Managed Care Opportunities and Approaches to Supporting Appropriate Selection of Treatment for Sight Prevention

July 19, 2019

When evaluating the impact of vision-destroying diseases, pharmacologic therapies represent a significant cost to patients, insurance providers, and society. Currently, up to 11 million people in the United States have some form of age-related macular degeneration (AMD), which is one of the leading causes of vision loss in older Americans. Ophthalmologists have administered more than 6 million intravitreal injections of aflibercept, bevacizumab, pegaptanib, and ranibizumab last year. Comprehensive assessment requires managed care administrators and clinicians to understand the direct and indirect costs of vision loss as well as the comparative safety and efficacy profiles for each agent. In AMD, it is critical to understand the established and emerging treatment patterns.

When evaluating the impact of vision-destroying diseases, pharmacologic therapies represent a significant cost to patients, insurance providers, and society. Currently, up to 11 million people in the United States have some form of age-related macular degeneration (AMD), which is one of the leading causes of vision loss in older Americans. Ophthalmologists have administered more than 6 million intravitreal injections of aflibercept, bevacizumab, pegaptanib, and ranibizumab last year. Comprehensive assessment requires managed care administrators and clinicians to understand the direct and indirect costs of vision loss as well as the comparative safety and efficacy profiles for each agent. In AMD, it is critical to understand the established and emerging treatment patterns.

Am J Manag Care. 2019;25:-S0

Introduction

Visual impairment has a significant impact on many aspects of a patient’s life. Although many individuals with vision impairment live independently, caregivers and society typically assume the burden of caring for these patients. When evaluating the impact of diseases that affect vision, pharmacologic therapies represent a significant cost. Yet clinicians, policy makers, and managed care administrators must also consider the total disease burden, including indirect costs. This is particularly important as the number and kind of therapies for age-related macular degeneration (AMD) increase.

AMD leads to a loss of the sharp, fine-detail “straight ahead” vision required for activities such as reading, driving, recognizing faces, and seeing the world in color. As the disease progresses, patients lose more of their vision field. AMD is a leading cause of legal blindness and visual impairment in the United States and around the world.1,2 The risk of developing advanced AMD increases from 2% for people between 50 and 59 years of age to almost 30% in people older than 75 years. Currently, as many as 11 million people in the United States have some form of AMD, and it is the leading cause of vision loss in Americans aged 60 years and older. This number is expected to double to nearly 22 million by 2050.3,4 Currently, just 10% of patients experience neovascular (wet) AMD (nAMD) for which existing treatments are indicated.

Aflibercept, bevacizumab, pegaptanib (which has been largely replaced by the other agents because of their better efficacy),5 and ranibizumab have changed how AMD is treated. These treatments have only been approved for the treatment of nAMD. An indication of how quickly anti-vascular endothelial growth factor (VEGF) utilization has grown is underscored by Medicare payments for physician services associated with the administration of anti-angiogenic drugs. In 2000, physicians reported 3000 Medicare-covered intravitreal injections. In 2008, they reported 1 million, and, in 2013, Medicare paid for 2.5 million intravitreal injections at a cost of more than $300 million.6 The American Academy of Ophthalmology (AAO) estimated that more than 4 million intravitreal injections were administered in 2014, and experts estimate more than 6 million were given in 2016.7

The Ultimate Cost: Visual Impairment

Visual impairment affects individuals, caregivers, and society as a whole in a ripple effect. In a comparison of community-dwelling, older Americans with and without vision impairment, visually impaired individuals reported significantly more disability, even with simple daily activities, than those with acceptable vision. Vision loss can lead to loss of independence.

