Anti-vascular endothelial growth factor therapies have become the mainstay of treatment for both diabetic macular edema and neovascular age-related macular degeneration. This treatment is imperative for vision preservation including visual acuity. However, treatment burdens include high costs, frequent injections, continued visual loss, and loss of ability to perform day-to-day functions. Although clinical trial data have provided insights to treatment options and protocols, real-world patient experiences and adherence to therapies do not often mimic clinical trials as patients cannot fully adhere to their treatment schedule, leading to poor disease outcomes. Payers may consider various strategies such as step therapies, fee schedule management, and driving utilization through specialty pharmacies to contain costs. However, it is important to recognize not all patients will respond to a one-size-fits-all approach to treatment, warranting a more personalized approach.
Am J Manag Care. 2022;28(suppl 3):S44-S51. https://doi.org/10.37765/ajmc.2022.88854
Background and Prevalence
Intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment has provided patients with ocular diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) with a chance to improve vision and quality of life.1 Although there have been advances in treatment, these diseases continue to be a major cause of vision loss despite use of anti-VEGF therapy worldwide.1 AMD is the leading cause of legal blindness and visual impairment in the world and is the leading cause of vision loss for Americans 60 years or older. The risk of developing AMD in people aged 50 to 59 years is about 2% and increases to almost 30% for people older than 75 years. An estimated 11 million people are living in the United States with some form of AMD. The number is expected to increase to 22 million by the year 2050.2 Globally, the projected number of people with AMD is expected to be 288 million in 2040.3 Currently, about 10% of patients have nAMD.2 Diabetic retinopathy (DR), the leading cause of blindness among working-age adults, affects approximately 93 million individuals worldwide with approximately 21 million experiencing DME, a severe form of DR.4,5 These numbers globally and in the United States are expected to grow as a result of increasing prevalence of diabetes.6 A study by Saaddine et al projected that by the year 2050, the number of Americans 40 years or older with vision-threatening DR would increase to 3.4 million.7
Burden of Disease and Treatment
Costs due to visual impairment affect not only patients but also caregivers, providers, and society. Some of these nonmedical costs include support services, home modifications, assistive devices, and caregivers to assist with activities of daily living. Indirect costs such as lost productivity and income also cause significant burden to patients and caregivers alike.2 Furthermore, data suggest patients and caregivers in addition to healthcare professionals are negatively affected by the treatment burden of anti-VEGF frequent injections, office visits, and patient monitoring. Patients may experience poorer outcomes by not receiving the proper number of intravitreal injections required to properly maintain their vision and anatomic benefits observed in clinical trials.1
For patients with AMD, as visual function deteriorates and progresses, their quality of life (QOL) also declines. Patients with severe disease experience a 53% decline in QOL. Additionally, loss of one’s visual acuity (VA) also increases risk of falls and associated injury. As vision loss progresses, so do loss of function and ability to complete activities of daily living, such as grocery shopping, meal preparation, and out of home travel. Cognitive decline is also affected by 1 in 7 patients. Vision loss associated with AMD can also increase risk of comorbid conditions, such as depression. One study found 44.4% of patients with AMD had clinically significant depression symptoms resulting in loss of social functioning.8
One study aimed to evaluate the psychosocial impact of repeated intravitreal injections for patients with nAMD. Forty patients were included to take part in the survey using the Macular Disease Treatment Satisfaction Questionnaire and underwent private interviews. Results reveal patients understood the importance of treatment for preservation of eyesight but experienced psychosocial and practical burdens from frequency of treatment schedules. Burdens include treatment-related anxiety, financial impact, and transport burden for patients and caregivers. Posttreatment, patients were limited to sedentary activities due to medication adverse effects (AEs). Patients reported that to prioritize treatment, which was driven by fear of losing their eyesight, they often sacrificed family, travel, and social commitments.9
