Cost of Ranibizumab Port Delivery System vs Intravitreal Injections for Patients With Neovascular Age-Related Macular Degeneration

This cost analysis investigates costs of intravitreal anti-vascular endothelial growth factor injections vs ranibizumab port delivery system for patients with neovascular age-related macular degeneration.

Key Points

Question

How do costs modeled for the ranibizumab port delivery system (PDS) compare with intravitreal anti–vascular endothelial growth factor for patients with neovascular age-related macular degeneration?

Findings

In this cost analysis based on a model using trial data and Medicare reimbursement rates, compared with ranibizumab PDS with 1 refill, the mean (SD) break-even point was 10.8 (1.3) ranibizumab injections, 9.3 (1.1) aflibercept injections, and 34.5 (4.2) bevacizumab injections. Over 1 year, PDS with fixed 6-month refills costs $21 106 (SD, $2102); monthly ranibizumab, aflibercept, and bevacizumab injections cost $22 960 (SD, $2296), $26 718 (SD, $2672), and $4285 (SD, $429), respectively; and bimonthly aflibercept cost $13 359 (SD, $1336).

Meaning

In this analysis, ranibizumab PDS with 1 refill was costlier than intravitreal ranibizumab and aflibercept injections if less than or equal to approximately 11 and 10 injections, respectively, were given within the first year.

Abstract

Importance

The study team investigated costs associated with the ranibizumab port delivery system (PDS) for neovascular age-related macular (nAMD), an alternative to conventional intravitreal anti–vascular endothelial growth factor (VEGF) injections.

Objective

To investigate costs of intravitreal anti-VEGF injections vs ranibizumab PDS for patients with neovascular AMD (nAMD).

Design, Setting, and Participants

This cost analysis used trial data and Medicare reimbursement rates and included patients with nAMD who were receiving ranibizumab, aflibercept, bevacizumab injections, or ranibizumab PDS.

Main Outcomes and Measures

The number of intravitreal ranibizumab, aflibercept, and bevacizumab injections to break even with costs of ranibizumab PDS. Total direct medical costs over 1 year and 5 years for the ranibizumab PDS arm with refills at fixed 6-month intervals compared with monthly or bimonthly injections were calculated using Medicare rates. Scenario and sensitivity analyses accounted for uncertainty and variation.

Results

The mean (SD) number of ranibizumab, aflibercept, and bevacizumab injections to break even with the cost of ranibizumab PDS with 1 refill was 10.8 (1.3), 9.3 (1.1), and 34.5 (4.2), respectively. Ranibizumab PDS with fixed 6-month refills over 1 year cost $21 016 ($2102). Comparatively, monthly intravitreal ranibizumab cost $1943 (95% CI, −$3047 to $6932; P = .34) more, aflibercept cost $5702 (95% CI, $253-$11 151; P = .04) more, and bevacizumab cost $16 732 (95% CI, −$20 170 to −$13 294, P < .001) less. For bimonthly injections, aflibercept cost $7658 (95% CI, −$11 649.52 to −$3665.61; P = .006) less. Over 5 years, monthly intravitreal ranibizumab projected to cost $25 581 (95% CI, $2275-$48 887; P = .04) more, aflibercept cost $44 374 (95% CI, $18 623-$70 125; P = .008) more, and bevacizumab cost $67 793 (95% CI, −$82 501 to −$53 085; P < .001) less than PDS with fixed refills (mean [SD] cost, $89 218 [$8921]). For bimonthly injections, aflibercept cost $22 422 (95% CI, −$40 287 to −$45,56; P = .03) less. In scenario analyses, ranibizumab PDS with refills as needed offered cost savings compared with real-world intravitreal ranibizumab or aflibercept use at 5 years but not at 1 year.

Conclusions and Relevance

In this cost analysis, ranibizumab PDS with 1 refill cost more than intravitreal ranibizumab or aflibercept injections if less than or equal to approximately 11 or 10 injections, respectively, are required within the first year. Long term, if less than 4.4 and 3.8 injections are needed per refill, intravitreal ranibizumab and aflibercept is lower cost. Ranibizumab PDS costs more than intravitreal bevacizumab injections throughout scenarios.