For example, people who reported vision problems were significantly more likely than others to report difficulty getting into or out of a chair or bed, accessing outside places, preparing meals, shopping for groceries, handling money, and managing medication. Visually impaired individuals also reported a negative impact when participating in activities such as meetings, talking on the phone with friends and relatives, and partaking in various social activities. Among patients who are older than 70 years, those with vision problems were twice as likely to report depression, recent falls, or a broken hip.8

The economic consequences of vision impairment are significant. A review of 22 interventional, noninterventional, and cost-of-illness studies quantified the direct costs, indirect costs, and intangible effects related to visual impairment and legal blindness.9 Hospitalization, use of medical services related to the visual impairment diagnosis, and treatment all contributed the most to direct medical costs. Assistive devices and aids, home modifications, and healthcare services, such as home-based nursing or nursing home placements, were the major contributors to direct nonmedical costs. As visual impairment worsened, costs for support services and assistive devices increased; these were coded as direct nonmedical. Time spent caring for or assisting visually impaired individuals correlated to the degree of visual impairment, with individuals with most severe visual impairment requiring the most assistance. The time spent by caregivers ranged from 5.8 hours per week for a person with a visual acuity of more than 20/32 to 94.1 hours per week for an individual with a visual acuity of 20/250 or worse.9

Indirect costs that were associated with visual impairment are also significant. These costs, which emanate from patient and caregiver impact, include productivity losses, employment changes, income loss, premature mortality, and dead-weight losses (the costs to society created by market inefficiency).9

Economic Implications of Age-Related Macular Degeneration

A number of studies have attempted to quantify the economic costs associated with visual impairment, but few separate the burden by underlying diagnosis. Most authors still rely on figures calculated by Rein et al in 2006. They estimated the total economic burden of major visual disorders in 2004 dollars at $35.4 billion, which included $16.2 billion in direct medical costs, $11.1 billion in indirect costs, and $8 billion in lost productivity. Annually, the federal government and state Medicaid agencies are responsible for at least $13.7 billion of these costs.10 These figures are 12 years old, but no recent studies with updated data have been located.

A cross-sectional, prevalence-based healthcare economic survey assessed the annual, incremental, and societal costs associated with nAMD. They included direct ophthalmic medical costs, direct nonophthalmic medical costs, direct nonmedical costs, and indirect medical costs that are associated with nAMD in 4 cohorts. Patients with nAMD (n = 200, designated “the study cohort”) were compared with a control cohort of patients with good (20/20—20/25) vision. Three other cohorts included patients with diminishing vision in their better-seeing eye. Patients in the control cohort incurred a mean of $6116 in expenses, whereas those with AMD incurred an average of $39,910. Individuals whose impairment had no light perception incurred $82,984. Direct ophthalmic medical costs decreased, and indirect costs also decreased as a percentage of the total societal costs as patients’ vision worsened. In the study cohort, direct costs represented 17.9% of the overall total. Among the controls, direct costs were 74.1% of total societal costs. In individuals with no light perception, direct costs were 10.4% of total societal cost, indicating considerable indirect costs.11

Age-Related Macular Degeneration Treatment Costs

Based on safety and efficacy evidence, clinicians currently use intravitreal bevacizumab, aflibercept, and ranibizumab injection.12 Although researchers have published several cost-effectiveness studies about nAMD therapies, many included older treatments, such as laser photocoagulation, photodynamic therapy, and the early anti-VEGF medication pegaptanib.13 The direct cost of nAMD treatment in 2004 dollars was estimated at $575 million, which is expected to increase as society ages and more costly treatments are introduced.3,10

Ophthalmologists and policy makers want to know specifics when they consider the costs of AMD. Safety and efficacy are always primary concerns, and sufficient data are available to confirm that these agents are safe and approximately equally effective.12 The primary treatment goal of AMD is to restore or maintain vision, which is critical to the patient’s overall quality of life (QOL). The anti-VEGF agents improve vision-related quality of life (VRQOL) for patients with nAMD. Patients whose vision is maintained have better VRQOL, irrespective of which eye is treated (better or worse seeing eye).14

Stakeholders regularly compare new options to old options; those studies generally precede head-to-head comparisons. As early as 2011, researchers working in pharmacoeconomics compared laser photocoagulation and photodynamic therapy with verteporfin and intravitreal bevacizumab, pegaptanib, and ranibizumab. Anti-VEGF therapies appeared to be highly cost-effective compared with old therapies. The researchers indicated that although the anti-VEGF treatments improved visual acuity compared with older therapies, their increased cost was troublesome. Researchers concluded that ranibizumab was consistently shown to be a cost-effective therapy for nAMD compared with all other approved options. The cost-effectiveness of pegaptanib was marginal, depending on the disease stage. Few published studies compared active treatments at that time, and the researchers did not find any acceptable studies that addressed the off-label use of bevacizumab.13

