems centrally Note trends Note trends Update matrix Update matrix Take advantage of manufacturer resources Take advantage of manufacturer resources

42. Financial Good Housekeeping Good inventory procedures and accountability Good inventory procedures and accountability Rotate stock of drugs Rotate stock of drugs Good clinical practices with staff Good clinical practices with staff –Don’t open drug until MD/patient makes final treatment decision Seek replacement drug when appropriate Seek replacement drug when appropriate

43. AMD Treatment Collections Relative collections per treatment type Staff time Staff time Buy and bill practice or CAP Buy and bill practice or CAP Supplies Supplies PDT laser and infusion maintenance cost assessed per case PDT laser and infusion maintenance cost assessed per case Diagnostic and E/M differences Diagnostic and E/M differences

44. Collections by Treatment Type 0 100 200 300 400 500 600 BevacizumabPDTPegaptanibRanibizumabPDT/IVK PDT = photodynamic therapy; IVT = intravitreal triamcinolone.

45. Patient Cost Education Avoid discussion of cost in lanes Avoid discussion of cost in lanes Instead refer to billing person Instead refer to billing person ABN responsibility of clinical staff ABN responsibility of clinical staff Billing person needs tools to answer intelligently Billing person needs tools to answer intelligently –Fee schedules (including self-pay) –Coverage matrix –Decision-making ability within guidelines –Understanding of manufacturing support programs

46. Manufacturer Resources For FDA-approved drugs and applications For FDA-approved drugs and applications Direct-sales person Direct-sales person Retinal business/reimbursement manager Retinal business/reimbursement manager Assistance programs Assistance programs –Copay assistance foundations –Uninsured and noninsured drug programs

47. Insurance Carriers Know and communicate with decision makers about AMD therapies Know and communicate with decision makers about AMD therapies Make sure they get latest data ASAP Make sure they get latest data ASAP Work cooperatively with manufacturers’ representatives as appropriate to seek drug approval Work cooperatively with manufacturers’ representatives as appropriate to seek drug approval Be thorough, insistent, and consistent as patient’s advocate Be thorough, insistent, and consistent as patient’s advocate

48. Implications of Anti-VEGF Therapies in Managed Care: Reimbursement Strategies Kirk A. Mack, COE, CPC, COMT Senior Consultant Corcoran Consulting Group San Bernardino, CA

49. Intravitreal Injection Reimbursement Medicare utilization Medicare utilization Medicare reimbursement Medicare reimbursement Antiangiogenic therapy Antiangiogenic therapy Medicare coverage of off-label drugs Medicare coverage of off-label drugs Medicare coverage of ranibizumab Medicare coverage of ranibizumab Medicare coverage of allied services Medicare coverage of allied services Chart documentation Chart documentation

50. Top 10 Ophthalmic Procedures Medicare Utilization Patterns (18 - Ophthalmology) RankCPTCodeProcedureRankCPTCodeProcedure 166984 Cataract w/IOL 665855 Laser Trabeculoplasty 266821 YAG Capsulotomy 767221PDT 368761 Punctal Occlusion plugs 867228PRP 467820 Epilation Lashes 966761Iridotomy 567210 Focal Laser 1067028 Intravitreal Injection CPT = current procedural terminology; IOL = intraocular lens; YAG = yttrium aluminum garnet; PDT = photodynamic therapy; PRP = panretinal photocoagulation. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/MedicareMedicaidStatSuppl/ Accessed July 20, 2006

51. Medicare Utilization 67028 Intravitreal Injection 0 50000 100000 150000 200000 250000 300000 19981999200020012002200320042005 Year From Eyetech IOQ reports. Available at: http://www.eyetech.net Procedures

52. Part B Growth in Services Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/NonIdentifiableDataFiles/03_PartBExactSummarySystem.asp. Accessed July 20, 2006 ServicesServices Intravitreal injection 92% Fundus photography 9% Pachymetry42% Fluorescein angiography 8% Scanning laser 26% Extended ophthalmoscopy 7% PDT19% Glaucoma lasers 7% B-scan18% A-scan biometry 7% PPV10% Outpatient consultations 6%

53. Intravitreal Injection Reimbursement Medicare utilization Medicare utilization Medicare reimbursement Medicare reimbursement

54. Medicare Reimbursement Intravitreal Injection (67028) Participating surgeon, non-facility rate$202.75 Participating surgeon, non-facility rate$202.75 Participating surgeon, facility rate$155.38 Participating surgeon, facility rate$155.38 Non-par surgeon, non-facility rate$192.61 Non-par surgeon, non-facility rate$192.61 Non-par surgeon, facility rate$147.61 Non-par surgeon, facility rate$147.61 Non-par surgeon, limiting charge$221.51 Non-par surgeon, limiting charge$221.51 Separate payment for the injected agent Separate payment for the injected agent Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/PhysicianFeeSched/ Accessed July 20, 2006

55. Intravitreal Injection Reimbursement Medicare utilization Medicare utilization Medicare reimbursement Medicare reimbursement Antiangiogenic therapy Antiangiogenic therapy

56. Intravitreal Injections for Wet AMD Anti-VEGF Agents Antiangiogenic therapy Pegaptanib Pegaptanib –Dec 2004, for neovascular (wet) AMD Bevacizumab Bevacizumab –For metastatic colorectal cancer Ranibizumab Ranibizumab –June 2006, for neovascular (wet) AMD AMD = age-related macular degeneration; VEGF = vascular endothelial growth factor.

