Supplements and Featured Publications
Improving Treatment Strategies for Wet Age-Related Macular Degeneration
Volume 26
Issue 5

Managed Care Opportunities and Approaches to Select Treatment for Sight Preservation

Neovascular (or wet) age-related macular degeneration (AMD) affects more than 10% of people older than 65 years in North America, Europe, Australia, and Asia. It is estimated that about 11 million Americans have some form of AMD, with that number expected to double by 2050. Approximately 20% of patients will advance from a nonneovascular form of the disease to neovascular AMD, which is associated with central visual acuity loss that can result in severe visual impairment and blindness. Improvements in vision preservation and quality of life require regular clinical visits for intravitreal therapy, which, while effective, come at high cost and potential financial strain, often complicated by the fact that most patients with the disease will be covered by Medicare and subject to the regulations and restrictions within their insurance plans. The requirement for frequent treatment also threatens adherence to therapy, and many patients do not follow up clinically as advised. The confluence of high-cost drug therapy and growing demand for treatment of a sight-threatening disease creates a mandate that managed care professionals and payers focus on current and emerging management options in neovascular AMD and on how to administer therapies in both a clinically responsible and cost-effective manner to diminish risk of vision loss and improve overall patient outcomes.

Am J Manag Care. 2020;26:S112-S117. Burden of AMD

Impact on Patient Quality of Life

As a patient’s visual function deteriorates with progressive AMD, their quality of life (QOL) also declines in a parallel fashion.1-3 Decrements in QOL associated with visual disability in neovascular AMD can be as severe as seen in other diseases, such as renal failure or stroke.4 In an early study, the degree of vision loss in patients with AMD was quantified and correlated with their decline in QOL. A mild visual acuity deficit was associated with a 17% decline in QOL. A moderate visual acuity deficit was associated with a 32% decline in QOL, similar to that seen with severe angina or a hip fracture. Patients with severe visual acuity deficit experienced a 53% decline in QOL, more than that seen in patients undergoing hemodialysis. Very severe loss of vision correlated to a 60% decline in QOL, similar to that seen in patients with end-stage prostate cancer or a catastrophic stroke that had left them bedridden and needing continual medical care. Importantly, patients with varying degrees of disease severity were found to experience QOL impairment that ranged from 96% to 750% greater than the damage estimated by the ophthalmologists treating their AMD.1,5 Loss of visual acuity also increases the risk of falls and subsequent injury. With increasing loss of visual function, activities of daily living, including basic activities like meal preparation, grocery shopping, and out-of-home travel, may be markedly negatively impacted.3,6 Diminished ability to perform activities of daily living and the number of relinquished activities related to AMD progression have been linked to impairment in cognitive functioning.3,6,7 One in 7 patients with AMD has demonstrated cognitive decline. Following severe central vision loss, depression and visual hallucinations (Charles Bonnet syndrome) can occur.8 Patients with AMD have also demonstrated increased risk for depression versus patients without the disease. One study found that 44.4% of patients with AMD had clinically significant depressive symptoms and that AMD was independently associated with depressive symptoms that both directly and indirectly reduced general health and social functioning.3,9 Results of a more recent study showed a 24% prevalence of depression among patients with AMD, with the odds of a patient having depression or anxiety 1.3 times higher than patients without AMD.10

Patient-Centered Outcomes in AMD

In terms of treatment and AMD management, the outcomes that patients with AMD value most must be taken into consideration to improve their overall QOL and functioning. Results of data gathered by the Angiogenesis Foundation showed that the following treatment outcomes were most valued by patients with neovascular AMD5:

  • Interpersonal relationships: Loss of vision compromises and changes a patient’s relationships with family and friends.
  • Identity and independence: Patients with neovascular AMD often state that the disease has cost them their identity and sense of purpose.
  • Safety: With diminishing vision, personal safety becomes more problematic.
  • Financial stability: Vision loss associated with neovascular AMD may lead to a significant decline in a patient’s economic resources.
  • Measuring functional vision in terms of QOL: Patients want to mainly retain 3 vision-related functions: reading comprehension, depth perception, and facial recognition. Actual data on patient-reported outcomes vary, including the types of analysis and scoring used in individual studies; however, patient-reported outcome measures (PROMs) are being increasingly emphasized in clinical research. One recent study by Jelin et al explored outcomes in self-reported visual function, symptom status, general health, and satisfaction of treatment in patients with neovascular AMD. Results indicated that both self-reported visual function and symptom state significantly improved following 12 months of intravitreal anti-vascular endothelial growth factor (VEGF) treatment, with treatment including better-seeing eye and best-corrected visual acuity of the treated eye as main predictors of outcome. Overall, increased use of PROM tools in the future as part of a multimodal approach to neovascular AMD management could potentially improve understanding of how the disease and related therapy actually affect patients, and it could also reinforce a focus on patient-centered care.11

Compliance and Adherence to Therapy

Another conundrum that clinicians often face in optimal management of patients with neovascular AMD is limited compliance and adherence to prescribed therapy. Data have borne out the negative impact of noncompliance and nonadherence. One study assessing factors influencing compliance with therapy followed patients receiving anti-VEGF injections, in whom treatment consisting of 3 consecutive monthly injections with monthly follow-up thereafter. At 1 year, 39.8% of the patients who completed therapy were found to be unable to fully comply with the pro re nata (PRN; as needed) regimen. Key factors associated with increased compliance included better visual acuity at baseline, smaller lesion size, living closer to the treatment location, higher education and sociocultural status, and greater financial status. The most frequent reasons cited by patients for discontinuing therapy were fear of injection, lack of belief in treatment effectiveness, financial limitations, switching to another site for treatment, and comorbidities beyond AMD.12 Results of data from patient/caregiver surveys performed by the Angiogenesis Foundation showed that despite long-term studies indicating that regular monthly or every-other-month treatments lead to best outcomes, more than 20% of patients were getting injections fewer than 6 times annually. In addition, 34% admitted to missing an injection, and among those patients, 23% lost vision.5 Another study by Obeid et al assessed 9007 patients treated for neovascular AMD from 2012 to 2016 in a multistate US practice for loss to follow-up (LTFU). Using an LTFU criterion of a patient having no follow-up within 1 year after at least a single anti-VEGF injection, results demonstrated that 2003 (22.2%) of the patients studied had at least 1 LTFU episode. Factors associated with LTFU included older age, lower regional adjusted gross income, longer distance to the therapy site, and requiring injections in just 1 eye. There were also racial and ethnic differences cited, including higher LTFU rates in both Asian and African American patients.13,14 These findings emphasize the need for clinicians to pay greater attention to the patient to better understand the complicated dimensions of each individual who needs therapy, to explain the seriousness of the disease as clearly as possible, to identify barriers to seeking care, and to motivate patients to follow up appropriately.14

Economic Impact of AMD

Direct and Indirect Medical Costs

The ultimate cost associated with AMD and other optical diseases is visual impairment. This impairment negatively impacts the patient with the disease as well as caregivers and society as a whole. In addition to the clinical consequences, the economic consequences of visual impairment can be substantial.15 An assessment by Köberlein et al of 22 interventional, noninterventional, and cost-of-illness studies was performed to quantify the direct costs, indirect costs, and intangible effects associated with both visual impairment and legal blindness. Data were obtained from studies performed within the United States and other countries, including Canada, Australia, France, Germany, and the United Kingdom. Results demonstrated that hospitalization, medical services surrounding the visual impairment diagnosis, and therapy were the primary drivers of direct medical costs. Assistive devices and aids, necessary home modifications, and other services, including in-home nursing or assisted living/nursing home placement, were the main factors for direct nonmedical costs. Overall costs for support services and assistive devices increased as a patient’s vision deteriorated. The mean annual expenses per patient identified in terms of US purchasing power parities ranged from $12,175 to $14,029 for patients with moderate visual impairment; $13,154 to $16,321 for those with severe visual impairment; and $14,882 to $24,180 for blindness, which was almost twice that seen for nonblind patients. Caregiver hours and effort correlated to the degree of visual impairment. Caregiver time 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 patients with more severe visual impairment (visual acuity of 20/250 or worse).15,16