Next, clinicians wanted long-term data about cost-effectiveness for options; patients who have nAMD can live with the disease for 20 years or longer.5 US data for bevacizumab became available in 2012 when researchers with the Veterans Affairs San Diego Healthcare System and University of California San Diego analyzed the cost-effectiveness of monthly ranibizumab and bevacizumab.15 The researchers developed a Markov model with 3-month cycles in a hypothetical cohort of 65-year-old patients (N = 1000) with nAMD. The economic analysis included physician visits, drugs, and monitoring costs. The total direct cost for bevacizumab was $30,349 per patient with a mean average of 21.6 quality-adjusted life-years (QALYs) over 20 years compared with $220,649 for ranibizumab with a mean average of 18.1 QALYs. Compared with ranibizumab, treatment with bevacizumab resulted in an incremental cost-effectiveness ratio (ICER) of —$54,649 to gain 1 additional QALY. Based on a willingness-to-pay (WTP) of $50,000, the researchers predicted bevacizumab would be more cost-effective than ranibizumab 95% of the time.15 These findings were replicated in 2013.16

Confirmation studies are of interest, especially when new dosing strategies are being explored. A 2014 cost-effectiveness analysis examined a hypothetical cohort of 80-year-old patients with newly diagnosed neovascular macular degeneration.17 The study looked at monthly bevacizumab, as-needed bevacizumab, monthly ranibizumab, or as-needed ranibizumab over a period of 20 years. In addition to costs, the researchers examined the potential for differences in risks of serious adverse effects (AEs) and therapeutic effectiveness. They concluded that17:

  • ICERs for monthly bevacizumab and monthly ranibizumab for nAMD were $242,357/QALY and $10,708,377/QALY, respectively.
  • As-needed ranibizumab was more costly and less effective than bevacizumab, and bevacizumab along with as-needed dosing represented the best value.
  • When the researchers varied the model parameters (ie, the proportion of patients with serious systemic AEs, the number of injections administered, the cost per injection, and patient’s life expectancy), bevacizumab was preferred in nearly two-thirds of the simulations using WTP of $100,000/QALY.

Medicare: Bearing a Disproportionate Share

As Medicare bears most of the cost of AMD, studies about the spending are important. A 2011 retrospective, longitudinal cohort study compared random sample cohorts from 1994, 2000, and 2006. The length of the study is important as several new treatments became available during that time. Between 1994 and 2006, the number of beneficiaries who were newly diagnosed with nAMD increased by a factor of 2.41. Annual part B payments increased significantly from $3567 in 1994 to $5991 in 2006 per beneficiary and were adjusted to 2008 dollars. Payments for eye care alone roughly doubled from $1504 in 1994 to $3263 in 2006, with anti-VEGF injections accounting for 73% of the cost. Payments for laser photocoagulation decreased significantly. The researchers noted that they observed a shift from pegaptanib and ranibizumab to bevacizumab between 2006 and 2008; they predicted it would continue and would be associated with savings of about 80%.18

The trend toward bevacizumab developed as it was predicted. Researchers found significant geographic and demographic variations in treatment for AMD in Medicare beneficiaries in ensuing years. By 2009, just 35% of beneficiaries received ranibizumab for initial nAMD treatment, and black individuals were 45% less likely to receive ranibizumab than others. The geographic variation was large. Clinicians in urban areas, zip codes with high median incomes, and the New England and East South Central census regions were more likely to use ranibizumab.19 From 2008 to 2015, statisticians estimated that using bevacizumab for AMD instead of ranibizumab or aflibercept saved Medicare a conservative $17.3 billion because beneficiaries enrolled in Medicare Advantage plans were excluded from the study.20