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in individuals older than 50 years in industrialized countries; by 2040, 288 million people worldwide will have AMD.^1,2 While neovascular AMD (nAMD) is only responsible for 10% to 15% of AMD cases, it caused 90% of AMD–related visual impairment before the introduction of anti–vascular endothelial growth factor (VEGF) drugs.^3,4 Late atrophic AMD does not have adequate therapeutic options and is leading to increasing visual impairment comparatively.⁵ Anti-VEGF drugs have reduced AMD-attributed blindness by approximately 50% to 72%.^6,7

While anti-VEGF drugs have similar visual gains and are safe for nAMD, one notable difference is cost.⁸ Increasing use of these contribute significantly to Medicare Part B, costing $3.5 billion annually.^9,10 Frequent treatment regimens present problems for patients owing to travel to care, low health literacy, fear of injections, and cost concerns.¹¹

In 2022, the US Food and Drug Administration approved Susvimo (Genentech), the first port delivery system (PDS) with sustained delivery of ranibizumab. Implantation requires initial surgery with office refills per labeling as often as every 6 months. In the Archway phase 3 randomized clinical trial¹² of PDS with ranibizumab for nAMD, 98% of participants were stable with fixed 24-week refills. We describe cost differentials between intravitreal injections of ranibizumab, bevacizumab, and aflibercept compared with ranibizumab PDS use for nAMD.

Methods

This study complied with the Declaration of Helsinki and did not involve human subjects research. Institutional review board approval was waived by the University of Miami. We compiled data from published trials of ranibizumab PDS and patterns of anti-VEGF use in patients with nAMD.^12,13,14 We investigated total costs of ranibizumab PDS and intravitreal anti-VEGF injections (ranibizumab, aflibercept, bevacizumab) over 1 year and 5 years and assessed the number of anti-VEGF injections for costs to break even with ranibizumab PDS. We followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) for reporting standards.

Model Inputs

Ranibizumab PDS

We obtained data from the 2 studies investigating the PDS. The first was the phase 3 randomized clinical trial investigating the safety and efficacy of ranibizumab PDS, 100 mg, with fixed 24-week refills vs fixed interval monthly dosing of ranibizumab 0.5-mg injections.¹² As the phase 3 trial did not incorporate as-needed or pro re nata (PRN) refills, to determine the cost of receiving PRN refills, data were obtained from the phase 2 trial. This trial investigated different formulations of ranibizumab PDS with PRN refills compared with monthly ranibizumab, 0.5 mg, injections.¹⁴ Given that only 2 randomized clinical trials are available, we adapted the outcomes reported as inputs in our cost models.

In the phase 3 trial, 98.4% of those with the PDS were maintained on a fixed 24-week schedule. Thus, in the base case, we assumed a fixed 24-week schedule with 1 refill used as an input in our model in the first year, and 9 refills over 5 years.

In scenario analyses, we modeled PRN dosing of PDS refills from the phase 2 trial,^13,14 in which 59.4% of patients went 12 months or longer without meeting refill criteria. We assumed 40.6% would require refill in the first year (Table 1). The median time to refill was 15.8 months (80% CI, 12.1-20.4).¹⁴ Only the median and 80% CI were published. For our 5-year projections, we assumed that refills would be needed every 15.8 months, which totals to 3.80 refills (Table 2). Only 1 patient (1.7%) in the phase 2 trial,¹² and 4 patients (1.3%) in the phase 3 trial,¹⁴ necessitated supplemental treatment. Rescue injections were not included in our model given low incidence.

Table 1. Direct Costs of Procedures, Medications, and Health Visits Used in the Analysis.