Another study aimed to quantify the burden and QOL of patients and caregivers in a cohort of patients with nAMD in an Australian setting. A total of 103 patients undergoing anti-VEGF therapy for nAMD who were included in the study completed questionnaires relating to financial and time burdens of their disease. Results showed that loss of productivity due to having to take time off to attend appointments were 4.4 plus or minus 1.7 hours per month, with additional time loss of caregivers.10 There is a new report adding to the literature from the Macular Society that reveals patients with AMD experience a high burden of treatment including high levels of anxiety. More than half (55%) of the 456 respondents admitted to feeling anxious “always” or “some of the time” before their appointments, regardless of treatment length. This goes against the thought that patients become less anxious the longer they receive treatment. One patient reported they “worry about the future” and “losing more and more of my vision” during each visit. Two-thirds of respondents said they rely on family and friends to transport them to and from appointments, averaging a time commitment between 1 and 3 hours for each visit.11
Similarly to studies in nAMD, DME also has a negative effect on QOL. A cross-sectional study of 148 patients with DR and 149 patients without DR aimed to assess the effect DR has on QOL. QOL was assessed using the Audit of Diabetes-Dependent Quality of Life (ADDQoL) questionnaire. Results showed that DR was associated with significantly lower QOL (P <.001) and greatly affected by the severity of DR.12
A cross-sectional, prevalence-based healthcare economic survey assessed the annual, incremental, and societal costs associated with nAMD compared with a control cohort. They included direct ophthalmic and nonophthalmic medical costs as well as direct and indirect nonmedical costs associated with nAMD. Patients in the control cohort incurred an average of $6116 in expenses, whereas those with AMD incurred an average of $39,910. This population was mostly composed of patients with Medicare insurance (95%).13 Another study of 6076 patients with commercial insurance found that the mean standard deviation (SD) annual total all-cause cost for patients with nAMD was $24,520 ($43,950). This cost was largely driven by outpatient costs.14
A retrospective study evaluating claims data for 466,251 employees found that direct medical costs for commercial drivers with DR and DME were $8021 and $6470, respectively. The direct medical costs for nondrivers with DR and DME were $19,280 and $17,433, respectively. Additionally, this study found that absenteeism was highest in the DME subgroups for both drivers (27.0 days) and nondrivers (13.8 days).15 Another study analyzed claims data for 44,403 patients with diabetes from 17 large companies. They compared direct and indirect costs for patients with and without DR over a 5-year period. Employees with DR had higher mean annual costs ($18,218) compared with the control group ($11,898) with medical services and prescriptions accounting for 77.2% and 22.8% of the direct costs, respectively. A subgroup analysis demonstrated that mean costs for patients with DME were 74.8% higher than patients without DME with approximately 20% of those costs being indirect costs.16
A comprehensive societal cost-benefit analysis of anti-VEGF therapy for nAMD in the United States was performed by the Center for Value-Based Medicine using published trial and Medicare data that included 168,400 patients with new-onset nAMD. The analysis compared intravitreal bevacizumab, ranibizumab, and aflibercept monotherapies. The cost-benefit analysis used 2018 US real dollars. The main outcome measure was 11-year direct ophthalmic medical costs expended for bevacizumab, ranibizumab, and aflibercept monotherapies comparing ophthalmic and other direct and indirect (productivity) costs saved by therapies. Results revealed bevacizumab monotherapy has an individual 11-year $14,772 treatment cost and net $357,680 societal return (11-year 2421% return on investment [ROI]). Ranibizumab therapy cost $106,582 and returned $265,870 to society (249% ROI) whereas aflibercept treatment cost $61,811 and returned $310,611 to society (503% ROI). The authors concluded that substituting bevacizumab for ranibizumab and aflibercept for patients with newly diagnosed nAMD would save an estimated $1.343 billion over 11 years. This analysis revealed the considerable financial benefit to patients and payers with the use of anti-VEGF therapies.17
Another study also aimed to estimate the economic value and cost-benefit for patients with AMD, as well as societal value generated from visual improvements with anti-VEGF therapy. Data were collected between March 2018 and November 2018 and included 168,820 patients with AMD aged 65 years or older. Two current treatment scenarios were considered in the analysis: less frequent injections (mean [SD], 8.2 [1.6] injections annually) and more frequent injections (mean [range], 10.5 [6.8-13.1] injections annually). Results of the study showed that the less frequent injection scenario generated $1.1 billion in patient benefits for the full population in year 1 and $5.1 billion of benefits in year 3, whereas more frequent injections generated $1.6 billion in benefits in year 1 and $8.1 billion in benefits in year 3 (see Figure18). In the single ingredient cohort, total costs were $1.7 billion in 3 years for less frequent injections compared with $2.2 billion in total costs incurred in the more frequent injection scenario. At the population level, 3-year total costs were $4.3 billion for less frequent injections and $5.2 billion for more frequent injections. This study’s findings suggest that increased number of injections may improve VA with anti-VEGF therapies leading to added value; therefore, future treatment innovations aimed to increase adherence could potentially generate an increased economic benefit for patients and society.18