Keeping an Eye on Off-label Concerns

Researchers note that dollar-for-dollar, bevacizumab is significantly less expensive than the FDA-approved anti-VEGF inhibitors, but a compounding pharmacy must prepare it. Some safety concerns about endophthalmitis surfaced in 2011, and others have been identified (see Table 1).5,21-27 Regulatory bodies have implemented additional oversight since identifying outbreaks of endophthalmitis. Compounding pharmacies are required to comply with United States Pharmacopeia Chapter <797>, which sets standards for compounding, transporting, and storing compounded sterile product. Clinicians should ensure that they use reliable sources of bevacizumab. The AAO guidelines recommend that clinicians include discussion of the risks and benefits of treatment and treatment alternatives, including the off-label status of bevacizumab for AMD when they consider using this monoclonal antibody.28 On the other hand, clinicians should also note that a 2015 study did not find an increased risk of endophthalmitis compared with ranibizumab.27 Stability studies have found that bevacizumab repackaged in plastic syringes is stable for 3 to 6 months, if handled properly.29,30

Following the publication of studies that demonstrate the clinical equivalence of ranibizumab and bevacizumab for nAMD, the majority of the cost analyses have been performed on these agents. Although the 2010 Patient Protection and Affordable Care Act prohibits the use of QALYs for making reimbursement decisions in the United States, QALYs are used frequently outside of the country.31,32 Using QALYs, a 2007 British study found that bevacizumab would need to be approximately 40% as effective as ranibizumab for the treatment of classic AMD for ranibizumab to achieve £30,000 ($39,106 in 2019 US dollars) per QALY, which is the threshold for drug approval of the National Institute for Health and Care Excellence.33 In the United Kingdom, it wasn’t until 2018 that bevacizumab was approved for use in nAMD.34

In a 2009 review of 44 cost-effectiveness studies in AMD, the researchers determined that older treatments, such as laser photocoagulation and photodynamic therapy, were cost-effective compared with no treatment. New therapies, such as ranibizumab, were more cost-effective than older treatments. Across the studies analyzed, at least 5 years of treatment was necessary to show cost-effectiveness for the new and clinically effective treatments for nAMD at standard WTP thresholds compared with older, less-effective therapies such as laser photocoagulation.13

The 2011 FDA approval of aflibercept for nAMD introduced another option. Aflibercept’s phase 3 clinical trial results suggest that this agent might have a longer duration of action than ranibizumab or bevacizumab. With the approval of aflibercept, managed care administrators and clinicians looked for comparative data. European researchers created a model that compared ranibizumab (as needed), aflibercept (bimonthly), and bevacizumab (as needed). In Europe, bevacizumab treatment costs €27,087 ($31,677 in 2018 US dollars) per year, about €4,000 ($4678) less than aflibercept and €6000 ($7016) less than ranibizumab. Based on an assumption of similar effectiveness for all drugs, these researchers also found that bevacizumab was the most cost-effective.35

Managed Care Strategies to Optimize Outcomes

Managed care organizations need to consider the financial implications of physician-administered drugs in 2 ways: a microeconomic (patient and ophthalmologist) perspective and a macroeconomic (societal) perspective. At the microeconomic level, managed care organizations should be aware that professional associations provide limited guidance on cost considerations when selecting ophthalmic anti-VEGF agents.36

As most patients with AMD are Medicare beneficiaries; part B covers 80% of physician-administered drugs, and patients cover the remaining 20% of the allowable reimbursement for the drug and the associated physician administration charges. The differential is $400 to $500 for aflibercept and ranibizumab compared with approximately $11 for bevacizumab.7,37

Out-of-pocket (OOP) costs can accumulate rapidly for patients, so managed care organizations should understand their patient demographics. Managed care organizations also need to consider a patient’s indirect costs.37 Policy makers need to be aware that in terms of time required to complete office visits, treating AMD is burdensome for patients and the ophthalmology staff. Office staff reports that patients with AMD consume 20% of their time. An average patient visit for nAMD is 90 minutes, but it can sometimes be as long as 4 hours. Patients report that the average visit takes about 12 hours from preparing to leave the home to post-appointment recovery, which can take up to 9 hours.38

Anti-VEGF drug costs for ophthalmologists can also be daunting, so managed care plans need to know how drug procurement is structured for practitioners. Ophthalmologists prefer to have biologics on hand because they do not know whether patients will need treatment until they examine the affected eyes.7 Patients who will have to pay for and maintain their own drug inventories may find it risky. A policy for determining how to deal with patients who cannot afford the 20% copayment is also a necessity, as ophthalmologists cannot be expected to absorb costs of $400 to $500 per treatment.37

