Clinical and Socioeconomic Burden of Retinal Diseases: Can Biosimilars Add Value? A Narrative Review

Abstract

Retinal diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion, pose a significant global burden on individuals, families, and healthcare systems. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has become the standard treatment for retinal diseases, improving clinical outcomes, while delaying disease progression. Although effective, biologics are associated with high costs, which can lead to underutilisation and, consequently, suboptimal patient treatment outcomes, further contributing to healthcare costs. Additionally, the expansion in the elderly population is predicted to significantly increase costs and burden on healthcare systems due to retinal diseases, requiring effective strategies and the utilisation of emerging technologies that are crucial public health priorities for tackling global vision impairment. Recently, anti-VEGF biosimilars have been approved and are expected to provide a cost-effective alternative, while providing equivalent efficacy and comparable safety, immunogenicity, and pharmacokinetic profiles as the reference product. The entry of biosimilars holds the promise of meeting some of these unmet needs, giving physicians and patients access to sustainable treatments that can provide cost-effective therapy, enabling savings to be reinvested into healthcare facilities. This article aims to review the impact of retinal diseases on clinical, social, and financial aspects of patient care, emphasising the potential value of biosimilars in ophthalmology.

Key Summary Points

Retinal diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, diabetic macular oedema, retinal vein occlusion, and myopic choroidal neovascularisation, significantly contribute to global blindness and vision loss and pose a significant global burden on individuals, families, and healthcare systems.

While the current standard treatment of anti-vascular endothelial growth factor therapy is effective, it also reveals unmet clinical needs involving treatment access and sustainability, further adding to clinical and socioeconomic burden.

Biosimilars, which undergo the same stringent regulatory approval process as their reference product, could offer a more cost-effective approach to the treatment of retinal diseases and long-term sustainability for healthcare systems, and optimise patients’ access to gold standard treatment.

While the uptake of biosimilars has experienced some barriers, it is hoped that they will meet some of the existing unmet clinical and socioeconomic needs within the ophthalmology space and enable investment into healthcare facilities.

Introduction

Retinal diseases are among the leading global causes of blindness in those over the age of 50 years [1]. They are associated with a significant burden for patients and their families, the communities they inhabit, as well as clinicians, nurses, and payors [2]. This is underscored by the association of retinal diseases with diminished quality of life (QoL), restricted life opportunities, and an elevated risk of all-cause mortality [2]. Retinal diseases, including retinal vascular diseases (RVDs) and choroidal vascular diseases (CVDs), are significant causes of visual impairment. In 2020, age-related macular degeneration (AMD) had an estimated global prevalence of 196 million and is projected to rise to 288 million by 2040 as a result of an ageing population. Approximately 10% of people with AMD develop neovascularisation, resulting in around 20 million cases of neovascular AMD (nAMD) in 2020. As such, nAMD is the most prevalent CVD. Diabetic retinopathy (DR) is a microvascular complication of diabetes and ranks as the most common RVD and one of the leading causes of blindness in patients aged 20–74 [3]. In 2012, DR, including proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DME), affected 93 million, 17 million, and 21 million individuals worldwide, respectively. Retinal vein occlusion (RVO), the second most common RVD, had a global prevalence of 16.4 million in 2008, and a large percentage of patients with RVO develop macular oedema [4]. Although less prevalent, myopic choroidal neovascularisation (mCNV) is also of relevance and a common cause of vision loss in patients with pathological myopia [5]. The percentage of the global population aged ≥ 65 years is expected to reach approximately 12% in 2030, 16% in 2050, and 23% in 2100, with a much faster rate of growth for those aged ≥ 80 years old. The expansion of the elderly population is predicted to significantly increase costs and burden on health systems due to retinal diseases [6], requiring effective strategies and the utilisation of emerging technologies that are crucial public health priorities for tackling global vision impairment [1].

Since its introduction into the clinical paradigm, intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGF) therapy has become the standard of care for retinal diseases. These biologic therapies improve clinical outcomes, while delaying disease progression [7]. Table 1 outlines currently approved anti-VEGF therapies and other biologics for the treatment of retinal diseases in the USA and EU. Although effective, biologics are associated with high costs, which can lead to underutilisation and, consequently, suboptimal patient treatment outcomes, further contributing to healthcare costs [7]. Anti-VEGF therapies also impose a burden on both patients and the healthcare system, involving multiple treatments, frequent hospital visits, and ancillary testing [8]. Recently, anti-VEGF biosimilars have been approved and are expected to provide a cost-effective alternative, while providing equivalent efficacy and comparable safety, immunogenicity, and pharmacokinetic profiles as the reference product [7]. The aim of the current article is to provide an up-to-date narrative review of the impact of retinal diseases on the clinical, social, and financial aspects of patient care, and to discuss the value that biosimilars can bring to the field of ophthalmology. We have restricted discussion to biosimilars available in the EU and USA where they have recently become available.

Table 1.

