Stakeholder insights on cost, quality, and incorporating patient voice in managed care decisions on neovascular (wet) age-related macular degeneration: Findings from the AMCP Market Insights program

Abstract

Wet age-related macular degeneration (AMD) is an acquired degeneration of the retina that can lead to central vision impairment. It is primarily treated with intravitreal injections of vascular endothelial growth factor inhibitors. Although vascular endothelial growth factor inhibitors can effectively prevent progression of vision loss in many patients, they require ongoing regular administration and are therefore associated with considerable treatment burden. To gain insights into the impact of wet AMD and its treatment, AMCP convened an expert panel of managed care stakeholders in April 2024 through its Market Insights program. Key issues related to wet AMD identified by participants included cost and affordability, provider-related considerations, biosimilar adoption, measuring and improving quality, and incorporating the patient voice. Suggested payer best practices related to these issues in wet AMD also emerged from the discussion.

Plain language summary

Wet age-related macular degeneration is a condition that can lead to significant vision loss. It is treated with regular injections, which often work well at preventing vision loss but are a burden to patients with the condition. Health care organizations can help by better understanding this burden and doing what they can to lessen it. Importantly, this includes talking to doctors and patients to better understand their problems and their needs.

Implications for managed care pharmacy

Vascular endothelial growth factor inhibitors for the treatment of wet age-related macular degeneration are effective; however, they pose significant economic and treatment burden. It is important for managed care organizations to be aware of treatment strategies and emerging treatments aimed at reducing this burden and to partner with providers and patients or their representatives to provide high-quality, individualized care.

Age-related macular degeneration (AMD) is an acquired degeneration of the retina that can lead to central vision impairment.¹ It presents as either non-neovascular, nonexudative (dry) AMD or neovascular, exudative (wet) AMD.¹ In 2019, approximately 20 million individuals aged older than 40 years were living with AMD in the United States.² Although up to 90% of AMD cases are dry AMD, wet AMD is the primary cause of severe vision loss.¹ Treatment of dry AMD may involve supplementation and lifestyle recommendations, whereas wet AMD is primarily treated with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors (Figure 1; Table 1).^1,3,4

FIGURE 1.

AMD Treatment Guidelines^3,4

TABLE 1.

VEGF Inhibitors for the Treatment of Wet AMD^17-22,33,34

Agent	FDA approval date	FDA-label dosing
Aflibercept	2011	2 mg via intravitreal injection every 8 weeks
	2023	8 mg via intravitreal injection every 8-16 weeks
Bevacizumaba	NA	1.25 mg via intravitreal injection monthly
Brolucizumab	2019	6 mg via intravitreal injection every 8-12 weeks
Faricimab	2022	6 mg via intravitreal injection every 8, 12, or 16 weeks
Ranibizumab	2006	0.5 mg via intravitreal injection monthly or up to every 3 months
	2021	2 mg via ocular implant every 6 months

^aNot FDA approved for the treatment of wet AMD.

AMD = age-related macular degeneration; FDA = US Food and Drug Administration; NA = not applicable; VEGF = vascular endothelial growth factor.

Evolution of Treatments for Wet AMD

Prior to approval of the first VEGF inhibitor in 2004, wet AMD was treated using laser photocoagulation or photodynamic therapy (PDT).⁵ In laser photocoagulation, light energy is applied, decreasing new blood vessel growth.⁶ This treatment is associated with potentially significant side effects such as burns, fibrosis, and scarring.⁶ PDT involves administering a photosensitizing compound (eg, verteporfin), which accumulates in target cells, followed by light irradiation, causing target cell necrosis.⁷ Adverse effects of PDT may be short-term, eg, pain and edema, or long-term, eg, scarring.⁷ Although both therapies remain in use, for example in other conditions for which there are limited therapeutic options, the safety and efficacy of VEGFs primarily precludes their treatment of wet AMD.^3,5