Managed care organizations can address the costs associated with biologics for AMD in several ways. They may consider implementing or refusing to implement a white bagging process, a requirement that replaces buy-and-bill with purchasing the agents through a specialty pharmacy. They can make a case for payers to be compensated fairly for overhead costs that are typically 25% to 30% of average wholesale price. Large systems may find that developing their own specialty pharmacy or collaborating with other organizations may be cost-effective.7,39

Managed care organizations also need to be cognizant of early diagnosis and treatments that are essential. AMD can progress and cause vision loss rapidly, so even minor delays in treatment can have tremendous impacts on vision. For some patients, monthly office-based assessments will be insufficient.40 Implementing better screening programs, increasing public awareness, and treating aggressively are essential. Other factors can influence how patients respond to treatment and need to be considered when selecting treatment (see Table 25).

At a macroeconomic level, managed care plans should be forward-looking and estimate how they expect the number of patients with AMD to grow. There are other issues to consider, including6,37:

  • If the allowable reimbursement is less than the costs of the drug (a situation that occurs more often than is acceptable)
  • If rebates or purchasing discounts are available
  • State and local sale tax regulations on gross revenue or drug revenues
  • The number of intravitreal injections expected to be administered

Acknowledging that anti-VEGF biologic use is also expanding in diagnoses other than AMD (eg, diabetic retinopathy-associated macular edema and macular edema associated with retinal venous occlusive disease) is also prudent. If bevacizumab is used, the managed care organization should ensure that their compounding pharmacy is reliable, responsive, and trustworthy.6,37

Specialty Pharmacy’s Role

The specialty pharmacist’s role starts with appreciating the value of an early diagnosis and treatment. The National Health and Nutrition Examination Survey (NHANES) found that 84% of people with AMD were unaware of their condition.41 During contact with aging patients, specialty pharmacists can encourage eye examinations and educate patients about eye health. Patients can access exceptional information about AMD from the AAO and the American Society of Retina Specialists.42,43

Prevention and lifestyle modifications are basic interventions, and pharmacists should be aware of appropriate approaches and recommendations. Eight million Americans aged 55 years and older are at high risk for developing advanced AMD. Age-related eye disease study supplementation could help roughly 300,000 at-risk individuals avoid advanced AMD and associated vision loss over a 5-year period.42 Pharmacists must also promote educational campaigns and increase awareness about AMD risk factors including age, family history, cardiovascular risk factors, and cigarette smoking.5

Specialty pharmacists often provide anti-VEGF therapies and may have compounding roles in which they repackage products for single use. These tasks come with parallel responsibilities for monitoring potential systemic AEs and ensuring response and adherence.

Specialty pharmacists will continue to play a significant role in changing buy-and-bill models. A recent Kantar Health Payer Survey found that the percentage of payers encouraging the use of specialty pharmacies to manage physician-administered injectable agents (white bagging) grew from 29% in 2014 to 36% in 2016. The percentage of payers mandating the use of specialty pharmacies on certain drugs remained steady at 24% from 2014 to 2016. According to the study, 36% of payers encourage the purchase of physician-administered intravenous drugs through specialty pharmacies by creating favorable reimbursement policy (36% of payers).44 This allows payers to purchase drugs and biologics at a better price, shift coverage from medical to pharmacy benefit, and increase visibility in their drug spending.39

In 2017, The Lancet published a study conducted by a multinational vision loss expert group that updated statistics on vision loss.45 The report does not break down vision loss and legal blindness by cause, but it does deliver some good news. This group noted a reduction in the age-standardized prevalence of legal blindness and vision impairment in 2010, and the trend has continued. The authors cite research that indicates vision interventions. Intravitreal injections that have been available in the past 15 years provide some of the largest returns on investment.46 Managed care organizations, clinical staff, and affected patients need to embrace that fact.