Approved reference biologics for the treatment of retinal diseases in the USA and EU (as of November 2024) [115–131]

Biologic/brand	Phase of development	Class	Approval year
Ranibizumab/Lucentis	FDA/EMA approved	Antibody	2006/2007
Aflibercept/Eylea	FDA/EMA approved	Fusion protein “trap”	2011/2012
Aflibercept/Eylea HD	FDA/EMA approved	Fusion protein “trap”	2023/2024
Brolucizumab/Beovu	FDA/EMA approved	Antibody	2019/2020
Ranibizumab/Susvimo port delivery systems	FDA approved	Antibody	2021
Faricimab/Vabysmo	FDA/EMA approved	Bi-specific antibody	2022
Pegcetacoplan/Syfovre	FDA approved	C3 complement inhibitor	2023
Avacincaptad pegol/Izervay	FDA approved	C5 complement inhibitor	2023

C3 complement component 3, C5 complement component 5, EMA European Medicines Association, FDA US Food and Drug Administration, HD high dose

Literature searches on key topics were performed using the PubMed database and restricted to English language publications. The search strategy was initiated in November 2023 and was reinstated in March 2024 to capture recent full-text publications. Search terms included 'retinal diseases’,’biosimilars’, ‘biologics’, ‘neovascular age-related macular degeneration’, ‘diabetic retinopathy’, ‘retinal vein occlusion’, ‘myopic choroidal neovascularisation’, and ‘anti-vascular endothelial growth factor’.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Clinical Burden

For patients with vision loss, health consequences extend well beyond the eye. Vision loss can affect a person’s QoL, mobility, and independence, and is linked to falls, injury, and worsened status in domains spanning mental health, cognition, social function, employment, and educational attainment [2, 9–13]. The QoL of people with major blinding retinal diseases such as nAMD and DME is severely compromised and is undoubtedly a highly emotional experience. Retinal diseases can also impact life satisfaction and the ability to perform daily activities [9–12].

Neovascular (Wet) Age-Related Macular Degeneration (nAMD)

Approximately 200 million individuals globally are affected by AMD, encompassing both dry AMD and nAMD, and this figure is projected to reach 288 million by 2040 [4]. While nAMD constitutes roughly 10% of AMD cases, it disproportionately leads to 90% of cases resulting in legal blindness [14]. As highlighted by the Bright Focus Foundation, nAMD stands as the foremost cause of irreversible blindness and visual impairment globally [15]. The global prevalence of nAMD in people aged ≥ 45 years is estimated at 0.4% [16]. Although data on the prevalence of nAMD within individual countries is limited, it is estimated that about 200,000 new cases of nAMD are diagnosed each year in the USA [16]. A 2017 meta-analysis including 42,080 Europeans estimated the prevalence of advanced AMD (including nAMD and dry AMD) at 0.1% in people 55 to 59 years of age, increasing to 9.8% in those older than 85 years [17]. A recent Finnish study of approximately 410,000 inhabitants demonstrated a constant 1.2- and 2.4-fold increase in the incidence of nAMD in the elderly population aged 75–84 and 85–96 years during the last 15 years, with a 3% prevalence of nAMD in 2020 [18].

The onset of nAMD is often rapid, and age-related, with most patients being > 60 years of age and the incidence increasing rapidly thereafter [19]. Several studies have investigated the impact of nAMD on QoL [9, 10, 20–25]. A longitudinal clinic-based study was conducted by Vu et al. using the National Eye Institute Visual Function Questionnaire-25 (VFQ-25), Short-Form 36 (SF-36), and EuroQoL EQ-5D-5L questionnaires to assess vision-related and health-related QoL. Of the 83 patients assessed at 1-year follow-up, results found mild-to-moderate visual impairment or blindness at baseline had significantly lower VFQ-25 scores at follow-up. Having ≥ 3 chronic diseases correlated with reduced SF-36 mental component scores (MCS; p = 0.04) and EuroQol-visual analogue scale (EQ-VAS) scores (p = 0.05). The authors suggest that the reasons for poorer mental health in patients with multiple chronic diseases may be due to patients perceiving themselves as a burden upon their families, or the management of their conditions causing financial stress, as well as the potential burden of symptoms and treatment side effects. Additionally, the presence of depressive symptoms was linked to significantly lower MCS (p < 0.0001) and EQ-VAS scores (p = 0.02) [9]. A systematic review of 184 patients with nAMD showed a decrease in visual acuity (VA) in the best eye to below 0.5 (Snellen scale) occurs within 4.3 years, and significantly impacts QoL as measured by the Health Utilities Index issue 3 (HUI-3) questionnaire. For example, driving ranks among the activities highly valued by individuals, where a VA of at least 0.5 Snellen in one eye permits driving. Moreover, the review predicted that patients may lose approximately 25% of their initial QoL after 10 years. Further, the authors suggest that QoL scores for patients with nAMD are comparable to or worse than those for individuals with conditions such as diabetes, colorectal cancer, or multiple sclerosis, and may worsen with time [20].