Ongoing research is also evaluating gene therapy, which may be the future of wet AMD treatment.⁸ In the most advanced programs, a vector containing a VEGF inhibitor protein is administered, causing retinal cells to produce the protein for a sustained anti-VEGF effect.⁸ Early clinical findings from the OPTIC trial evaluating a single injection of ixo-vex, containing the aflibercept protein, showed stable best-corrected visual acuity (BCVA) at 2 years.⁹ Additionally, the currently recruiting ATMOSPHERE and ASCENT trials are evaluating RGX-314, which has a similar mechanism of action and contains the ranibizumab protein.⁸

Treatment Burden in Wet AMD

Although VEGF inhibitors can effectively prevent progression of vision loss in many patients, and have significantly decreased wet AMD–attributed blindness, they require ongoing regular administration and are therefore associated with considerable treatment burden on patients and caregivers.^10-14 Clinic visits to receive the injections involve time (eg, preparation, transport, waiting time, treatment, and recovery) and logistics (eg, making appointments and arranging transport) and other potential challenges such as lost work productivity. The injections themselves may be uncomfortable or painful, and aftercare may be necessary, for instance because of blurred vision. Cost shares related to visits and injections may also be challenging for patients, many of whom live on fixed incomes and have expenses from comorbid conditions. Additionally, there may be mental health consequences related to both the potential for vision loss from the condition and the treatments required to prevent this loss. These might include, but are not limited to, stress/guilt about the increased need for caregiving, anxiety/sleep disturbances related to upcoming treatment, and grief and other feelings related to any lost vision/disability or loss of activities such as driving.^10-14

Fixed-dosing (eg, monthly or bimonthly) regimens are generally used in clinical trials evaluating the initial safety and efficacy of VEGF inhibitors; however, these regimens are the most burdensome.^11,15-20 Other real-world dosing strategies intended to mitigate this burden include as-needed (PRN), treat-and-extend, and high-dose regimens (Table 2).^11,15,16 In PRN regimens, a regular schedule of clinic visits is maintained; however, patients only receive treatment with disease activity.^11,15 In treat-and-extend regimens, patients receive treatment at each visit, but the interval between visits is maintained, increased, or decreased according to the patient’s disease activity.^11,15,16 High-dose regimens rely on the increased durability achieved with products that supply a higher dose per treatment.^21-24

TABLE 2.

VEGF Maintenance Dosing Strategies for the Treatment of Wet AMD^11,15,16

Strategy	Description
Fixed dosing	Patients receive regular treatment doses at a fixed interval, eg, monthly or bimonthly.
As needed (PRN)	Patients usually follow a schedule of monthly clinic visits but are only treated upon disease reactivation.
Treat and extend	Patients receive treatment doses at every scheduled clinic visit; however, the interval between each visit is maintained, increased, or decreased according to the patient’s disease activity.
High dose	A higher treatment dose is used to increase duration of treatment, eg, 2 mg ranibizumab via intravitreal implant or 8 mg aflibercept via intravitreal injection.

AMD = age-related macular degeneration; VEGF = vascular endothelial growth factor.

A meta-analysis comparing treat-and-extend regimens against monthly, bimonthly, and PRN regimens across 6 randomized controlled trials and nearly 1,700 eyes reported no significant differences in the safety and efficacy between regimens.¹⁵ Weighted mean differences in the primary efficacy outcome of BCVA at last follow-up were −0.62 letters (vs monthly; 95% CI = −2.12 to 0.87; P = 0.41), −1.68 letters (vs bimonthly 95% CI = −3.55 to 6.91; P = 0.53), and −1.08 letters (vs PRN 95% CI = −2.95 to 5.11; P = 0.60). The incidence of ocular adverse events (AEs) in treated eyes was 30.17% (n = 442). Common AEs such as reduced visual acuity, retinal pigment epithelium tear, and eye pain were similar between treat-and-extend and monthly regimens (P = 0.47, P = 0.70, and P = 0.60, respectively). The safety data to compare with PRN regimens were insufficient.¹⁵