Conclusions

Visual impairment and its associated costs affect not only patients but also caregivers, providers, and society. There are nonmedical costs to patients, such as the need for support services and assistive devices, and caregivers also incur substantial indirect costs that stem from lost productivity and income as a result of needing to assist patients with AMD with activities of daily living and attending appointments. To provide cost-effective treatments to patients with AMD, managed care professionals must consider that new treatment options are more cost-effective than older treatments. The surge in anti-VEGF utilization and Medicare-covered intravitreal injections has proven to enhance patients’ VRQOL, but they are accompanied by high direct costs. In several economic and cost-effectiveness analyses, bevacizumab for the treatment of AMD was proved to be less costly and more effective compared with ranibizumab. Further complicating treatment decisions are the OOP costs for patients, which differ based on patient demographics and a lack of specific guidelines. Despite the cost-effectiveness of bevacizumab, ranibizumab is more often preferred by clinicians in several geographic locations. Additionally, there are no existing policies that address challenges with elderly patients with AMD who are Medicare part B beneficiaries and cannot afford a 20% copayment after Medicare. As both the numbers of available treatment options for patients with AMD and the overall patient population continue to grow, managed care professionals must consider a multitude of factors that contribute to direct and indirect costs for these patients and society when initiating an appropriate, cost-effective therapy for a patient with AMD.&ensp;

Author affiliation: Vice President, Pharmacy Benefits, SelectHealth, Murray, UT.

Funding source: This activity is supported by an independent medical educational grant from Regeneron Pharmaceuticals, Inc.

Author disclosure: Dr Cannon has the following relevant financial relationships with commercial interests to disclose:

BOARD MEMBERSHIP: DUR Board State of Utah

EMPLOYMENT: SelectHealth / Intermountain Healthcare

Authorship information: Concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

Address correspondence to: eric.cannon@selecthealth.org.

Medical writing and editorial support: Jeannette Y. Wick, RPh, MBA, FASCP.