Characteristics	Component	Cost, $	Source
Ranibizumab PDS implant insertion	ASC Facility fee (CPT code 67027)	1596	2022 Medicare Procedure Look-Up Tool
	ASC Professional fee (CPT code 67027)	853	2022 Medicare Procedure Look-Up Tool
	Anesthesia fee	300	Author estimate
	SUSVIMO injection and initial fill carton (NDC 50242-078-55)	8240a	Genentech information
	SUSVIMO ocular implant with insertion tool assembly carton	1250	Genentech information
	Total	12 239	NA
Ranibizumab PDS implant refill	Non-facility fee (CPT code 67028)	114	2022 CMS physician fee schedule
	SUSVIMO Refill Exchange Kit (NDC 50242-078-12)	8240a	Genentech information
	Total	8354	NA
Ranibizumab, 0.5 mg, injection	Non-facility fee (CPT code 67028)	114	2022 CMS physician fee schedule
	Medication fee (J2778) 5 units	1628b	2022 ASP drug pricing files
	Total	1742	NA
Aflibercept, 2 mg, injection	Non-facility fee (CPT 67028)	114	2022 CMS physician fee schedule
	Medication fee (J0178) 2 units	1941b	2022 ASP drug pricing files
	Total	2056
Bevacizumab, 1.25 mg, injection	Non-facility fee (CPT 67028)	114	2022 CMS physician fee schedule
	Medication fee (J2778) 1 unit	68b	2022 ASP drug pricing files
	Total	186	NA
Endophthalmitis treatment	Facility fee (CPT 67015)	670	2022 CMS physician fee schedule
	Non-facility fee (CPT 67028)	114	2022 CMS physician fee schedule
	J3370 (5 mg vancomycin)b	3	2022 ASP drug pricing files
	J0713 (1 mg ceftazidime)b	2	2022 ASP drug pricing files
	Total	789	NA
Conjunctival erosion/retraction treatment	Facility fee (CPT 66250)	853	2022 Medicare Procedure Look-Up Tool
	ASC professional fee (CPT 66250)	658	NA
	Anesthesia fee	300	Author estimate
	Total	1713	NA
Office visit	CPT 99214 Type IV E&M; established patient	130	2022 CMS physician fee schedule
	CPT 92134OCT; imaging	41	2022 CMS physician fee schedule
	Total	171	NA

Abbreviations: ASC, Ambulatory Surgical Center; ASP, average sales price; CMS, US Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; NA, not applicable; NDC, National Drug Code.

^a Wholesale acquisition cost of injection plus 3%.

^b ASP plus 6% plus units required for treatment.

Table 2. Model Inputs.

Characteristic	Measure	Source
Time to first refill, ranibizumab PDS, mo	Median (80% CI), 15.8 (12.1-20.6)	Khanani et al, 202114
Patients receiving at least 1 refill in 1 y, ranibizumab PDS (%)	Median, 40.60	Khanani et al, 202114
Endophthalmitis complication rate, PDS ranibizumab, %	Median, 1.6	Holekamp et al, 202212
Conjunctival erosion/retraction rate, PDS ranibizumab, %	Median, 4.03a	Holekamp et al, 202212.
No. of refills over 5 y, ranibizumab PDS	Mean, 3.80; Median time to refill is 15.8 mo	Khanani et al, 202114
Anti-VEGF injections per year—real-world scenario
Ranibizumab	Mean (SD), 6.4 (2.4)	Rao et al, 201815
Aflibercept	Mean (SD), 6.2 (2.4)	Rao et al, 201815
Bevacizumab	Mean (SD), 5.9 (2.4)	Rao et al, 201815

NA, not applicable; PDS, port delivery system.

^a 10 of 248 patients with a conjunctival bleb, erosion, or retraction required surgical intervention in the clinical trial.

We modeled costs of complications resulting from PDS implantation. In the phase 3 trial,¹² 1.6% of patients had endophthalmitis before the first refill. We assumed the endophthalmitis risk following refills is equivalent to the risk following intravitreal injections (0.05%-0.10%, per US claims analysis).¹⁶ We included costs of additional surgery for conjunctival bleb/erosion/retraction, which occurred in 4.0% of patients in the phase 3 trial. Of severe adverse events reported, these had the highest incidence and costs. No patients with vitreous hemorrhage required additional surgery; therefore, no added costs were implicated.

Intravitreal Anti-VEGF Injections

In both the phase 2 and phase 3 trials, ranibizumab PDS was compared with monthly ranibizumab injections and shown to be noninferior. To our knowledge, there are no other trials reporting similar visual outcomes using ranibizumab PDS vs other injection regimen. Thus, in our base case, we assumed monthly injections of intravitreal agents. We also included an arm with bimonthly aflibercept injections (every 8 weeks) given that patients were not treatment naive.