Products used in high-dose regimens include aflibercept 8 mg, delivered via intravitreal injection, and ranibizumab 2 mg, delivered via a refillable ocular implant.^21,22 In a phase 3 randomized controlled trial evaluating aflibercept 8 mg every 12 (n = 336) and 16 weeks (n = 338), against the previously approved regimen of aflibercept 2 mg every 8 weeks (n = 337), both aflibercept 8 mg groups demonstrated noninferiority vs aflibercept 2 mg as measured by the least squares mean difference in BCVA from baseline to week 48 (12 weeks: −0.97 letters; 95% CI = −2.87 to 0.92; P = 0.0009 and 16 weeks: −1.14 letters; 95% CI = −2.97 to 0.69; P = 0.0011).²³ The incidence of ocular AEs was similar across all aflibercept groups (12 weeks: 39%; 16 weeks: 38%; 8 weeks: 39%).²³

Similarly, ranibizumab 2 mg every 24 weeks demonstrated noninferiority to the previously approved regimen of ranibizumab 0.5 mg monthly in a phase 3 randomized controlled trial evaluating change in BCVA from baseline averaged over weeks 36 to 40 (difference: −0.3 letters; 95% CI = −1.7 to 1.1; P = not reported).²⁴ The incidence of ocular AEs was higher in the every-24-week group vs the monthly group (n = 67 vs n = 10), with many of these occurring within the first month after surgery (n = 38).²⁴

Treatment Discontinuation in Wet AMD

Despite the effectiveness of VEGF inhibitors, treatment discontinuation is high; in one systematic review of risk factors for nonadherence/nonpersistence, including 37 studies from the United States and Europe, it was up to 60% at 24 months.²⁵ The majority of discontinuation in this review occurred in the first 6-12 months, indicating that an established regimen over time may help diminish treatment barriers. Other factors that correlated strongly with discontinuation were comorbidities, longer travel distances, lack of transport assistance, and poorer baseline visual acuity. The authors note, however, that much of the data were in patients on PRN regimens and may not reflect trends in treat-and-extend or high-dose regimens.²⁵

A retrospective clinical cohort study, which included 4- (n = 577), 6- (n = 1,862), 8- (n = 1,923), 10- (n = 1,372), 12- (n = 948), and greater-than-12-week regimens (n = 1,485), evaluated treatment discontinuation following 24 months up to 60 months of treatment and reported a rate of 30.4%.²⁶ Compared with the 8-week treatment group, those in the greater-than-12-week treatment group had a 55% higher likelihood of treatment discontinuation (hazard ratio [HR] = 1.55; P < 0.01) and those in the 4-week group had a 28% lower likelihood (HR = 0.72; P < 0.01). The authors propose that this may be a result of the perceived immediate benefits of treatment outweighing treatment fatigue, as a shorter duration between treatments indicates increased disease activity. Other factors that affected discontinuation included being male (12% lower risk; HR = 0.88; P < 0.05) and older age (1% higher risk; HR = 1.01; P < 0.05). It should be noted that this study was also conducted prior to the approval of either product used in high-dose regimens.²⁶

Expert Stakeholder Insights in Wet AMD

To better understand the impact of wet AMD and its treatment, AMCP virtually convened an expert panel of managed care stakeholders in April 2024 through its Market Insights program. This moderated, 4-hour panel included representatives from health plans (n = 4), integrated delivery networks (IDNs; n = 2), pharmacy benefit managers (n = 1), employer (n = 1) and patient organizations (n = 1), and a practicing retinal specialist. Panelists considered the associated condition and treatment burden, available treatments and dosing strategies, and opportunities to optimize benefit design and quality in the management of wet AMD. This report describes key takeaways from the panel discussion (Figure 2) and provides suggested payer best practices (Table 3).

FIGURE 2.

Key Takeaways from AMCP Market Insights Panel on Wet AMD

TABLE 3.