Results of FDA trials with fixed dosing anti-VEGF therapy have shown gains of roughly 2 lines (10 letters) at 1 year. However, clinical trial protocols and results can be difficult to replicate in real-world settings.19 Real-world patients may differ from those selected for clinical trials and may present with more advanced disease with poor VA or may present with visual findings that may have been excluded in trials (eg, retinal pigment epithelial tears, eccentric non-foveal choroidal neovascularization, large subretinal hemorrhages). They may also not be able to make office visits due to debilitating medical and/or social issues.20
A real-world, retrospective analysis aimed to assess anti-VEGF therapy intensity and its relationship on VA changes in patients with nAMD using medication records of a diverse sample of patients. The main outcome measure was mean VA change assessed at 1 year and stratified based on number of anti-VEGF injections received over 1 year. The analysis included 49,485 eyes; the mean age was 80.9 years, and the mean baseline VA was 53.8 letters. At 1 year, after a mean of 7.3 anti-VEGF injections, the mean gain in VA was 1 letter (0.95 letter; 95% CI for change in VA, +0.77 to +1.13 letter; P <.001). There was a direct linear relationship between mean letters gained and mean number of injections (between 4 and 10) over 1 year, with 4 or fewer or 10 or more injections associated with loss of vision or a plateau, respectively. This real-world study concluded that those patients with nAMD who received fewer anti-VEGF injections experienced poorer visual outcomes compared with patients receiving more frequent therapy similar to those included in clinical trials. Older patients or those with poor baseline VA may be at greater risk of undertreatment. The exact reason why these patients opted to receive fewer treatments is unknown, but ironically, patients with poor baseline VA have the most to gain from a more intense therapy, as these patients generally gain more vision than patients with better baseline VA.21
Another study aimed to characterize real-world baseline VA and anti-VEGF treatment patterns in patients with nAMD between 2012 and 2015. This retrospective, multicenter study included 98,821 eyes from 79,885 patients. Baseline characteristics were comparable across years. Baseline VAs (mean SD) were similar for 2012, 2013, and 2014 (53.6 ± 23.3, 53.2 ± 23.4, and 53.1 ± 23.6, respectively), but was lower for 2015 (50.7 ± 24.4). For patients that completed a 4-year follow-up, both VA and anti-VEGF injection frequency decreased; 36.7% of eyes had less than or equal to 8-week dosing intervals and 21.2% had greater than or equal to 12-week dosing intervals. Dosing frequency increases may be a result of treatment intensification and disease progression.22
An analysis by Kiss et al aimed to compare the real-world frequency and cost of ranibizumab and aflibercept injections among treatment-naïve and previously treated patients with nAMD and DME. Evidence suggests that in practices outside the clinical trial setting, specialists are more likely to use a “treat-and-observe” protocol; therefore, the real-world frequencies are similar between ranibizumab and aflibercept and lower than labeled dosing schedules. The study found that after adjusting for demographics and clinical characteristics, per-patient injection frequencies and costs were not significantly different between treatment-naïve patients with nAMD 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). In treatment-naive patients with DME, ranibizumab was associated with significantly fewer injections and lower costs than aflibercept over 6 months (2.60 vs 2.92 and $3379 vs $5925, respectively; both P <.001). Although frequencies and cost of ranibizumab and aflibercept injections were comparable among patients with nAMD, ranibizumab was associated with estimated per-patient per-month overall cost savings of $3500 to $4500 in those treated for DME. Most patients received fewer injections than FDA-indicated dosing regimens, which may indicate undertreatment and suboptimal outcomes.23