Diabetic Retinopathy (DR) and Diabetic Macular Oedema (DME)

While asymptomatic in its early stages, DR emerges as a prominent cause of vision impairment and blindness in individuals with diabetes, with a growing clinical burden as the disease advances. In working-aged adults, DR has been identified as a leading cause of registered blindness [12, 26]. A pooled analysis of 204,189 patients with diabetes estimated that the global prevalence of DR in the diabetic population in general, women, and men was 28.41%, 25.93%, and 28.95% respectively [27]. Recently, a systematic review and meta-analysis calculated the global prevalence and number of people with DR in 2020 to be 103 million and by 2045 this figure is projected to increase to 160 million [28].

As DR advances, its clinical burden also increases. DR can be divided into two stages: the early stage known as non-proliferative diabetic retinopathy (NPDR) is marked by microaneurysms and retinal haemorrhages, while the advanced stage of PDR involves neovascularisation within the retina [29]. Severe DR is also significantly associated with worse ocular pain, vision, driving (all p < 0.001), and visual-specific mental health (p < 0.046) versus mild-moderate DR as assessed by the VFQ-25 functioning questionnaire and the locus of control tool [30].

In DR, the accumulation of fluid in the macular area leads to increased central retinal/macular thickness, resulting in DME [31]. This can occur at any stage of DR, with the risk increasing as DR worsens [32]. A recent systematic review and meta-analysis reported the pooled prevalence of DME is estimated at 5.47% worldwide, 5.81% in low-to-middle income countries, and 5.14% in high-income countries, respectively. The prevalence of DME is higher in individuals with type 1 diabetes mellitus (T1D) than those with type 2 diabetes mellitus (T2D). Nonetheless, as a result of the higher worldwide occurrence of T2D, a larger number of DME cases originate from people with T2D [33].

The impact of DME on patients’ QoL is considerable and comparable to that of nAMD [33]. In a phase II study involving 43 patients with DME, participants demonstrated low baseline vision-related QoL scores: 0.14 for reading, 1.05 for mobility, and 0.34 for emotional well-being scales [34]. With an ever-ageing global population and the increasing prevalence of diabetes, the clinical impact of DR and DME is set to increase dramatically [35, 36]. An observational study in 33 patients with T2D and clinically significant DME demonstrated that these patients experience a decreased vision-related QoL compared with T1D with DR, glaucoma or cataracts, and similar to that to those individuals with AMD [37]. A study comparing vision-related QoL between 104 patients with NPDR and PDR using the VFQ-25 and Vision Preference Value Scale found that patients with PDR suffer significant loss of vision-related QoL when compared to NPDR [38]. A recent systematic review and meta-analysis conducted by Zayed and colleagues found that both vision-related QoL and overall health-related QoL are notably diminished in individuals with vision-threatening DR, particularly in advanced stages and DME. Findings from this analysis underscore the significant impact of DR on QoL, revealing that even non-vision-threatening DR, which accounts for an estimated 30% or more of the DR population, is likely to exert a substantial influence on QoL at the population level as a result of its widespread prevalence [39].

Retinal Vein Occlusion (RVO)

After DR, RVO is the second most common RVD leading to severe vision loss [40]. RVO is estimated to affect between 14 and 19 million adults worldwide [41]. A systematic review and meta-analysis of the global prevalence of RVO found that in 2015, the prevalence of any RVO in people aged 30–89 years was 0.77% (95% CI 0.55–1.08), equivalent to approximately 28 million affected people worldwide [42]. The likelihood of experiencing a second RVO is estimated to be between 6.3% and 6.4%, while the annual risk of any vascular occlusion in the other eye is around 0.9% [43]. While the incidence of RVO increases with age, research has shown distinct differences in disease onset based on RVO subtypes, particularly in relation to gender and ocular laterality [44]. Potential risk factors identified for RVO include advanced age, hypertension, and various vascular factors [42].

RVO is an obstruction of the retinal venous system by thrombus formation and may involve a central retinal vein occlusion (CRVO), or branch retinal vein occlusion (BRVO). BRVO is more common yet causes less severe visual impairment compared with CRVO. In RVO, macular oedema is the most common cause of visual impairment followed by foveal ischaemia [42]. Untreated BRVO may see limited improvement in VA although rarely surpassing 20/40. Conversely, VA in untreated CRVO tends to decline over time. Macular oedema develops in 5–15% of BRVO eyes within a year, while most patients with CRVO exhibit signs of macular oedema at presentation. Vitreous haemorrhage occurs in approximately 40% of BRVO eyes over an unspecified time period and 10% of CRVO eyes within 9 months of initial presentation [45]. While the clinical and pathological consequences of RVO are well understood, their impact on QoL is less well known [46]. In 2022, a Save Sight Registries study showed that among retinal conditions, in general, people with DME had the worst Impact of Visual Impairment scores followed by those with RVO and AMD. Weak yet statistically significant correlations between scores and VA were observed [47]. Among RVDs, macular oedema due to RVO in the acute phase is likely the most directly mediated by VEGF, making it potentially the most responsive to anti-VEGF therapy [48].