Payer Best Practices in Wet AMD Suggested by AMCP Market Insights Panel

Facilitate timely access to appropriate treatment	Timeliness and access to appropriate treatment are critical to achieving the best outcomes in wet AMD. They can be facilitated by ensuring the process for prior authorization of treatment is as efficient as possible. This could be through gold carding, for example, or not requiring authorization of the first treatment injection.
Gather multistakeholder input	Having a holistic view of wet AMD and its challenges is a significant element of coverage and care-related decision-making. Regular communication to gather input from multiple stakeholders, such as retinal specialists and patients or their representatives, can assist in achieving this.
Embrace appropriate new technologies	Processes for embracing appropriate new technologies related to wet AMD are important. This includes new medication technologies (eg, gene therapy) and other technologies that have the potential to impact the condition in the future as they continue to evolve (eg, telemedicine and artificial intelligence).
Consider value-based agreements	These could be based, for example, on improvement or maintenance of BCVA or visual field. If a proportion of the membership does not achieve the outcome criteria after a specified length of treatment, the cost of the product or the difference in claim costs for switching would be reimbursed to the payer.
Encourage screening and advocate for incorporation into quality measures	Early screening and diagnosis assist with timely treatment and high-quality outcomes; however, currently, formal quality measures for eye health screenings (eg, HEDIS measures, Star ratings) exist only for patients with diabetes. Encouraging regular screenings and advocating for an age-related eye health quality measure are steps payers can take to ensure high-quality patient care.

AMD = age-related macular degeneration; BCVA = best-corrected visual acuity; HEDIS = Healthcare Effectiveness Data and Information Set; VEGF = vascular endothelial growth factor.

COST AND AFFORDABILITY

Key takeaway: All stakeholders are concerned with the cost and affordability of treatments for wet AMD.

Payer participants acknowledged that there may be clinical parity among some agents, but they still need to consider cost and related factors such as contracting opportunities when determining coverage placement and developing coverage policies. Participants indicated that many or most payers have coverage policies that require the off-label use of bevacizumab first in wet AMD and other ophthalmic conditions, as it is included as a recommended VEGF inhibitor by the American Academy of Ophthalmology AMD preferred practice parameter and is relatively low cost.³ Less common are biosimilar first coverage policies, although some participants thought more of these may be on the horizon.

From the employer perspective, although they may recognize the value of upfront investment in high-cost medications to promote employee health and avoid future expenditures, they must also consider the possibility of lost investment because of employee churn. Participants discussed that for some employers, wet AMD may not be a significant concern as the primary patient population is not of working age; however, VEGF inhibitors can be used for other conditions such as diabetic macular edema and diabetic retinopathy and so are still a priority to manage.

Additionally, participants noted that cost and affordability issues are also a challenge for providers to balance when evaluating the best treatment choice and dosing strategy. For patients, even with coverage, cost shares related to clinic visits or injections may be a concern for some as they are often on fixed incomes and have expenses from comorbid conditions. This is especially true if the medication is required to be dispensed from a specialty pharmacy and shipped to the treating provider (white-bagging) or to the patient (brown-bagging), as the patient is then responsible for a specialty medication copay.²⁷

A potential best practice that emerged related to the cost and affordability of VEGF inhibitors for the treatment of wet AMD is to consider value-based agreements (Table 3).

“It sounds like based on the clinical presentation that there are targeted outcomes for these therapies. And so, I think there’s some missed opportunity between payers and pharma to contract based on those outcomes.” – Health plan representative

One payer proposed, for example, an agreement based on outcomes such as improvement or maintenance of BCVA or visual field. If a proportion of the membership treated with the contracted product does not achieve the agreed upon criteria after some amount of time on the product, the payer would get reimbursed for the cost of the product or the difference in claim costs for the product the member switched to.

PROVIDER-RELATED CONSIDERATIONS

Key takeaway: Top provider-related considerations for payers are access and how to incorporate provider input into decisions.

Participants discussed that access to specialized care both for diagnosis and for treatment is variable, eg, based on rural vs urban location. Challenges to timely diagnosis identified by participants include patients waiting for occurrence of symptoms to receive screening, and whether nonspecialist providers recognize when there is need to refer patients for further evaluation. Participants wondered whether assistive diagnostic technologies, eg, telemedicine and artificial intelligence, might offer solutions; however, the real-world experience presented indicated these technologies are still evolving.