We also included a scenario analysis modeling real-world use of anti-VEGF injections based on data from the American Academy of Ophthalmology Intelligent Research in Sight (IRIS) Registry.¹⁵ We obtained the mean annual number of intravitreal anti-VEGF injections from a retrospective study of patients with nAMD receiving at least 3 consecutive injections of a single 3 anti-VEGF drug (ranibizumab, 0.5 mg; aflibercept, 2 mg; and bevacizumab, 1.25 mg) for 1 year.¹⁵ Over 1 year, patients treated with ranibizumab, aflibercept, and bevacizumab received a mean (SD) of 6.4 (2.4) injections, 6.2 (2.4) injections, and 5.9 (2.4) injections, respectively (Table 2).¹⁵ We did not include faricimab as published studies only include treatment-naive patients.¹⁷

Costs

Ranibizumab PDS Case

We obtained cost information for ranibizumab PDS initial implantation and refills from the 2022 Centers for Medicare and Medicaid (CMS) Physician Fee Schedule and information from the manufacturer.^18,19 For implantation, Ambulatory Surgical Center facility and professional fees were obtained from Medicare Procedure Look-Up Tool and the 2022 Physician Fee Schedule for Current Procedural Terminology (CPT) code 67027. The PDS (Susvimo) Implantation Kit costs were obtained from the manufacturer at wholesale acquisition costs (WAC) (Table 1). The PDS (Susvimo) injection and initial fill carton (National Drug Code 50242-078-55) was $8000. The WAC of the implant with insertion tool assembly carton was $1250 for a total of $9250. The drug cost (National Drug Code 50242-078-55) was estimated at the WAC plus 3% ($8240). The anesthesia fee was $300, per expert opinion.²⁰ The total cost for PDS implantation was $12 239.

For refills, the nonfacility fee for the CPT code 67028 was used. The PDS (Susvimo) Refill Exchange Kit (National Drug Code 50242-078-12) cost was estimated at the WAC plus 3%. The total cost for a PDS refill was $8354 (Table 1).

Intravitreal Anti-VEGF Injections

The nonfacility fee for CPT code 67028 was used for all injections.^18,19,21 Drug prices were obtained from the 2022 Average Selling Price Drug Pricing files for ranibizumab, 0.1 mg, (J2778), aflibercept, 1 mg, (J0178), and bevacizumab, 1.25 mg (J9035).^18,19,21 We used national payment amount Medicare Administrative Contractor data provided in the Fee Schedule and Drug pricing files for all the drugs. The Medicare allowable payments for Part B drugs are the average selling price plus 6%, which was incorporated into our total cost. This resulted in a total cost of $1742 for ranibizumab, 0.5 mg, $2056 for aflibercept, 2 mg, and $186 for bevacizumab, 1.25 mg (Table 1).

Complications of PDS Implantation

For endophthalmitis, the CPT codes 67028 and 67015 and drug costs for vancomycin (J3370) and ceftazidime (J0713) were incorporated for a total of $789 as shown in Table 1. The treatment for corneal bleb, retraction, and erosion included the facility and professional fee for CPT code 66250 and an anesthesia fee resulting in the total cost of treatment of $1713 (Table 1).

Other Direct Costs

We included costs of office visits with optical coherence tomography (OCT) imaging as they guide clinical management. We excluded the cost of fluorescein angiography, given infrequent use.²² The total cost of an office visit with OCT imaging was $171 (CPT code 99124 with 92134; Table 1). Given the cost analysis design and short time horizons, we did not account for discounting.

Statistical Analysis

Break-even Analyses and Cost Models

We calculated the number of anti-VEGF injections to break even with the base cost of PDS alone, a single refill, and PDS with 1 refill and 2 refills. The cost of the injection included an office visit with imaging. We conducted sensitivity analyses on the break-even points by varying the cost, number of office visits, and complication rate. We used Microsoft Excel and Stata (version 17.0; StataCorp) for all modeling and statistical analysis.