Myopic Choroidal Neovascularisation (mCNV)

Another sight-threatening complication associated with myopia and pathological myopia is mCNV [49]. The incidence of mCNV in highly myopic eyes is notably high, impacting around 4–10% of individuals diagnosed with pathological myopia [50], and developing in 62% of individuals before reaching the age of 50. Moreover, an individual who has experienced mCNV in one eye carries an average risk of 34.8% for developing CNV in the corresponding fellow eye [51]. It is currently acknowledged that mCNV may arise in patients with any degree of myopia, even in the absence of distinct degenerative retinal alterations. Without treatment, the prognosis for mCNV is poor, with over 90% of affected individuals likely to have disease progression and irreversible deterioration of vision leading to blindness within 10 years [52]. Early detection and effective management strategies are crucial to mitigate the clinical, QoL, and socioeconomic burdens of mCNV.

Socioeconomic Burden

All chronic diseases have significant costs, as exemplified by Fig. 1 which outlines the healthcare costs of key chronic conditions in the USA, including nAMD, and diabetes. The burden of retinal diseases can be underestimated if only the burden of acute care, such as treatment and medication, is considered. The socioeconomic burden placed on patients, families, healthcare providers, and government systems can be classified as direct (medical and non-medical disease-related expenses) and indirect (productivity loss of patients and informal caregivers) costs (Table 2). As such, when estimating healthcare demand in a growing and ageing society it is advised to estimate the societal burden of disease, including indirect and long-term care costs [53].

Fig. 1.

Estimated annual healthcare costs of key chronic diseases in the USA [139, 140]. nAMD neovascular age-related macular degeneration

Table 2.

Direct and indirect costs associated with retinal diseases

Direct costs	Indirect costs
Number of hospital visits per year	Productivity loss of patients
Anti-VEGF medication/vitamins	Productivity loss of informal caregivers caring for patient and accompanying patients to appointments
Assessment and intravitreal procedure	Early retirement or disability
Other treatment and consultations (GP/ophthalmologist/psychiatrist)	Educational loss
Treating complications
Travel and parking costs of patients
House adaptation and supportive equipment

Anti-VEGF anti-vascular endothelial growth factor, GP general practitioner

Economic Burden of Blindness

Impairment of vision can cause or worsen poverty, through reduced employment prospects and work productivity, as well as adversely affecting educational opportunities and outcomes [54]. A UK study of 112,314 participants, where 759 (0.7%) of the participants had visual impairment or blindness, and an additional 25,678 (22.9%) had reduced vision in one or both eyes, showed that the vision level correlated with elevated risks of unemployment (risk ratio (RR) 1.55 [95% CI 1.31–1.84]), holding a lower-status job (RR 1.24 [95% CI 1.09–1.41]), living alone (RR 1.24 [95% CI 1.10–1.39]), and experiencing mental health issues (RR 1.12 [95% CI 1.04–1.20]) [55].

In 2017, Rein et al. estimated the economic impact of vision loss in the USA at $134.2 billion, comprising $98.7 billion in direct costs and $35.5 billion in indirect costs. The largest proportion of costs were attributed to nursing homes ($41.8 billion), other medical care services ($30.9 billion), and reduced labour force participation ($16.2 billion), all of which accounted for 66% of the total [56]. In Canada, the cost of vision loss was estimated at $32.9 billion in 2019, which included $17.4 billion in reduced well-being, $9.5 billion in healthcare system costs, and $4.3 billion productivity and informal caregiving losses [57]. In the EU, a study conducted by Chakravarthy et al. using three simple models based on (1) minimum wage (MW), (2) gross national income (GNI), and (3) purchasing power parity-adjusted gross national product (GDP-PPP) losses estimated that the total costs of blindness and moderate/severe visual impairment (population > 50 years) ranged from $25.83 billion to $56.52 billion in 2014/15 [58].

Economic Burden of nAMD

A US claims-based analysis of 6076 patients found that significant drivers of total nAMD-related costs were anti-VEGF choice and injection frequency (p < 0.0001). Moreover, in both prevalent and incident cohorts, nAMD-related outpatient visit costs were roughly four and seven higher, respectively, for patients with active CNV ($8658 [SD = $11,612]) compared with inactive CNV ($2406 [SD = $5510]) or inactive scar ($1198 [SD = $3035]) groups (p < 0.0001) [8]. Jaffe and colleagues showed that anti-VEGF-treated patients with nAMD in the EU demonstrated greater healthcare resource utilisation, reduced QoL, and increased overall activity impairment compared to non-nAMD controls [59]. Similarly, a retrospective analysis of 79 patients from France, Germany, Italy, Spain, and UK showed that patients with nAMD reported greater use of healthcare resources: 2.36 times more for healthcare professionals (HCP) visits, 8.39 times more for ophthalmologist visits, 2.59 times more for hospitalisations, and 2.33 times more for emergency room visits (N = 316; all p < 0.001) [60].