It is important to acknowledge the significant challenge that adherence plays in a successful treatment regimen with anti-VEGF therapy. Frequent underutilization and discontinuation in real-world studies lead to poor outcomes. Approximately 57% of Medicare patients discontinue treatment within the first year.24 Many studies aim to determine the influencing factors associated with adherence in patients with nAMD undergoing anti-VEGF therapy. Randomized trials on AMD show significant improvements in patients treated with ranibizumab compared with placebo, though ranibizumab therapy is recommended monthly to achieve the most efficacious visual outcomes.25 Some retinal specialists prefer a treat-and-extend regimen consisting of 3 monthly intravitreal injections followed by as-needed injections administered based on VA, optical coherence tomography, and fundus fluorescein angiography findings if the patient is unable to stay adherent to the monthly regimen.26
To explore the extent of patient nonadherence, a cohort study aimed to examine the percentage of patients with nAMD that are lost to follow-up when receiving anti-VEGF injection therapies. The study included data from 9007 patients and found that 2003 (22.2%) patients were lost to follow-up and 7004 (77.8%) had a follow-up visit within 12 months. Of the patients considered lost to follow-up, 92.6% had no follow-up visit and 7.4% had a follow-up visit after the 12-month period. The rate of patients lost to follow-up increased with age and distance from clinic, decreased with average gross income, and differed by ethnicity.27 This study helps identify risk factors of patients who may be less adherent to stringent treatment protocols.
A retrospective analysis examined medical records of patients with nAMD to determine factors influencing compliance. Compliant patients were defined as those who regularly received 3 consecutive intravitreal ranibizumab injection treatments after being diagnosed with nAMD and followed regularly for 1 year. Noncompliant patients were those who regularly did not receive 3 consecutive intravitreal ranibizumab injection treatments or could not be followed regularly for 1 year. Of the 125 patients who failed to comply with follow-up and treatment, the most common reason was fear of intravitreal injection (29.6%). See Table 125 for a list of the most common factors negatively affecting compliance. Factors shown to improve compliance were better VA at baseline, smaller lesion size, living closer to the hospital, higher education and sociocultural level, and better financial status. This study concluded identifying factors affecting compliance can improve success rates of anti-VEGF therapies.25
A retrospective study of electronic medical records of 110 patients (121 eyes) with DME who received anti-VEGF treatment found that over 12 months, only 59% of study eyes had regular (at least quarterly) visits, and fewer than 2% had the monthly visits utilized in large randomized clinical trials. Additionally, only 3% of eyes in the study received injections at a frequency approaching monthly dosing with nearly 70% received 3 or fewer anti-VEGF injections over the 12-month study period. This resulted in less favorable visual outcomes than those seen in clinical trials.28
Cost-Efficacy of Anti-VEGF Strategies
Although anti-VEGF therapies have changed the treatment landscape for both DME and nAMD, the economic burden is high, as previously discussed. One study, which aimed to determine the incremental cost-effectiveness ratios (ICERs) of anti-VEGF therapies including aflibercept, bevacizumab, and ranibizumab for the treatment of DME included 660 patients randomly assigned to each therapy. Patients were followed every 4 weeks for 1 year, with injections provided monthly for the first 6 months for most patients. Results showed for all participants over 1 year, the ICERs of aflibercept compared with bevacizumab were $1,110,000 per quality-adjusted life-year (QALY), and ranibizumab compared with bevacizumab were $1,730,000 per QALY. Over 10 years, they increased to $349,000 per QALY with aflibercept and $603,000 per QALY, respectively. When compared with ranibizumab, aflibercept’s ICER was $694,000 per QALY at 1 year and $203,000 per QALY at year 10. Generally, $50,000 to $150,000 per QALY are frequently cited as thresholds to be considered cost effective in the United States.29
Novel and Emerging Therapies to Address Challenges With nAMD and DME
As discussed, the considerable economic burdens associated with DME and nAMD are attributed to medical care costs, nonadherence to therapy, and decreased patient productivity due to vision loss. Although many studies have demonstrated the success of anti-VEGF therapies in preserving sight, most real-world studies fall short of outcomes seen in clinical trials.28,30 Literature shows there is a direct correlation between the number of injections and better visual outcomes, so nonadherence, a multifactorial problem influenced by various factors including but not limited to fear of injections, transportation difficulty, comorbidities, and costs, is imperative to address.25,28,31,32 A potential solution to nonadherence is to reduce treatment burden, which was ranked as the No.1 unmet need by retina specialists in the United States in the 2018 American Society of Retina Specialists survey.33 Therapies that are long-acting or have sustained delivery options will reduce injection frequency and provide longer intervals between appointments, reducing the burden for patients and their caregivers, which in turn has the potential to improve visual outcomes.