  1. Facts about age-related macular degeneration. National Eye Institute website. www.nei.nih.gov/health/maculardegen/armd_facts. Updated November 2018. Accessed April 7, 2019.
  2. Global data on visual impairments 2010. World Health Organization website. www.who.int/blindness/GLOBALDATAFINALforweb.pdf. Accessed April 7, 2019.
  3. Rein DB, Wittenborn JS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J; Vision Health Cost-Effectiveness Study Group. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol. 2009;127(4):533-540. doi: 10.1001/archophthalmol.2009.58.
  4. Age-related macular degeneration: facts & figures. Bright Focus Foundation website. www.brightfocus.org/macular/article/age-related-macular-facts-figures. Published January 5, 2016. Accessed April 6, 2019.
  5. Wykoff CC, Clark WL, Nielsen JS, Brill JV, Greene LS, Heggen CL. Optimizing anti-VEGF treatment outcomes for patients with neovascular age-related macular degeneration. J Manag Care Spec Pharm. 2018;24(2-a suppl):S3-S15. doi: 10.18553/jmcp.2018.24.2-a.s3.
  6. Williams GA. IVT injections: health policy implications. Rev Ophthalmol website. www.reviewofophthalmology.com/article/ivt-injections-health-policy-implications. Published June 5, 2014. Accessed May 17, 2019.
  7. House Energy & Commerce Subcommittee issues testimony from American Academy of Ophthalmology Targeted News Service; Washington, DC; January 30, 2018.
  8. Crews JE, Campbell VA. Vision impairment and hearing loss among community-dwelling older Americans: implications for health and functioning. Am J Public Health. 2004;94(5):823-829. doi: 10.2105/ajph.94.5.823.
  9. Köberlein J, Beifus K, Schaffert C, Finger RP. The economic burden of visual impairment and blindness: a systematic review. BMJ Open. 2013;3(11):e003471. doi: 10.1136/bmjopen-2013-003471.
  10. Rein DB, Zhang P, Wirth, KE, et al. The economic burden of major adult visual disorders in the United States. Arch Ophthalmol. 2006;124:1754-1760.
  11. Brown MM, Brown GC, Lieske HB, Tran I, Turpcu A, Colman S. Societal costs associated with neovascular age-related macular degeneration in the United States. Retina. 2016;36(2):285-298. doi: 10.1097/IAE.0000000000000717.
  12. Bakri SJ, Thorne JE, Ho AC, et al. Safety and efficacy of anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2019;126(1):55-63. doi: 10.1016/j.ophtha.2018.07.028.
  13. Mitchell P, Annemans L, White R, Gallagher M, Thomas S. Cost effectiveness of treatments for wet age-related macular degeneration. Pharmacoeconomics. 2011;29(2):107-131. doi: 10.2165/11585520-000000000-00000.
  14. Finger RP, Guymer RH, Gillies MC, Keeffe JE. The impact of anti-vascular endothelial growth factor treatment on quality of life in neovascular age-related macular degeneration. Ophthalmology. 2014;121(6):1246-1251. doi: 10.1016/j.ophtha.2013.12.032.
  15. Patel JJ, Mendes MA, Bounthavong M, Christopher ML, Boggie D, Morreale AP. Cost-utility analysis of bevacizumab versus ranibizumab in neovascular age-related macular degeneration using a Markov model. J Eval Clin Pract. 2012;18(2):247-255. doi: 10.1111/j.1365-2753.2010.01546.x.
  16. Stein JD, Newman-Casey PA, Kim DD, Nwanyanwu KH, Johnson MW, Hutton DW. Cost-effectiveness of various interventions for newly diagnosed diabetic macular edema. Ophthalmology. 2013;120(9):1835-1842. doi: 10.1016/j.ophtha.2013.02.002.
  17. Stein JD, Newman-Casey PA, Mrinalini T, Lee PP, Hutton DW. Cost-effectiveness of bevacizumab and ranibizumab for newly diagnosed neovascular macular degeneration. Ophthalmology. 2014;121(4):936-945. doi: 10.1016/j.ophtha.2013.10.037.
  18. Day S, Acquah K, Lee PP, Mruthyunjaya P, Sloan FA. Medicare costs for neovascular age-related macular degeneration, 1994-2007. Am J Ophthalmol. 2011;152(6):1014-1020. doi: 10.1016/j.ajo.2011.05.008.
  19. Gower EW, Stein JD, Shekhawat NS, Mikkilineni S, Blachley TS, Pajewski NM. Geographic and demographic variation in use of ranibizumab versus bevacizumab for neovascular age-related macular degeneration in the United States. Am J Ophthalmol. 2017;184:157-166. doi: 10.1016/j.ajo.2017.10.010.
  20. Rosenfeld PJ, Windsor MA, Feuer WJ, et al. Estimating Medicare and patient savings from the use of bevacizumab for the treatment of exudative age-related macular degeneration. Am J Ophthalmol. 2018;191:135-139. doi: 10.1016/j.ajo.2018.04.008.
  21. Trivizki O, Schwartz S, Negri N, Loewenstein A, Rabina G, Shulman S. Noninfectious inflammatory response following intravitreal bevacizumab injections: description of a cluster of cases in two centers and a review of the literature. Ophthalmologica. 2018;240(3):163-166. doi: 10.1159/000492681.