Economic Burden of DR and DME

In the USA, the annual healthcare costs associated with retinal disorders in 2013 totalled nearly $8.7 billion, with $4.1 billion of this attributed to diabetes-related retinal disorders [61]. From the employer perspective, a US study from 17 large companies (1999–2004) found that annual direct costs for employees with DR and diabetes were $18 218 (indirect = $3548) compared to $11,898 (indirect = $2374) for employees without DR and diabetes (p < 0.0001). Costs differences were larger across DR employee subgroups including DME versus non-DME ($28,606/$16,363) [62]. A further US healthcare claims assessment study (2007 to 2011) showed that non‑elderly patients with DME had an average of 24.7 annual days with healthcare visits compared with 14.4 for age‑matched controls with diabetes but no DME [63].

Economic Burden of RVO

There is a scarcity of information regarding the economic impact linked to RVO in both the USA and EU [45]. However, one US study conducted between 2001 and 2006 estimated patients with BRVO had 16% and 12% higher costs at 1 and 3 years, respectively, compared to patients with hypertension, and 18% and 13% higher costs at 1 and 3 years compared to patients with glaucoma. For patients with CRVO, costs were 22% and 15% higher and 24% and 16% higher respectively [45]. A 2014 US study investigating the direct medical costs and resource use of treating CRVO and BRVO found significantly higher healthcare utilisation and costs for both working-age and Medicare populations than those for control subjects, persisting for at least 3 years post-diagnosis [64].

Economic Burden on Caregivers

The caregivers of patients with retinal diseases report that the time taken off work for caregiving can be costly and means that they are often unable to meet their personal and employment obligations [65]. A cross-sectional survey of 236 caregivers of 236 patients whose sole impairment was visual found that female caregivers, caregivers providing greater hours of care, and caregivers of patients who have not completed vision rehabilitation programmes are at higher risk for depression [66]. A retrospective study of 546 visually impaired individuals found that informal care was reported by 39.6% of the participants, with the median number of caregivers’ hours per year reported as 390 h, representing a median opportunity cost of €2586. Moreover, the probability of reporting informal care was higher in those non-married, with comorbidities, with lower visual ability, and worse VA [67].

Treatment Burden

The burden of treatment related to nAMD and DME has been reported to result in patients receiving fewer anti-VEGF injections and less frequent monitoring than those participating in clinical trials [68]. A number of studies have evaluated the impact of delays in anti-VEGF treatment due to the COVID-19 pandemic on VA. The COVID-19 pandemic resulted in a significant reduction in the capacity of clinics, combined with staff shortages due to infections, and quarantine measures or reassignments to departments in need [69]. In one such study patients with 4 months or longer between subsequent injections (mean 5.1 months) experienced significant worsening of vision: 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or 1 line of vision deterioration for patients with nAMD, and 1 letter deterioration for patients with RVO or DME. This suggests that during instances of healthcare pressure similar to lockdown, patients with nAMD may require priority treatment over patients with DME or RVO [70].

Outside of a pandemic scenario, several studies have also demonstrated greater vision loss among patients with nAMD, DME, and RVO who experience delays in re-treatment [71, 72]. A retrospective analysis evaluating 3304 patients with nAMD ≥ 18 years who experienced treatment lapses ≥ 3 months compared with control found that lapse patients experienced a significant increase in central subfield thickness (p < 0.01), which normalised on resumption of treatment, as well as loss in the VA after lapse when compared with controls that did not recover through 12 months of follow-up [73].

The financial burden of anti-VEGF therapy on healthcare systems [74] can also vary across countries as a result of heterogeneity in the use of on-label and off-label therapies. In the USA, use of off-label bevacizumab has been considered to be an effective and lower-cost treatment option for nAMD. However, use of an off-label therapy is not ideal and may create a sense of uncertainty among prescribers. Recently, repackaged bevacizumab has been linked to instances of endophthalmitis outbreaks worldwide, wherein non-sterile compounding procedures have resulted in microbial contamination and subsequent occurrences of endophthalmitis [75]. In a recent study of 20 European countries investigating the current off-label use of bevacizumab to treat nAMD, substantial variations among nations were found, ranging from non-existent (0%) to remarkably high (97%). Within individual countries, significant disparities were also observed, with proportions ranging from 0 to 80%. These variations were attributed to differences in regional decision-making processes [76]. On 21 March 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product bevacizumab gamma (Lytenava®) intended for the treatment of nAMD [77].

Cost-effectiveness Considerations for Anti-VEGF Treatment

Both IVT aflibercept and ranibizumab have been shown to be cost-effective treatment options in different settings. In 2014, a UK analysis compared the cost-effectiveness of immediate ranibizumab treatment in patients with nAMD with good initial VA (> 6/12) against the standard UK practice of delaying treatment until vision is below 6/12, using real-world outcomes data. Results showed that over 2 years, the early treatment arm accumulated 1.59 quality-adjusted life years (QALYs) and £8469.79 cost. The delayed treatment arm accumulated 1.35 QALYs and £7460.21 cost. The mean incremental cost-effectiveness ratio estimate (ICER) was £4251.60 [78]. A US cost-effectiveness analysis was conducted to compare IVT aflibercept injection (2 mg every 8 weeks after three initial monthly doses [IAI 2q8]) versus ranibizumab 0.5 mg monthly [Rq4] and pro re nata (PRN) in the treatment of patients with nAMD. Results showed that IAI 2q8 provided equal health benefits to Rq4 (5.44 QALYs) at a lower total cost ($33,745 vs. $48,031) due to fewer injections received and lower cost of treatment over the 2 years. IAI 2q8 yielded greater QALYs compared with ranibizumab PRN (5.440 vs 5.404) at a higher cost ($33,745 vs. $33,652), with an ICER of $2583. These results suggest that IAI 2q8 can be cost-saving and cost-effective compared with ranibizumab Rq4 and PRN, respectively, for the treatment of nAMD in the USA [79].