57. Intravitreal Injections for Wet AMD Anti-VEGF Agents Antiangiogenic therapy Pegaptanib Pegaptanib –On-label Bevacizumab Bevacizumab –Off-label Ranibizumab Ranibizumab –On-label

58. Pegaptanib (Pegaptanib Sodium Injection) J2503* – injection, pegaptanib sodium, 0.3 mg J2503* – injection, pegaptanib sodium, 0.3 mg Payment based on ASP + 6% Payment based on ASP + 6% –ASP updated quarterly Widespread coverage by Medicare and other payers Widespread coverage by Medicare and other payers *Use C9128 in hospital setting; same payment: Since 1/1/06, J2503 replaces J3490 on claims ASP = average sale price.

59. Intravitreal Injection Reimbursement Medicare utilization Medicare utilization Medicare reimbursement Medicare reimbursement Antiangiogenic therapy Antiangiogenic therapy Medicare coverage of off-label drugs Medicare coverage of off-label drugs

60. Unlabeled Use of Drug “If a medication is determined not to be reasonable and necessary for diagnosis or treatment of an illness or injury according to these guidelines, the carrier excludes the entire charge (i.e., for both the drug and its administration). Also, carriers exclude from payment any charges for other services (such as office visits) which were primarily for the purpose of administering a noncovered injection (i.e., an injection that is not reasonable and necessary for the diagnosis or treatment of an illness or injury)... ” “If a medication is determined not to be reasonable and necessary for diagnosis or treatment of an illness or injury according to these guidelines, the carrier excludes the entire charge (i.e., for both the drug and its administration). Also, carriers exclude from payment any charges for other services (such as office visits) which were primarily for the purpose of administering a noncovered injection (i.e., an injection that is not reasonable and necessary for the diagnosis or treatment of an illness or injury)... ” Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/manuals/Downloads/bp102c15.pdf Accessed July 20, 2006

61. Drug Coverage Criteria Were standard, accepted treatments, including approved drugs, tried or contraindicated before considering a drug for an off-label use? Were standard, accepted treatments, including approved drugs, tried or contraindicated before considering a drug for an off-label use? Do any of the major drug compendia and related peer-reviewed scientific articles support the off-label use (MCM 2049.1)? Do any of the major drug compendia and related peer-reviewed scientific articles support the off-label use (MCM 2049.1)? Do any specialty society publications recommend this off-label use? Do any specialty society publications recommend this off-label use? Is this off-label use an accepted standard of medical practice? Is this off-label use an accepted standard of medical practice? Is authoritative medical literature available to support this use? Are the level of evidence, endpoint measured, and number of patients adequate (MCM 2049.C.3)? Is authoritative medical literature available to support this use? Are the level of evidence, endpoint measured, and number of patients adequate (MCM 2049.C.3)?

62. Intravitreal Injection of Bevacizumab “Off-label” use when injected in the eye “Off-label” use when injected in the eye –Neovascular age-related macular degeneration –Clinically significant macular edema –Macular edema from Central retinal vein occlusion Vigorous informed consent needed Vigorous informed consent needed –“Off-label” status –Absence of controlled trials studies for ophthalmic use

63. Intravitreal Injection of Bevacizumab Utilize an Advance Beneficiary Notice (ABN) Utilize an Advance Beneficiary Notice (ABN) Coding Coding –67028 GA – intravitreal injection* –J3490 GA – unclassified drug (rather than J9035) Description of drug in comment field (box 19) Description of drug in comment field (box 19) *Some Medicare carriers require 67299-GA.

64. Advance Beneficiary Notice Items or services: Intravitreal injection of bevacizumab for the treatment of neovascular (wet) age-related macular degeneration (AMD) Because: Medicare’s Benefit Policy Manual does not usually cover use of a drug that is not included as an indication on the drug’s label as approved by the FDA. While there are exceptions to this general prohibition, use of bevacizumab to treat wet AMD is off-label, investigational, experimental and noncovered

65. Intravitreal Injection of Bevacizumab Limited Medicare Coverage BC/BS Montana BC/BS Montana CIGNA (ID, NC, TN) CIGNA (ID, NC, TN) Empire (NY, NJ) Empire (NY, NJ) First Coast (CT, FL) First Coast (CT, FL) NHIC (New England) NHIC (New England) Noridian (Rocky Mountains) Noridian (Rocky Mountains) Wisconsin Physician Services (MN, WI, MI, IL) Wisconsin Physician Services (MN, WI, MI, IL) Coverage at the discretion of the local carrier Coverage at the discretion of the local carrier