Impact on Medicare Spending

Costs associated with neovascular AMD are greater than those seen with earlier disease stages (ie, dry AMD). A study of Medicare data used to assess the costs of disease progression to neovascular AMD found that total costs for these patients were approximately double that of controls and also 30% higher than costs for patients with dry AMD. Over a 10-year period, average annual Medicare expenditures increased from $11,265 to $24,494 for patients without progressive disease versus $11,712 to $34,308 for those whose disease had progressed. When ophthalmic expenditures were taken into account, costs for those with neovascular AMD were found to be at least 5-fold higher than for those with dry AMD (range of 4.5 to 9 times higher).17,18 Any discussion about the cost of care essentially revolves around Medicare because of the age demographic for neovascular AMD and the fact that Medicare is the primary payer for anti-VEGF therapy.15 A pivotal study by Day et al assessed a sample of Medicare beneficiaries in 1994, 2000, and 2006 with new diagnoses of neovascular AMD. First-year healthcare and eye care costs were calculated for each beneficiary in the 5% sample. The number of beneficiaries with newly diagnosed neovascular AMD was 2 times higher in 2006 compared with 1994. Overall, yearly Part B payments per beneficiary showed a substantial increase from $3567 for the 1994 group to $5991 for the 2006 group, measured in constant 2008 dollars. Eye care payments alone more than doubled from $1504 in 1994 to $3263 for patients in 2006. It is critical to note that the increase in payments for eye care in 2006 strongly reflected payments for anti-VEGF injections, which were estimated at $1609 over a 1-year period. In addition, the mean annual numbers of both clinical visits and imaging studies were also found to increase considerably between the 1994 and 2006 cohort. Overall, the development of anti-VEGF therapies provided important clinical benefits for patients with neovascular AMD; however, these benefits must be weighed along with the significantly increased costs of providing care for these patients.19 Data highlight how much the use of anti-VEGF agents has grown over the past 2 decades, with Medicare payments for physician services associated with the administration of anti-angiogenic drugs. Physicians reported 3000 Medicare-covered intravitreal injections in 2000. By 2008, this number had grown to 1 million, and, in 2013, Medicare paid for 2.5 million intravitreal injections. The cost for these injections was estimated at more than $300 million.15,20

Patient Out-of-Pocket Cost Issues

Most patients with neovascular AMD are 65 years and older and are Medicare beneficiaries who must cover 20% of allowable reimbursement for anti-VEGF therapy and associated physician administration charges out-of-pocket (OOP). Aside from circumstances when the agent bevacizumab is used, OOP expenses can be considerable and can accumulate quickly for patients with neovascular AMD. With such a heavy cost impact, managed care professionals and payers must become better aware of the demographics surrounding patients with neovascular AMD who are covered by their organization.15

Cost Efficacy of Anti-VEGF Strategies

Although the main focus of clinicians is to provide optimal care to maximize clinical outcomes, these outcomes must also be balanced with the cost of care. Payers are responsible both for providing access to high-quality healthcare services and for controlling costs. In doing so, they encounter 2 main barriers to healthcare management. First, they are not always familiar with the scoring metrics used in clinical trials to measure disease activity or progress. Second, it can be a challenge for payers to apply clinical trial data to real-world patient populations, because the inclusion criteria for a trial frequently do not match or correlate to real-world patient populations and clinical practice.21