In our base case, we compared ranibizumab PDS use with fixed 6-month interval refills with monthly ranibizumab, aflibercept, and bevacizumab injections, and bimonthly aflibercept injection use over 1 year and 5 years. We assumed the incidence rate of endophthalmitis following PDS implantation would be 1.6% and that of corneal bleb, erosion, or retraction necessitating surgery would be 4.0% (Table 2). Costs were projected over 5 years for both the ranibizumab PDS arm and the injection arms. For ranibizumab PDS, we assumed 9 refills would be required over 5 years assuming fixed-interval dosing. For the bimonthly aflibercept arm, we assumed 6 injections would be given annually. We assumed those in the PDS arm would require 2 annual office visits with OCT images, those in the monthly injection arm would require 12 annual visits, and the bimonthly arm would require 6 annual visits. All total costs were varied by 10%. Using unpaired t tests, we compared the costs over 1 year between the ranibizumab PDS and each of the injection arms and reported the 2-tailed P value. The level of significance was P < .05. We conducted sensitivity analyses varying the complication rate and number of annual visits (6 annual visits and 12 annual visits).

Scenario Analyses

We conducted 2 sets of scenario analyses. In the first, we assumed as-needed or PRN dosing of PDS ranibizumab following the data from the phase 2 trial. In the second, we assumed real-world anti-VEGF treatment regimens following the IRIS registry data. In our scenario analyses, we varied the number of PDS refills to reflect PRN dosing. In the 1-year cost model, we compared the cost of ranibizumab PDS, assuming 40.6% would require a refill within the first year.¹⁴ Costs were projected over 5 years for the ranibizumab PDS arm assuming a mean 3.8 PDS refills would be required (Table 2).¹⁴

We calculated the costs of real-world anti-VEGF injections based on the mean number of annual injections reported by Rao et al¹⁵ for each drug (over 5 years: 32 ranibizumab injections, 31 aflibercept injections, and 29.5 bevacizumab injections).²³

Results

Break-even Analyses

The mean (SD) of injections to break even with the cost of initial ranibizumab PDS implantation and medication was 6.4 (0.8) ranibizumab injections, 5.5 (0.7) aflibercept injections, and 34.5 (4.2) bevacizumab injections. To break even with the cost of ranibizumab PDS and 1 refill, a mean (SD) of 10.8 (1.3) ranibizumab injections, 9.3 (1.1) aflibercept injections, and 58.1 (7.1) bevacizumab injections were required. To account for PDS with 2 refills, a mean (SD) of 15.2 (1.9) ranibizumab injections, 13.1 (1.6) aflibercept injections, and 81.6 (10.0) bevacizumab injections were required (Table 3; eFigure in the Supplement). Additionally, to break even with the cost of a single refill, a mean (SD) of 4.4 (0.5) ranibizumab, 3.8 (0.5) aflibercept, and 23.6 (2.9) bevacizumab injections were required.

Table 3. Results of Break-even Analyses.

Characteristics	Injections, mean (SD)
	Ranibizumab PDS alonea	Ranibizumab PDS plus 1 refilla	Ranibizumab PDS plus 2 refillsa
Base cost
Ranibizumab arm	6.4 (0.8)	10.8 (1.3)	15.2 (1.9)
Aflibercept arm	5.5 (0.7)	9.3 (1.1)	13.1 (1.6)
Bevacizumab arm	34.5 (4.2)	58.1 (7.1)	81.6 (10.0)
Base cost and 2 yearly visits with imaging
	Ranibizumab PDS aloneb	Ranibizumab PDS plus 1 refillb	Ranibizumab PDS plus 2 refillsb
Ranibizumab arm	6.6 (0.8)	11.0 (1.4)	15.4 (1.9)
Aflibercept arm	5.7 (0.7)	9.5 (1.2)	13.2 (1.6)
Bevacizumab arm	35.5 (4.4)	59.0 (7.3)	82.6 (10.2)
Base cost and 6 yearly visits with imaging
	Ranibizumab PDS alone c	Ranibizumab PDS plus 1 refill c	Ranibizumab PDS plus 2 refills c
Ranibizumab arm	7.0 (0.9)	11.4 (1.4)	15.8 (1.9)
Aflibercept arm	6.0 (0.7)	9.8 (1.2)	13.6 (1.7)
Bevacizumab arm	37.4 (4.6)	60.3 (7.2)	84.5 (10.4)
Base cost and 12 yearly visits with imaging
	Ranibizumab PDS aloned	Ranibizumab PDS plus 1 refilld	Ranibizumab PDS plus 2 refillsd
Ranibizumab arm	7.5 (0.9)	11.9 (1.5)	16.3 (2.0)
Aflibercept arm	6.5 (0.8)	10.2 (1.3)	14.0 (1.7)
Bevacizumab arm	40.3 (5.0)	63.8 (7.9)	87.4 (10.7)

Abbreviation: PDS, port delivery system.