  22. Avery RL, Castellarin AA, Dhoot DS, et al. Large silicone droplets after intravitreal bevacizumab (Avastin). Retin Cases Brief Rep. 2019;13(2):130-134. doi: 10.1097/ICB.0000000000000570.
  23. Ricci F, Calabrese A, De Felici C, Missiroli F, Pileri M, Regine F. A cluster of presumed, noninfectious endophthalmitis after intravitreal injection of bevacizumab: long-term follow-up. Digit J Ophthalmol. 2016;22(2):41-45. doi: 10.5693/djo.01.2016.03.001.
  24. Mackey TK, Cuomo R, Guerra C, Liang BA. After counterfeit Avastin—what have we learned and what can be done? Nat Rev Clin Oncol. 2015;12(5):302-308. doi: 10.1038/nrclinonc.2015.35.
  25. Kuehn BM. FDA warning: new batch of fake bevacizumab found. JAMA. 2013;309(9):864. doi: 10.1001/jama.2013.1719.
  26. Sun X, Xu X, Zhang X. Counterfeit bevacizumab and endophthlamitis. N Engl J Med. 2011;365(4):378-379. doi: 10.1056/NEJMc1106415.
  27. VanderBeek BL, Bonaffini SG, Ma L. The association between compounding bevacizumab and post-injection endophthalmitis. JAMA Ophthalmol. 2015;133(10):1159-1164. doi: 10.1001/jamaophthalmol.2015.2556.
  28. Age-Related Macular Degeneration Preferred Practice Pattern—Updated 2015. American Academy of Ophthalmology website. aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-2015. Updated January 2015. Accessed March 27, 2019.
  29. Paul M, Vieillard V, Roumi E, et al. Long-term stability of bevacizumab repackaged in 1mL polypropylene syringes for intravitreal administration. Ann Pharm Fr. 2012;70(3):139-154. doi: 10.1016/j.pharma.2012.03.006.
  30. Khalili H, Sharma G, Froome A, Khaw PT, Brocchini S. Storage stability of bevacizumab in polycarbonate and polypropylene syringes. Eye (Lond). 2015;29(6):820-827. doi: 10.1038/eye.2015.28.
  31. Neumann PJ, Weinstein MC. Legislating against use of cost-effectiveness information. N Engl J Med. 2010;363(16):1495-1497. doi: 10.1056/NEJMp1007168.
  32. Dang A. Use of QALY in healthcare decision-making—the controversy continues. www.linkedin.com/pulse/use-qaly-healthcare-decision-making-controversy-continues-dang/. Published February 7, 2017. Accessed April 7, 2019.
  33. Raftery J, Clegg A, Jones J, Tan SC, Lotery A. Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness. Br J Ophthalmol. 2007;91(9):1244-1246. doi: 10.1136/bjo.2007.116616.
  34. Cohen D. CCGs win right to offer patients Avastin for wet AMD. BMJ. 2018;362:k4035. doi: 10.1136/bmj.k4035.
  35. van Asten F, Michels CTJ, Hoyng CB, et al. The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration—a cost-effectiveness analysis from a societal perspective. PLoS One. 2018;13(5):e0197670. doi: 10.1371/journal.pone.0197670.
  36. Li E, Greenberg PB, Voruganti I, Krzystolik MG. Cost and selection of ophthalmic anti-vascular endothelial growth factor agents. R I Med J (2013). 2016;99(5):15-17.
  37. Shah AR, Williams GA. Regulatory and economic considerations of retinal drugs. Dev Ophthalmol. 2016;55:376-380. doi: 10.1159/000438965.
  38. Prenner JL, Halperin LS, Rycroft C, Hogue S, Williams Liu Z, Seibert R. Disease burden in the treatment of age-related macular degeneration: findings from a time-and-motion study. Am J Ophthalmol. 2015;160(4):725-731.e1. doi: 10.1016/j.ajo.2015.06.023.
  39. Fuller D. How to tackle the white bagging trend. Advisory Board website. www.advisory.com/Research/Oncology-Roundtable/Oncology-Rounds/2013/12/How-to-tackle-the-white-bagging-trend. Published December 20, 2013. Accessed April 6, 2019.
  40. Schwartz R, Loewenstein A. Early detection of age related macular degeneration: current status. Int J Retina Vitreous. 2015;1:20. doi: 10.1186/s40942-015-0022-7.
  41. Gibson DM. Diabetic retinopathy and age-related macular degeneration in the U.S. Am J Prev Med. 2012;43(1):48-54. doi: 10.1016/j.amepre.2012.02.028.
  42. EyeSmart. American Academy of Ophthalmology website. www.aao.org/eye-health. Accessed April 6, 2019.
  43. Saving vision. American Society of Retina Specialists website. www.asrs.org/patients. Accessed April 6, 2019.
  44. Basta N, Shellet S. The SP channel continues to grow, with manufacturers looking for more control over access. Pharmaceutical Commerce website. pharmaceuticalcommerce.com/business-and-finance/specialty-pharmacy-dynamics/. Published May 9, 2016. Accessed April 6, 2019.
  45. Bourne RRA, Flaxman SR, Braithwaite T, et al; Vision Loss Expert Group. Magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis. Lancet Glob Health. 2017;5(9):e888-e897. doi: 10.1016/S2214-109X(17)30293-0.
  46. Brown MM, Brown GC, Lieske HB, Lieske PA. Financial return-on-investment of ophthalmic interventions: a new paradigm. Curr Opin Ophthalmol. 2014;25(3):171-176. doi: 10.1097/ICU.0000000000000040.