Treatment Option Costs

Of significant importance now in real-time clinical practice is that CMS announced that Medicare Advantage (MA) plans would be able to apply step therapy for physician-administered agents and other Medicare Part B drugs as of January 1, 2019.22 Step therapy mandates that more cost-effective therapies be used initially before more-expensive alternative agents in a stepwise fashion. Failure of the less expensive drug must occur before the patient can be switched to a more expensive option.23 This policy change has raised concern among clinicians, especially retina specialists, about potential delayed access to more-expensive anti-VEGF agents for patients with neovascular AMD that could result in sight-threatening outcomes. In the setting of MA plans, concerns center on what exactly will constitute a treatment failure for a particular plan.24

Because of the importance of cost containment and these new Medicare factors, clinicians must pay greater attention to both the cost and overall value of anti-VEGF options for neovascular AMD. The AMD treatment market was estimated to be $7.1 billion in 2017, likely increasing to $11.1 billion by 2023.25 Managed care professionals and payers should estimate how the increasing numbers of patients with AMD will impact their organizations. Additional issues that organizations must take into consideration include allowable reimbursement versus acquisition cost, drug rebates and purchasing discounts, taxes on gross or drug revenue, and the expected growth in intravitreal injections that will likely occur as the population with AMD ages and grows.15

Currently, there are 3 FDA-approved anti-VEGF agents for treatment of neovascular AMD. These include previously approved aflibercept and ranibizumab, which are now joined by brolucizumab, approved in October 2019.15,26 In addition, bevacizumab is frequently used off-label for therapy in these patients despite its lack of FDA approval for this indication; however, a recent report from the American Academy of Ophthalmology noted that there are now data from prospective, randomized trials that demonstrate the noninferiority of bevacizumab to FDA-approved ranibizumab.27,28 Annual American Society of Retina Specialists survey responses provide insight into how retina specialists view anti-VEGF agents with respect to costs. In 2018, the anti-VEGF drug for neovascular AMD used most often in the first-line setting was bevacizumab (70%), followed by aflibercept (16%) and ranibizumab (13%).29 In 2019, when asked which anti-VEGF drug they would primarily use for new-onset neovascular AMD if cost were not a factor, they listed aflibercept (78%), followed by ranibizumab (14%) and bevacizumab (8%).30 Formulary selection and management of anti-VEGF agents is a critical factor in patient management, but managed care professionals and payers have been given minimal guidance from professional organizations on how to incorporate cost into these processes to help determine optimal treatment strategies.15 A key issue in the treatment of neovascular AMD is that although bevacizumab does not carry an FDA-approved indication for AMD therapy, it is the least costly option for treatment. Between 2008 and 2015, the use of bevacizumab over other agents is estimated to have saved Medicare at least $17.3 billion, corresponding to a $13.8 billion savings to Medicare and a $3.5 billion savings to patients.31 When evaluating treatment options, decision makers need to take real-world evidence into consideration. In a retrospective analysis of MarketScan Research Databases, the frequency and cost of ranibizumab and aflibercept injections were generally comparable in neovascular AMD. In treatment-naïve patients with neovascular AMD, per-patient injection frequency and cost were not significantly different between those who received ranibizumab versus aflibercept over 12 months (5.62 vs 5.54; P = .52, and $11,351 vs $10,702; P = .06, respectively) and 24 months (7.86 vs 8.37; P = .16, and $16,286 vs $16,666; P = .69, respectively).32 In previously treated patients with neovascular AMD, there was no significant difference in injection frequency (5.95 vs 6.09, P = .56) or treatment cost between ranibizumab and aflibercept over 12 months. At 24 months, injection frequency was significantly lower among ranibizumab- versus aflibercept-treated patients (7.98 vs 9.63; P = .03); however, treatment costs were comparable ($16,303 vs $19,361; P = .13).32

In a retrospective database analysis of 49,485 eyes, researchers found that patients with neovascular AMD receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients receiving fixed, frequent therapy in randomized controlled trials.33 This study demonstrates the gap between administration in practice compared with administration in a controlled trial setting. Although patients in clinical trials receive fixed, frequent therapy, in real-world practice, patients will have less than ideal adherence. This highlights the need for a clinically effective regimen with a lower injection burden.