^a Incorporating cost of office visits and imaging and complications.

^b With 40.60% of patients receiving 1 refill in the first year.

^c With median time to refill of 15.8 months.

^d Modeling aflibercept injections at fixed 8-week intervals (every 2 months).

Incorporating other direct costs, such as office visits with imaging, into the total cost of the ranibizumab PDS did not greatly affect the number of injections to break even with the cost of PDS (Table 3). Increasing number of PDS refills to 2 affected to a greater degree the number of injections to break even, making this the most sensitive parameter (Table 3).

Total Costs

In the base case with fixed 6-month interval dosing, the mean (SD) total cost of the ranibizumab PDS with refills over 1 year was $21 016 ($2102) (Table 4). Over 1 year, the cost differences between the ranibizumab PDS and monthly ranibizumab, aflibercept, and bevacizumab injections were −$1943 (95% CI, −$3047 to $6932; P = .34), −$5702 (95% CI, $253-$11 151; P = .04), and $16 732 (95% CI, −$20 170 to −$13 294; P < .001), respectively. Bimonthly aflibercept injections cost $7658 (95% CI, −$11 645 to −$3666; P = .006) less than the ranibizumab PDS (Table 4).

Table 4. 6-Month Fixed Interval Dosing of Ranibizumab PDS Refills vs Monthly and Bimonthly Anti-VEGF Injections^a.

Characteristic	Cost over 1 y, mean (SD), $	Difference between injection arm and PDS arm for year 1, mean (95% CI), $	P value	Cost over 5 y, mean (SD), $	Difference between injection arm and PDS arm for year 5, mean (95% CI), $	P value
Ranibizumab PDS with refill (2 visits/y)	21 017 (2102)	NA	NA	89 218 (8922)	NA	NA
Ranibizumab injection (12 visits/y)	22 960 (2296)	1943 (−3047 to 6932)	.34	114 799 (11 480)	25 581 (2275-48 887)	.04
Aflibercept injection (12 visits/y)	26 718 (2672)	5702 (253-11 151)	.04	133 592 (13 359)	44 374 (18 623-70 125)	.01
Aflibercept injectionb (6 visits/y)	13 359.24 (1336)	−7658 (−11 650 to −3666)	.006	66 796 (6680)	−22 422 (−40 287 to −4556)	.03
Bevacizumab injection (12 visits/y)	4285 (429)	−16 732 (−20 170 to −13 294)	<.001	21 425 (2142)	−67 793 (−82 501 to −53 085)	<.001

Abbreviations: NA, not applicable; PDS, port delivery system; VEGF, anti–vascular endothelial growth factor.

^a Incorporating cost of office visits, imaging, and complications.

^b Modeling aflibercept injections at fixed 8-week intervals (every 2 months).

Over 5 years, the mean (SD) total cost of the ranibizumab PDS with associated medication costs and refill exchanges was $89 218 ($8922). Intravitreal ranibizumab cost $25 581 (95% CI, $2275-$48 887; P = .04) more than ranibizumab PDS. Intravitreal aflibercept injections cost $44 374.40 (95% CI, $18 623-$70 125; P = .008) more than ranibizumab PDS and bevacizumab injections cost $67 793 (95% CI, −$82 501 to −$53 085; P < .001) less. Bimonthly aflibercept injections cost $22 4212 less than the PDS (95% CI, −$40 287 to −$45,56; P = .03) (Table 4).

Scenario Analysis

With PDS refills PRN, the mean (SD) total cost of PDS over 1 year was $16 054 ($1605) (Table 5). Over 1 year, compared with ranibizumab PDS with PRN refills, the real-world ranibizumab injections cost $3878 (95% CI, $648-$7108; P = .03) less, aflibercept injections cost $2284 (95% CI, $1106-$5675; P = .13) less, and bevacizumab injections cost $13 931 (95% CI, $11 335-$16 526; P < .001) less (Table 5).

Table 5. Scenario Analyses.