Recently, a US evaluation assessed the direct and indirect benefits associated with DME treatment in four scenarios (untreated, anti-VEGF therapy, laser, and steroid). Results showed that a hypothetical 51-year-old treated for DME would have a 4–5% greater life expectancy, spending 30–35% additional years with excellent/good vision compared with someone who was untreated. They would work 8–9% more years and have increased earnings of 12–19%. For the same individual, treatment with anti-VEGFs increases QALY and disability-free life-years by 11% and 13%, respectively [80]. A UK based cost-effective analysis showed IVT ranibizumab is a highly cost-effective intervention for CNV due to causes other than nAMD and pathological myopia, with an ICER of £1363 per QALY compared to best supportive care [81].

Overall, these findings underscore the importance of considering not only the cost but also the cost-effectiveness of anti-VEGF treatments in making informed healthcare decisions.

Biosimilars in Retinal Disease

Potential Value of Biosimilars in Retinal Disease

Patients with retinal diseases appear to place a significant demand on health resources [82]. This is unsurprising given that the number of patients with retinal disease is steadily increasing in tandem with the ageing population. For example, the care-related challenges posed by nAMD on healthcare systems in the EU and USA—as well as on patients undergoing nAMD treatment—are substantial and may prove to be unsustainable [59]. Treatment strategies should prioritise minimising the burden associated with frequent IVT injections, while upholding rigorous standards of effectiveness and safety. A more cost-effective approach to the treatment of RVDs and CVDs is required to enable the full benefit of anti-VEGF therapy to be realised, while ensuring the long-term sustainability of healthcare systems.

Biosimilars are similar to approved biological medicines (reference products), with similarity being rigorously confirmed through analytical and clinical programmes including phase III equivalence studies, followed by a stringent regulatory approval process [7, 83]. There is over 15 years of post-approval clinical experience with biosimilars across different disease areas such as immunology, diabetology, and oncology [84] and they have changed healthcare ecosystems across different disciplines. The proactive use of biosimilars has provided large cost savings across therapy areas, resulting in savings in the EU of €5.7 billion in 2020 [85] and generating $7 billion in savings for patients and healthcare systems in the USA [86]. However, in reality, the benefits of biosimilars are much wider and have a greater clinical impact, including increasing access to healthcare and improved quality of care for more patients [87]. Table 3 outlines currently approved biosimilars for the treatment of retinal diseases in the EU and USA. Candidates for biosimilars of ranibizumab and aflibercept are presently undergoing development for retinal disease treatment, and some have received regulatory approval [7]. Other biosimilars have been, and are being, developed in Asia but these are not the focus of this review [88, 89].

Table 3.

Approved biosimilars for the treatment of retinal diseases in the USA and EU (as of November 2024) [125–127, 129, 132–138]

Biosimilar/brand	Phase of development	Class	Approval year
Ranibizumab/Byooviz	FDA/EMA approved	Antibody	2021
Ranibizumab/Cimerli	FDA approved	Antibody	2022
Ranibizumab/Cimerli/Ranivisio (FDA/EMA approved)	EMA approved	Antibody	2022
Ranibizumab/Ximluci	EMA approved	Antibody	2022
Ranibizumab/Rimmyrah	EMA approved	Antibody	2024
Aflibercept/Yesafili	FDA/EMA approved	Antibody	2024/2023
Aflibercept/Opuviz	FDA approved	Antibody	2024
Ranibizumab Midas	EMA approved	Antibody	2024
Ranibizumab/Pavblu	FDA approved	Antibody	2024
Ranibizumab/Enzeevu	FDA approved	Antibody	2024
Ranibizumab/Ahzantive	FDA approved	Antibody	2024