Horner et al reported the long-term effectiveness of a PRN ranibizumab protocol in patients with neovascular AMD. Researchers examined 95 eyes from 86 patients who completed 8 years of follow-up in a single treatment center. At year 8, 47.4% had stable or improved vision; 10.5% gained greater than or equal to 15 letters; and 33.7% lost 15 or more letters. The median injection frequency was 6 in year 1 and 3 injections in year 8. The mean number of total injections per eye over 8 years was 31.6.34

Future Therapy: Biosimilar Options

The situation is further complicated by the fact that biosimilars for bevacizumab are in continual development, with the first one approved for use in July 2019; however, the degree to which these will be repackaged for intravitreal administration by compounding facilities has yet to be elucidated.35,36 In addition, biosimilar versions of aflibercept and ranibizumab are also undergoing study.35 The actual effect of the entrance into the market of biosimilar options for treatment of neovascular AMD remains unclear at this time. However, because Medicare shoulders the burden of paying for neovascular AMD care, managed care professionals and payers should pay close attention to Medicare policies affecting biologics and biosimilar reimbursement. Medicare payment for biologics is based on the agent’s average sales price, net rebates, and other discounts, plus a fixed percentage. A smaller mark-up can penalize prescribers who pick a lower-cost drug. To remedy the disincentive to prescribe a lower-cost biosimilar, Medicare biosimilars payment includes a fixed percentage based on the reference biologic. Medicare has also implemented a new biosimilar payment policy that pays a blended average sales price for all biosimilars of a reference biologic drug, plus the fixed percentage of the reference biologic.37

Managed Care Issues and Strategies to Optimize Patient Outcomes

Collaboration With Retina Specialists and the Importance of Formulary Options

Retina specialists are seeing increasing numbers of patients with neovascular AMD, and specialty practice is complicated by the fact that they place a high value on having access to all available anti-VEGF treatment options in order to individualize care for all patients, especially those considered difficult to treat. Because of this, a comprehensive anti-VEGF agent inventory in ophthalmology practices is a critical consideration along with drug efficacy and cost-effectiveness. The proportion of practice time devoted to patients with AMD is also an important factor in patient management. A time-motion study estimated that caring for patients with AMD consumes 20% of ophthalmology practice office time. An office visit for an intravitreal injection can take anywhere from 1.5 to 4 hours. Patient burden surrounding therapy must also be considered. Patients have reported that the average therapy visit can encompass as much as 12 hours, from preparing to leave home to individual postinjection recovery, which can take as long as 9 hours.3,15 Managed care providers and payers must keep these additional factors in mind and optimize communication with retina specialists to provide the most clinically effective and cost-effective treatment strategies, along with safe and efficient drug administration and patient care.

The dilemma that managed care organizations face with respect to the anti-VEGF agents is cost. Managed care organizations are charged with walking the fine line of controlling cost while providing access to quality healthcare services. Relatively speaking, the cost of the FDA-approved anti-VEGF agents can be much costlier than the off-label anti-VEGF agents that many retina specialists consider as first-line therapy in neovascular AMD.

The difficulties associated with this situation are many. Typically, managed care organizations do not provide coverage for off-label indications, unless the off-label use is documented in the medical compendia to be adopted as a standard of care. As a specialty, retina specialists have not endorsed the use of the off-label anti-VEGF agent. The regimens being utilized today by retina specialists are in a constant flux ranging anywhere from changes in treatment duration, treatment frequency, or even the new concept of treat and extend. Changes in the treatment regimen will change the cost of the regimen. As the regimen is modified, cost-effectiveness evaluations will also change.