66. Intravitreal Injection Reimbursement Medicare utilization Medicare utilization Medicare reimbursement Medicare reimbursement Antiangiogenic therapy Antiangiogenic therapy Medicare coverage of off-label drugs Medicare coverage of off-label drugs Medicare coverage of ranibizumab Medicare coverage of ranibizumab

67. Medicare policies are in the process of being published for intravitreal injection of ranibizumab Ranibizumab

68. Ranibizumab FDA approval June 30, 2006 1 FDA approval June 30, 2006 1 J3590 Unclassified biologics J3590 Unclassified biologics Description in comment field (box 19) Description in comment field (box 19) Treatment of wet AMD (362.52) Treatment of wet AMD (362.52) 1 http://www.fda.gov/bbs/topics/NEWS/2006/NEW01405.html

69. Utilize an Advance Beneficiary Notice (ABN) Utilize an Advance Beneficiary Notice (ABN) Coding Coding –67028 GA – intravitreal injection* –J3590 GA – unclassified biologics Description of drug in comment field (box 19) Description of drug in comment field (box 19) Ranibizumab

70. Reimbursement unknown at this time Reimbursement unknown at this time –Usually, Average Selling Price (ASP) + 6% Transmittal 528; Change Request 3783 (effective 7/1/2005) Ranibizumab

71. Intravitreal Injection Reimbursement Medicare utilization Medicare utilization Medicare reimbursement Medicare reimbursement Antiangiogenic therapy Antiangiogenic therapy Medicare coverage of off-label drugs Medicare coverage of off-label drugs Medicare coverage of ranibizumab Medicare coverage of ranibizumab Medicare coverage of allied services Medicare coverage of allied services

72. Minor Surgery Reimbursed care during global period Diagnostic tests Diagnostic tests Exams or consultations Exams or consultations –Same day, unrelated diagnosis (-25) –Same day, separately identifiable (-25) –Postoperative, unrelated Evaluation and Management services (-24) Staged procedure (-58) Staged procedure (-58) Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/manuals/downloads/clm104c12.pdf Accessed July 20, 2006

73. Diagnostic Tests for AMD 92135 — optical coherence tomography (OCT) 92135 — optical coherence tomography (OCT) –Retina indications vary by carrier 1 92250 — fundus photography 92250 — fundus photography 92235 — fluorescein angiography 92235 — fluorescein angiography 92240 — indocynanine green angiography (ICG) 92240 — indocynanine green angiography (ICG) 1 Check specific carrier to determine if policy includes expanded retina indications.

74. Screening Tests for AMD MacuScope MacuScope Preferential hyperacuity perimetry (PHP) Preferential hyperacuity perimetry (PHP)

75. Billing Office Visit with Minor Procedure Evaluation and Management Service Resulting in the Initial Decision to Perform Surgery “...where the decision to perform the minor procedure is typically done immediately before the service, it is considered a routine preoperative service and a visit or consultation is not billed in addition to the procedure.” Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/manuals/downloads/clm104c12.pdf Accessed July 20, 2006

76. Billing Office Visit with Minor Procedure CPT Modifier 25 — Significant Evaluation and Management Service By Same Physician On Date of Global Procedure CPT Modifier 25 — Significant Evaluation and Management Service By Same Physician On Date of Global Procedure Pay for an evaluation and management service provided on the day of a procedure with a global fee period if the physician indicates that the service is for a significant, separately identifiable evaluation and management service that is above and beyond the pre- and post-operative work of the procedure. Pay for an evaluation and management service provided on the day of a procedure with a global fee period if the physician indicates that the service is for a significant, separately identifiable evaluation and management service that is above and beyond the pre- and post-operative work of the procedure. Centers for Medicare & Medicaid Services. Available at: http://www.cms.hhs.gov/manuals/downloads/clm104c12.pdf Accessed July 20, 2006

77. Modifier -25 Significant separate Evaluation and Management services on the day of a minor surgery ie, to cope with disease in both eyes 92012-25* 362.52 AMD OU 67028362.52 AMD OS *Some carriers do not want modifier on new-patient exams.

78. Operative Report Indications for surgery Indications for surgery Description of the procedure Description of the procedure Manner in which surgery performed Manner in which surgery performed Preop and postop diagnoses Preop and postop diagnoses Discharge instructions Discharge instructions

79. Executive Summary Extraordinary growth of procedure volume Extraordinary growth of procedure volume Plan for a lot more intravitreal injections Plan for a lot more intravitreal injections Several anti-VEGF agents; ranibizumab is the latest Several anti-VEGF agents; ranibizumab is the latest Off-label use per se does not exclude coverage Off-label use per se does not exclude coverage Coverage depends on standard of care Coverage depends on standard of care Use an ABN; beneficiary is financially responsible Use an ABN; beneficiary is financially responsible Document informed consent and operative report Document informed consent and operative report