Characteristic	Cost over 1 y, mean (SD), $	Difference between injection arm and PDS arm for year 1, mean (95% CI), $	P value	Cost over 5 y, mean (SD), $	Difference between injection arm and PDS arm for year 5, mean (95% CI), $	P value
As-needed/PRN dosing of PDS ranibizumab refills vs monthly and bimonthly anti–VEGF injectionsa
Ranibizumab PDS with refill (2 visits, y)	16 054b (1605)	NA	NA	45 755c (4576)	NA	NA
Ranibizumab injection (12 visits, y)	22 960 (2296)	6905 (2414-11 396)	.01	114 799 (11 480)	69 044 (49 234-88 853)	<.001
Aflibercept injection (12 visits, y)	26 718 (2672)	10 664 (5667-15 661)	<.001	133 592 (13 359)	87 837 (65 202- 110 473)	<.001
Aflibercept injectiond (6 visits, y)	13 359 (1336)	−2695 (−6043 to 653)	.09	66 796 (6680)	21 041 (8062.73- 34 020)	.01
Bevacizumab injection (12 visits, y)	4285 (429)	−11 769 (−14 433 to −9106)	<.001	21 425 (2142)	−24 330 (−32 429 to −16 231)	.01
6-Month fixed-interval dosing of ranibizumab PDS refills vs real-world anti–VEGF injectionsa
Ranibizumab PDS with refill (2 visits, y)	21 017 (2102)	NA	NA	89 218 (8922)	NA	NA
Ranibizumab injection (6 visits, y)	12 177 (1218)	−8840 (−12 734 to −4946)	<.001	60 884 (6088)	−28 334 (–45 648 to −11 020)	.01
Aflibercept injection (6 visits, y)	13 770 (1377)	−7246 (−11 274 to −3219)	<.001	68 852 (6885)	−20 366 (−38 431 to −2301)	.04
Bevacizumab injection (6 visits, y)	2124 (212)	−18 893 (−22 279 to −15 507)	<.001	10 619 (1062)	−78 599 (−93 001 to −64 196)	<.001
As-needed/PRN dosing of PDS ranibizumab refills vs real-world anti–VEGF injectionsa
Ranibizumab PDS with refill (2 visits, y)	16 054b (1605)	NA	NA	45 755c (4576)	NA	NA
Ranibizumab injection (6 visits, y)	12 177 (1218)	−3878 (−7108 to −648)	.03	60 884 (6088)	15 129 (2921 to 27 337)	.03
Aflibercept injection (6 visits, y)	13 770 (1377)	−2284 (−5675 to 1106)	.13	68 852 (6885)	23 097 (9845 to 36 348)	.01
Bevacizumab injection (6 visits, y)	2124 (212.3)	−13 931 (−16 526 to −11 335)	>.001	10 619 (1062)	–35 136 (–42 665 to –27 606)	>.001

Abbreviation: NA, not applicable.

^a Incorporating cost of office visits and imaging and complications.

^b With 40.60% of patients receiving 1 refill in the first year.

^c With median time to refill of 15.8 months.

^d Modeling aflibercept injections at fixed 8-week intervals (every 2 months).

Over 5 years, the mean (SD) total cost of the ranibizumab PDS with PRN refills was $45 755 ($4576) (Table 4). Real-world intravitreal ranibizumab cost $15 129 (95% CI, $2921-$27 337; P = .03) more than ranibizumab PDS and aflibercept injections cost $23 097 (95% CI, $9845- $36 348; P = .01) more. The bevacizumab injections arm cost $35 136 (95% CI, −$42 665 to $27 606; P < .001) less than ranibizumab PDS (Table 4). Similar patterns of cost saving were seen when PRN refills of PDS ranibizumab were compared with monthly anti-VEGF injection use (Table 5). However, when comparing 6-month fixed interval dosing of ranibizumab PDS, the PDS arm cost more across both time periods than real-world use of anti-VEGF injections (Table 5).

Sensitivity Analyses

The most sensitive input in the model, or the parameter that most greatly affected total costs and overall cost savings of the PDS, was the number of refills needed. The incidence of complications, including endophthalmitis and corneal bleb, retraction, or erosion, was the least sensitive input and was negligible in its effect on the total cost of PDS in both time horizons (eTable in the Supplement). Varying the number of office visits with imaging in the PDS arm to 6 per year or 12 per year increased the total cost of the PDS arm, but overall demonstrated similar cost patterns to the injection arms.