EMA European Medicines Agency, FDA US Food and Drug Administration

Undertreatment

Sustained treatment is needed to optimise outcomes. A meta-analysis of real-world outcomes on the use of ranibizumab for the treatment of nAMD showed that while treatment was effective in preventing severe visual loss, maintenance of response was dependent upon receiving sufficient injections. The majority of studies had injection rates well below those of clinical trials involving ranibizumab [67, 68]. In agreement with this finding, the global LUMINOUS real-world study showed that greater improvements in VA were observed with higher numbers of anti-VEGF injections (< 3, 3–6, > 6) over the first year of treatment for patients with nAMD [90]. One reason for anti-VEGF injection rate disparities across countries may be due to differing reimbursement policies. Additionally, variation may be due to differences in nAMD prevalence across countries and ethnic groups, and inequalities in treatment capacity between clinics [91]. Variations may also exist within countries where regional differences in access may result from uneven distribution of healthcare resources, creating pockets of limited availability. For example within the USA, compared to residents of large city suburbs, residents of central metropolitan areas receive poorer care for 25% of the core measures of quality, and residents of micropolitan and noncore areas receive poorer care for 30% of the core measures of quality [92]. The emergence of more affordable anti-VEGF biosimilars holds promise in expanding treatment access and alleviating undertreatment concerns. For example, in countries where off-label bevacizumab usage is common practice, access tends to be unhindered. However, in regions where bevacizumab is not readily available, patients may encounter challenges in access to effective treatments.

Research suggests a significant proportion of patients (up to 95%) with retinal diseases are undertreated through non-adherence to treatment leading to inferior results in visual function and poorer clinical outcomes [93]. Reasons for non-adherence are multifactorial and include factors related to the condition (e.g. worse baseline VA, worse final VA), patient-related factors (e.g. older age, ethnicity, comorbidities, side effects, reduced independence), health system factors (e.g. high treatment cost restrictions), and social/economic factors (e.g. financial burden, gross income, lack of care) [68, 94, 95]. In some countries, the high cost of reference biologics can impose a significant financial burden, potentially hindering sustained treatment for optimised clinical outcomes. In healthcare systems lacking reimbursement, this burden is borne by the patient, possibly resulting in treatment discontinuation or decreased adherence, leading to poorer visual outcomes. Likewise, systems with reimbursement may face challenges in providing financial coverage for these therapies, impacting patient accessibility [96]. Some nations may face challenges in providing financial coverage for these therapies, impacting patient accessibility [74]. Geographical variations in treatment rates have also been reported in countries such as the UK, Norway, and Portugal where anti-VEGF treatments are reimbursed by the healthcare system [74, 97]. Additionally, as new drugs receive approval for more common conditions, such as dry AMD, the number of patients requiring treatment is expected to further increase [98]. The introduction of anti-VEGF biosimilars offers a cost-effective option that may improve therapy adherence, enabling patients to seamlessly continue therapy, and also opens avenues for reinvestment to alleviate financial burdens on health systems and contribute to healthcare improvements, such as expanding clinic capacity.

The transition of biosimilars into ophthalmology faces challenges. Physicians have a lack of confidence in biosimilars, which is rooted in limited awareness of them, or how to use them practically. Furthermore, the use of biosimilars can be impacted by the nocebo effect, which is when patients experience a negative effect of a treatment through their expectations of that treatment and is unrelated to the treatment’s physiological action [7]. The nocebo effect can have a number of consequences including increasing symptom burden, non-adherence, and treatment costs while decreasing QoL. Patient and healthcare provider education on biosimilars is essential to ensure that patients are informed about their options, any potential nocebo effects can be mitigated, and adherence to treatment maximised. Moreover, healthcare providers and patients should be educated about the distinct regulatory principles guiding the approval of biosimilars, which may raise concerns due to their differences from those governing reference biologics. However, it is crucial to recognise that these concerns are unwarranted, as the regulatory approach for approving biosimilars is governed by rigorous scientific standards [7]. Disparities in the biosimilar regulatory processes of the USA and the EU can impact their adoption in these regions. In the EU, the biosimilar market has developed faster than its US counterpart. In 2021, an executive order on competition issued by the Biden administration highlighted the issue of high prescription drug costs for people living in the USA, surpassing prices observed in other countries. The order specifically identified the misuse of patents as a factor preventing or delaying the availability of lower-cost generic drugs and biosimilars [99]. With biologics patents expiring, there is a growing opportunity for the biosimilar market to offer more affordable options to patients. Consequently there is a crucial need for a more streamlined approach to biosimilar development and swift market access [100].

Cost Savings, Cost-effectiveness and Other Value Drivers

Lower-priced medications can trigger much needed savings for both the patient and healthcare systems [101]. A UK national budget impact analysis was developed to forecast the financial impact for the NHS of switching from reference to biosimilar ranibizumab in patients with nAMD over a period of 12 months for 265,597 units. Results showed that the annual cost-savings from biosimilar adoption could fund the annual salaries of 40 (minimum) to 897 (maximum) additional highly qualified nurses. The authors concluded that cost savings generated could be reinvested to address local capacity pressures faced across NHS England in the provision of nAMD care [102]. A Canadian two-scenario analysis (a market with ranibizumab biosimilars, and a market without) investigating the cost savings of biosimilars switching across provinces over a 3-year period found the total savings estimated for all identified non-proactive provinces with a non-proactive switching policy would be CAD$24,352,109. While for a proactive switching policy scenario modelled for all provinces, savings of CAD$142,593,234 were projected, with 66% of savings coming from non-proactive provinces [103]. Increased use of biosimilars and the associated cost savings can provide the ability for healthcare providers to invest in facilities, staff, and innovation to improve patient care through gain-share agreements. These are situations where a portion of the cost savings accrued by using biosimilars is reinvested into the participating clinical services by the health authorities [104–106].