Finally, with respect to clinical outcomes, based on the clinical trials, anti-VEGF treatments may be viewed as similar. Evaluation of a clinical outcome is difficult due to the lack of any standardized accepted metric to measure outcomes and benefit. Any differences in clinical outcomes due to differences in the patient populations or differences in the treatment regimen, by whatever means to measure, will most likely need to be evaluated further in real-world data and experience.

The treatment of neovascular AMD is likely not a high priority for managed care organizations today, given the higher cost of medications in other specialty areas. As such, managed care organizations are not familiar with subtle intricacies or clinical justification that would drive a specific anti-VEGF selection. Managed care organizations will use treatment guidelines, recommendations, or consensus that will help define the treatment options and process, as well as utilize key opinion leaders in their networks to help define the treatment selection process. It is incumbent upon the retina specialists to work with their managed care organizations to educate them on specific intricacies in the treatment selection process, as well as on any differences in clinical outcomes resulting from these intricacies, using real-world data and evidence. Such open dialogue between specialists and payers will lead to a greater appreciation of management expectations, as well as to minimization of barriers to the prior authorization/precertification criteria.

The Role of Specialty Pharmacies

The specialty drug market continues to grow at double-digit rates, and the specialty pharmacy provider market is also growing in tandem. Specialty pharmacies play a critical role in the provision of anti-VEGF therapies, including repackaging products for single use. These specialists are also keenly aware of potential adverse effects associated with individual therapies and can assist in patient surveillance and monitoring. In a recent Kantar Health Payer Survey, the proportion of payers encouraging the use of specialty pharmacies to manage physician-administered injectable agents grew from 29% in 2014 to 36% in 2016. A total of 24% of payers mandated the use of specialty pharmacies for certain drugs during this period. In addition, 36% of payers encouraged the purchase of physician-administered intravenous drugs through specialty pharmacies via the development of more favorable reimbursement policies for these therapies.15,38

As new products for treatment of neovascular AMD with different mechanisms of action are being developed and marketed, clinicians are likely to use both new options and potential combination therapy to obtain better efficacy and longer-lasting results. Therapy selection and costs will evolve over time with an increase in the use of emerging agents and multiple products. Switching between products after less-than-optimal results will likely become more common.39 There remains a need to consolidate and define parameters for switching opportunities, and further insight into the mechanisms of anti-VEGF resistance is also needed to guide treatment decisions on when and how to switch.40 Managed care professionals and payers, retina specialists, and specialty pharmacists must collaborate to evaluate pipeline agents and new regimens, and to select the best treatment options for individual patients.


Neovascular AMD is a severe ophthalmic disease than can seriously and negatively impact an affected patient’s health and functioning with progressive vision loss and even eventual blindness. The development and emergence of anti-VEGF therapies for neovascular AMD has significantly altered the treatment and patient management landscape, bringing great benefit by preserving vision in those with the disease. However, both the disease burden and the costs of its therapies can have a substantial financial impact on patients. The costs of healthcare are further complicated by the fact that most patients with neovascular AMD are covered by Medicare and thus affected by the accompanying regulations and restrictions placed on their therapy. The quest to determine the most cost-effective and valuable treatment strategies for neovascular AMD continues to be an important focus of patient management. Collaborating together, managed care professionals, retina specialists, and specialty pharmacists all play key roles in working with patients with neovascular AMD, including addressing the costs associated with the disease and its treatment. With their input and collaboration, therapy and overall management of patients with AMD can be optimized to reduce disease progression and improve overall outcomes.

Author affiliation: Winston Wong, PharmD, is president of the W-Squared Group, Longboat Key, FL.

Funding source: This activity is supported by an educational grant from Genentech.

Author disclosure: Dr Wong has no relevant financial relationships with commercial interests to disclose.

Authorship information: Substantial contributions to the intellectual content, including concept and design, critical revision of the manuscript, supervision.

Address correspondence to:

Medical writing and editorial support: Elizabeth Paczolt, MD, FACNM.

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