New therapies such as brolucizumab, faricimab, and ranibizumab port delivery system (PDS) may have extended dosing capabilities compared with aflibercept, bevacizumab, and ranibizumab, which are dosed every 4 to 8 weeks. Table 234-41 compares the dosing frequencies of therapies available for nAMD and DME.
Faricimab, the first bispecific monoclonal antibody that binds VEGF and Ang-2, is approved for the treatment of nAMD and DME. Studies consistently demonstrated that faricimab, given at intervals of up to 4 months, offered noninferior vision gains compared with aflibercept, given every 2 months. Approximately 75% of patients who were eligible for extended dosing with faricimab in the YOSEMITE and RHINE studies in DME and the TENAYA and LUCERNE studies in nAMD were able to be treated every 3 months or longer, and 50% were able to be treated every 4 months.42,43
Ranibizumab PDS, a novel drug delivery mechanism for anti-VEGF therapy indicated for the treatment of nAMD, is a refillable implant that is surgically inserted into the eye in the operating room and refilled in a retinal specialist’s office. A phase 2 LADDER trial showed that patients in the ranibizumab PDS 100 mg/mL group had median time to first implant refill of 15 months and approximately 80% of patients were able to go 6 months or longer before needing their first refill.44 The phase 3 Archway trial demonstrated that 98.4% of PDS patients were able to go 6 months without requiring added treatment and achieved vision outcomes equivalent to patients receiving monthly ranibizumab eye injections.45
In addition to therapies with extended durability reducing treatment burden and improving adherence, biosimilars is an area of interest that may address adherence issues related to cost barriers. Currently there are biosimilars for aflibercept, ranibizumab, and bevacizumab in the pipeline. However, only the ranibizumab biosimilar is FDA approved for ophthalmic indications; bevacizumab and aflibercept biosimilars are currently FDA approved for oncologic indications.46-48 Bevacizumab-vikg, the first ophthalmic formulation of bevacizumab, may soon be FDA approved for an ophthalmic indication based on the phase 3 NORSE TWO trial, which compared bevacizumab-vikg monthly injections with ranibizumab injections dosed per package labeling. The trial met its primary end point with 41% of patients receiving bevacizumab-vikg demonstrating a minimum of 15-letter increase in best-corrected VA compared with 23% with ranibizumab (P = .0052).49 Although biosimilars are in development for each of the 3 major anti-VEGF therapies used in the treatment of nAMD and DME, biosimilars may not be widely embraced due to the already low cost of off-label bevacizumab. Compared with the reference product, the expectation of reduced cost with a biosimilar may still drive future treatment selection as more biosimilars come to market.50
Managed Care Issues and Strategies to Optimize Outcomes
It is important to evaluate managed care strategies and protocols for anti-VEGF therapies. One common payer strategy for all lines of business (ie, commercial, Medicare, Medicaid, exchange) to manage appropriate drug use is step therapy. Step therapy requires the use of a health plan’s most preferred drug therapy before progressing to other therapies. Previously, Medicare Advantage did not allow step therapy protocols to be used on part B physician-administered drugs. In January 2019, the Centers for Medicare & Medicaid Services set forth a new policy that allowed step therapies for these drugs, noting that by doing so, Medicare Advantage plans would have increased leverage to negotiate drug prices.51 Ultimately, the goal of a step therapy strategy is to promote better utilization of most cost-effective products, thus eliminating overuse and abuse of healthcare resources.51 Specifically in the ophthalmic space, compounded bevacizumab is preferred by many health plans to be tried before other agents.