Since the presence of biosimilars in the ophthalmology therapy market is relatively new, studies on the cost-effectiveness of biosimilars for nAMD and other indications remain limited. Recently, a systematic review was conducted by the Professional Society for Health Economics and Outcomes Research (ISPOR) Biosimilar Special Interest Group to assess the gaps and challenges in the value assessment of biosimilars. The group concluded that given that a biosimilar is highly similar to its reference product, health technology assessment agencies should accept the comparability exercise approved by regulatory authorities and, thus, conduct a price comparison when biosimilar reimbursement is requested for the same indication as the reference product. In cases where the reference product is not reimbursed or is not the standard of care, a full economic evaluation of the biosimilar versus a relevant comparator needs to be conducted. Additionally, it was agreed that little consideration has been given to specific challenges, such as how biosimilar value assessment can account for the nocebo effect [7], potential differences between biologic-naïve and biologic-experienced patients, and the contribution of biosimilars for generating health gain at the population level [107].

Price competition generated between biosimilars and reference products can also decrease the cost of the reference products. The 2023 Samsung Bioepis biosimilars market report shows biosimilars are reducing drug costs across multiple therapy areas by lowering prices. Indeed, average selling price (ASP) declined by 41% on average 3 years post-first biosimilar launch, with the ASP for oncology biosimilars (including trastuzumab, bevacizumab, and rituximab) experiencing the steepest decline versus others [108]. Retinal biosimilars therefore generate an opportunity to optimise drug spending on retinal diseases by inducing competition.

Real-World Evidence

As biosimilars have only recently been introduced into the ophthalmologic space, real-world evidence for their use is limited, especially from the EU and USA. Indeed, only a few studies have been fully published, all based on biosimilars available within India and including small numbers of patients [109–111]. Data from these studies suggest that biosimilar ranibizumab has similar efficacy and comparable safety to reference ranibizumab in patients with retinal diseases. Data from the US IRIS database on the use of ranibizumab biosimilars have been presented at the American Academy of Ophthalmology 2023 and EURETINA 2024 meetings [112, 113]. These data outlined the baseline and demographic data of naïve or switched patients with nAMD receiving reference or biosimilar ranibizumab. Patients in the reference ranibizumab group tended to be older, while patients in the biosimilar ranibizumab group had a higher likelihood of poor visual acuity. No differences in clinical outcomes or safety were evident between patients treated with reference ranibizumab and those switched to biosimilar ranibizumab.

Conclusions

Retinal diseases, such as nAMD, DR, DME, RVO, and mCNV, significantly contribute to global blindness and vision loss, particularly among the ageing population. While the current standard treatment of anti-VEGF therapy is effective, it also reveals unmet clinical needs involving access, burden, and sustainability. The entry of biosimilars, including the much anticipated FDA approval of aflibercept biosimilars (aflibercept-jbvf and aflibercept-yszy) [114], holds the promise of meeting some of these needs, giving physicians and patients access to sustainable treatments that can provide cost-effective therapy, enabling savings to be reinvested into healthcare facilities.

Author Contributions

Seenu M. Hariprasad, Frank G. Holz, Carl V. Asche, Amine Issa, Oriol Mora, Simon Keady, Mourad F. Rezk, Phil Sarocco, and Steven Simoens all contributed to the conception or design of the work; the literature search; the acquisition, analysis, and interpretation of data; drafting of the work; and revising it critically for important intellectual content. All authors contributed to and approved the final manuscript.

Funding

Biogen International GmbH, Baar, Switzerland provided funding for medical writing support in the development of this article and for the journal’s Rapid Service Fee.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Seenu M. Hariprasad is a consultant or on the speakers' bureau for Bayer, Allergan/AbbVie, Coherus, Astellas/Iveric Bio, Alimera Sciences, Biogen, Harrow and Regeneron. Frank G. Holz reports research grants and consulting fees from Acucela, Allergan, Apellis, Bayer, Bioeq/Formycon, Roche/Genentech, Geuder, Heidelberg Engineering, Astellas/ivericBio, Pixium Vision, Novartis, Zeiss; consulting fees from Alexion, Alzheon, Annexon, Astellas, Boehringer-Ingelheim, Grayburg Vision, Janssen, LinBioscience, Stealth BioTherapeutics, Aerie, Oxurion. Carl V. Asche has no conflicts of interest. Amine Issa, Oriol Mora and Mourad F. Rezk are employees of Biogen International GmbH and may hold stock in Biogen. Simon Keady and Phil Sarocco are former employees of Biogen. Their new affiliations are: Phil Sarocco, Halozyme, Inc., employee and shareholder; Simon Keady, Galderma (UK) Ltd, employee. Steven Simoens is one of the founders of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL). He was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD; he has participated in advisory board meetings for Pfizer, Organon and Amgen; he has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma and Pfizer; and he has had speaking engagements for Abbott, Amgen, Biogen, Celltrion and Sandoz.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.