Timely access to the first treatment injection, which is crucial to achieving the best outcomes in wet AMD, was also discussed. Published clinical evidence indicates that progression is more rapid early in the disease course; therefore, although early detection is important, prompt treatment is also required to prevent vision loss.²⁸ Although the American Academy of Ophthalmology AMD preferred practice pattern does not include a specific time frame, the National Institute for Health and Care Excellence guidelines for AMD recommends patients receive treatment within 14 days of diagnosis of advanced AMD.^3,29

In part, timeliness to first injection relies on patient access to appropriate providers, but another key factor, particularly from a treating provider perspective, is prior authorization requirements. A best practice that arose for payers was to ensure the process for prior authorization of treatment is as efficient as possible (Table 3). Suggestions from participants to facilitate this were through gold carding, which relaxes prior authorization requirements for providers who have a demonstrated track record for complying with criteria; implementing performance guarantees to promote timely prior authorization decisions; or not requiring authorization of the first treatment injection or of treatments determined to be the most cost-effective.³⁰

Another top provider-related consideration for payers identified by participants was how to incorporate real-world clinical experience into decision-making.

“Payers need to make sure we’re educated—pulling in the specialists and having conversations, having the appropriate providers on our P&T, looking at the real-world evidence piece and taking that into consideration when making formulary decisions.” – Health plan representative

Although payers value input from treating providers, published real-world data to support coverage decisions are optimal. Real-world data that would be valuable to payers to differentiate products would demonstrate both cost savings and cost avoidance, for example. This might include cost savings from early screening and potential delay of progression to wet AMD and the need for VEGF treatment, lower medication costs with fewer injections owing to longer treatment duration, and cost avoidance with treatment, eg, avoiding falls, or hospitalizations.

BIOSIMILAR ADOPTION

Key takeaway: Challenges to biosimilar adoption exist for many stakeholders.

There was considerable dialogue among participants related to the utility of biosimilars for the treatment of wet AMD and other ophthalmic conditions, although it was clear that challenges to biosimilar adoption exist for many stakeholders. Among some treating providers, there are significant safety concerns with the use of biosimilars in ophthalmic conditions owing to the experience of inflammation, which can cause permanent damage when it occurs in the eyes. From the payer and employer perspectives, they want to encourage use of lower-cost products including biosimilars when clinically appropriate, and if there is a need for differentiation of biosimilars vs reference products based on safety, they require evidence to support it. Additionally, there was acknowledgment by participants that external influences such as rebates, advertising, and legal factors further challenge the debate around biosimilar adoption.

“We’ve got to get to more acceptance of biosimilars. I’m old enough as a pharmacist to remember when generics were scary, and biosimilars, in many ways, it’s just generics 2.0.” – Employer representative

A suggested best practice to improve appropriate biosimilar adoption is to increase communication between stakeholders to bridge the gap between provider experience and limited published clinical evidence (Table 3).

“Managed care can do a better job engaging with clinicians to exchange information and data. And most importantly dispelling myths or assumptions made on both sides so that we can help ensure access happens at the right time for the right people.” – Health plan representative

MEASURING AND IMPROVING QUALITY

Key takeaway: There is uncertainty around measuring and improving quality related to wet AMD.

Quality was another area of considerable dialogue among participants. Specifically, they discussed measuring and improving the quality of care provided by practice groups, quality in terms of treatment outcomes, and quality of life for patients. There was uncertainty among participants particularly around measuring quality of provider groups. One payer wondered, for instance, whether quality might be assessed based on how much generic, biosimilar, or brand product they used but also questioned the right proportion of each to achieve the best balance of clinical and financial outcomes.

“At the end of this, I still don’t know with 9 ophthalmology groups, how do I judge their quality? How do I look at this and say which group is better because I don’t know how to do that right now.” – IDN representative

Potential strategies for incentivizing provider quality were suggested by participants; however, there was acknowledgment that these are both payer and provider specific. For example, payers could establish a capitated injection model, but some thought that would work better for an IDN vs a national payer. One payer also suggested a quality-based reimbursement to providers; however, they again referred to uncertainty around the appropriate parameters to determine quality. Participants also recognized that the effectiveness of any strategy depends on the influence of provider groups, which differs by group or region; fewer providers in a region, for instance, might mean less ability for payers to employ management strategies.