The American Academy of Ophthalmology has challenged this payer strategy by voicing their concern that administrative burden to complete a step therapy request could potentially lead to delay in treatment.52 Despite the pushback, there has been documented positive outcomes with a step therapy approach. One study evaluated results of using bevacizumab as part of a step therapy for treatment of nAMD. A retrospective cohort study was performed for patients treated under this protocol to evaluate efficacy. The study included 133 patients who met inclusion criteria and were aged 59 to 106 years. The primary outcome was the success rate of bevacizumab step therapy, which was defined as achieving a stable injection regimen without recurrence of neovascular disease, loss of 3 or more Snellen chart lines, or requirement of switching to an FDA-approved anti-VEGF agent. Results showed that of the 133 patients, 106 (80%) achieved stability on bevacizumab therapy. Of the patients, 70 (53%) were able to achieve stability with injections every 8 weeks or longer, while 36 patients (27%) required more frequent injections than every 8 weeks. These findings show favorable results of treating nAMD with bevacizumab as a first-line step therapy approach.53
Fee Schedule Management and the Buy-and-Bill Model
Traditionally, the majority of anti-VEGF inhibitors for ophthalmic treatment have been dispensed through the physician buy-and-bill model. Payers would reimburse the physician following administration of these products via a designated fee schedule, which is typically based on the average selling price (ASP) of the drug plus a percentage margin. For products with a higher ASP, the margin would be higher, and therefore more enticing to the physician to use these expensive products. Because compounded bevacizumab is cheaper compared with the FDA-approved anti-VEGF inhibitors, through fee schedule management, payers often elect to increase the margin on compounded bevacizumab to be at parity with these other agents to increase its competitiveness.
Role of Specialty Pharmacy
Specialty pharmacists often dispense anti-VEGF therapies and may have additional compounding roles such as repackaging bevacizumab into single-dose syringes. Compounded bevacizumab is less expensive compared with FDA-approved therapies for AMD. However, as this medication must be compounded, there have been previous concerns for endophthalmitis since 2011. A 2015 study later found there was not an increased risk of endophthalmitis when compared with ranibizumab.54 Once repackaged into prefilled syringes, the medication is stable for 3 to 6 months if handled properly.55
Specialty pharmacists may provide additional responsibilities including monitoring for potential adverse effects and ensuring appropriate adherence to therapy.2 As previously discussed, adherence to regimens is an integral factor in patient outcomes and vision preservation.
In the traditional buy-and-bill model, physicians would be responsible for purchasing and stocking these products directly from wholesalers, but due to the increased cost and variation in fee schedules, many payers now encourage the use of “white bagging.” White bagging is when a specialty pharmacy dispenses the product directly to the physician’s office for administration to the patient. A Kanter Health Payer Survey found that the proportion of payers who encouraged physician-administered injectables to be managed by specialty pharmacies increased from 29% in 2014 to 36% in 2016. Payers that mandated the use of specialty pharmacies for certain drugs remained steady through 2014 to 2016. The study also found that 36% of payers created favorable reimbursement policies to encourage white bagging of physician-administered intravenous drugs.56
Tremendous advancements in the understanding of nAMD and DME and highly efficacious therapeutic agents have improved the ability to appropriately manage patients. Information from large clinical trials has provided guidance to physicians in selecting treatment regimens and frequencies. However, equally important is real-world studies and experiences that suggest one set algorithmic approach may not always be possible. Each patient may require specific modifications in their choice of agent and dosing regimen. In addition, cost of anti-VEGF medications adds to the burden of disease. New therapies that have increased durability may reduce treatment burden improving adherence and patient outcomes. Although step therapy protocols may be appropriate for a great number of patients, a tailored approach may be needed to allow the most clinically fulfilling outcomes.20
Author affiliation: YuQian Liu, PharmD, is Director, Specialty Clinical Solutions, Magellan Rx Management, Middletown, Rhode Island.
Funding source: This activity is supported by an educational grant from Genentech, a member of the Roche Group.
Author disclosure: Dr Liu has no relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.
Address correspondence to: email@example.com
Medical writing and editorial support provided by: Jenna Wood, PharmD