Discussion

Overall, we found that ranibizumab PDS is only lower cost compared with intravitreal ranibizumab and aflibercept injections if refills occur PRN, as approximately 11 and 10 injections, respectively, are needed to offset the cost of ranibizumab PDS and 1 refill. In our cost model, we found the most sensitive parameter was the number of refills needed. Compared with monthly regimens of intravitreal ranibizumab and aflibercept injections, both ranibizumab PDS with refills every 6 months or PRN offer cost savings. However, compared with bimonthly aflibercept injections or real-world intravitreal ranibizumab and aflibercept injections, only ranibizumab PDS with refills PRN offered potential long-term cost savings. Thus, ranibizumab PDS with refills at intervals longer than 6 months is more economically attractive. In the phase 2 trial,¹⁴ only 40.6% of the cohort met criteria (increase in central foveal thickness, decrease in best-corrected visual acuity, and evidence of macular hemorrhage) necessitating a refill within 1 year and the median time to refill was about 16 months. Ranibizumab PDS used on an as-needed or PRN basis is a competitive alternative to fixed anti-VEGF regimens.

The decreased treatment burden of ranibizumab PDS has important considerations as quality of life may be improved with less injections. McClard et al²⁴ report that, on average, patients require 8 or more hours to recover after a receiving an intravitreal injection and often report fear and discomfort. However, patients will still likely need to come into the office to be monitored with the PDS. Although no device is yet approved, at-home OCT may be an option for PDS or other long-acting agents to achieve their full potential in reducing the burden of clinic visits. However, we found costs of office visits with imaging were marginal in relation to drug cost. While ophthalmologists may be hesitant about ranibizumab PDS, given higher rates of surgical complications compared with injections, we found the direct costs of these were negligible, although the true harm of a devastating complication to both the physician and patient is both unquantifiable and substantial.

More robust and long-term, real-world clinical data of ranibizumab PDS efficacy and use is needed, including investigating practice patterns and disease progression with the implant. Especially with newer US Food and Drug Administration–approved drugs, like faricimab, with longer-lasting effects, some may prefer to continue injecting as opposed to a PDS system.¹⁷ The WAC for faricimab as of January 2022 is $2190, which is higher than both ranibizumab and aflibercept injections.²¹ However, if patients only require faricimab every 12 to 16 weeks as approximately 80% of patients did in clinical trials, there may be potential cost savings compared with both ranibizumab PDS and other anti-VEGF injections.¹⁷ The effect of biosimilars is expected to increase over time as patents protecting aflibercept and ranibizumab expire. Strategizing reimbursement patterns by the government and private insurance companies can increase uptake in biosimilar use faster than physicians without cost incentives.²⁵

Another concern is decreased use of bevacizumab, with bevacizumab injections representing 55.3% of all anti-VEGF injections in 2015 from 72.3% in 2012 in the US.⁹ Among Medicare beneficiaries in 2020, bevacizumab made up less than half of all anti-VEGF injections.¹⁰ While bevacizumab is low cost, if the cost of ordering, storing, and tracking the drug supersedes reimbursement, this may contribute to decreased use if these costs are greater than reimbursements.¹⁰ In our study, through the base case and scenario and sensitivity analyses, bevacizumab was significantly less expensive than the PDS.

Limitations

There are limitations to the current study. While data from the phase 2 clinical trial and the phase 3 clinical trial were used, there were outcome measures and control groups of interest not included. The protocol of this study was designed based on the results of clinical trials, IRIS registry data, and projected future use. We projected costs over the long term based on practice pattern assumptions cited previously. Our study did not incorporate clinical effectiveness; cost-benefit studies of ranibizumab PDS are warranted.

Conclusions

We demonstrate the cost-saving potential of ranibizumab PDS with PRN refill in patients receiving regular ranibizumab or aflibercept injections depending on number of injections and refills given. Use of PDS with fixed 6-month refills of ranibizumab is not cost saving compared with intravitreal anti-VEGF use.²³ Use of PDS will be based on other factors than cost, including safety, preferred practice, and willingness to undergo a surgery with frequent clinic visits. Further research on the ranibizumab PDS long-term safety, efficacy, and cost effectiveness is warranted.

Supplement.

eFigure. Break-even Charts

eTable. Sensitivity Analyses