Participant discussion around improving outcome quality underscored that currently, formal quality measures (eg, HEDIS measures, Star ratings) for eye health screenings are tied to patients with diabetes.^31,32 There is no age-related quality measure for eye health screening in patients without diabetes despite the potential for delayed progression to wet AMD and need for VEGF treatment with early screening. Advocating for this type of measure, therefore, might be a best practice to improve quality by providing additional incentive to encourage regular screenings (Table 3).

“In terms of screening, who’s going to pay for it? We have screening measures that are revenue generating, like mammograms and other cancer screenings. But there isn’t one for vision.” – Health plan representative

Participants also discussed that treatment choice can affect the quality of outcomes. For example, treatment durability is a key factor that may impact both treatment outcomes and quality-of-life outcomes.

“A lot of these patients with the newer medications can get to every 8 weeks, every 12 weeks, every 16 weeks, and so that helps patients enormously. About one-third of patients on every-4-week dosing will just stop, and that’s devastating for all of us. They’ll come back a few years later with complete vision loss because they just can’t handle coming in so often for their injections.” – Retinal specialist

However, cost is still an important consideration in coverage decisions. This is another instance in which published evidence of cost savings or cost avoidance would be beneficial, according to participants. For example, if cost avoidance is demonstrated with better outcomes, that can mitigate the issue of medication cost in determining which treatments to prefer.

INCORPORATING THE PATIENT VOICE

Key takeaway: Payers see value in the patient voice but are uncertain how to make it actionable.

All participants acknowledged the significant patient burden related to wet AMD. They discussed that to overcome potential barriers, patients need access to adequate support services. These may include low-vision aids, services related to social determinants of health (eg, transportation, cultural, and language), and mental health services. Health care stakeholders also need to ensure that patients have realistic expectations to promote treatment adherence; it can be difficult for patients to accept the burden of treatment, for example, if they expect their vision to improve, when maintaining their vision is the more likely outcome.

Although participants see value in collaboration with patients and their representatives, there are associated challenges. For participants that are engaging with patients, there is uncertainty around how to make it actionable in coverage decision-making. There is also concern for potential bias when a patient organization is strongly advocating for one product, for instance.

“We do have a member committee, with actual plan members giving us feedback, which is interesting, but we’re not quite sure how to make it actionable.” – Health plan representative

From the patient organization perspective, an opportunity related to understanding was identified. For example, patients and patient organizations may not be aware of the complexities payers must navigate when making decisions, just as payers may not be aware of some of the challenges faced by patients. A best practice, therefore, might be regular communication between stakeholders including patient organizations, to improve understanding of each other’s perspectives with the ultimate goal of helping guide and empower patients (Table 3).

“I think something to work towards is more conversations to further understand each other and how we can ultimately work with the patient population to make sure they’re navigating their care in the best way possible and be constructive additions to the conversation.” – Patient organization representative

Summary

Wet AMD and its treatment cause significant impact. In this Market Insights program, an expert panel identified and provided insight on key issues related to wet AMD including cost and affordability, provider-related considerations, biosimilar adoption, measuring and improving quality, and incorporating the patient voice. Suggested payer best practices related to these issues in wet AMD also emerged from the discussion and include partnering with providers and patients or their representatives to provide high-quality, individualized care

“It was very valuable to get a 360° view of a disease space that can be too narrowly focused on cost reduction alone. I think participants from all perspectives were able to walk away with some additional knowledge.” – Health plan representative

“I found the program extremely helpful in understanding the challenges and opportunities related to treatment of wet AMD. I have several takeaway ideas and strategies that will help members with improved access and affordability.” – Employer representative

Funding Statement

Dr Flavin received payment from AMCP for the preparation of this manuscript. Drs Schimel, Contreras, Shannon, and Bioc received an honorarium from AMCP for participation in this Market Insights program. Dr Schimel also discloses payment from Regeneron for participation in a speakers bureau. AMCP conceptualized this supplement, and funding was provided by Regeneron Pharmaceuticals.