Economic Evaluation

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Cost-Minimization Analysis of Ranibizumab Versus Aflibercept for

Treating Saudi Patients With Visual Impairment Owing to Age-Related
Macular Degeneration or Diabetic Macular Edema
Faris El-Dahiyat, PhD,1,* Islam Eljilany, MSc2
1
College of Pharmacy, Al Ain University, Al Ain, United Arab Emirates; 2Independent Pharmacoeconomic Researcher, Cairo, Egypt.

A B S T R A C T

Objective: The standard-of-care treatment for age-related macular degeneration (AMD) and diabetic macular edema (DME)
includes inhibiting blood vessel proliferation and reducing macular edema or swelling using anti–vascular endothelial
growth factor therapies, such as ranibizumab and aflibercept. To conduct a cost-minimization analysis of ranibizumab and
aflibercept for treating Saudi patients with visual impairment owing to AMD or DME.
Methods: Cost minimization was analyzed assuming that ranibizumab and aflibercept have equivalent clinical effectiveness.
The third-party payer’s perspective was used in several clinical scenarios. The base-case scenario was DME cases followed
monthly using a protocol-specific follow-up. In scenario 1, AMD cases followed a treat-and-extend protocol over 2 years.
In scenario 2, AMD cases followed the PRN (pro re nata) regimen over 2 years. In scenario 3, DME cases followed the PRN
regimen for 1 year only.
Results: Aflibercept yielded cost savings of 25.75%, 31.54%, 51.30%, and 9.28% compared with ranibizumab for the base case,
scenario 1, scenario 2, and scenario 3, respectively, which supports the premise that aflibercept is more cost saving than
ranibizumab.
Conclusions: From the third-party payer perspective, aflibercept is a cost-containment option that provides substantial
savings over ranibizumab for treating Saudi patients with AMD or DME.

Keywords: aflibercept, agerelated macular degeneration, diabetic macular edema, ranibizumab, Saudi Arabia. cost mini-
misation analysis.

VALUE IN HEALTH REGIONAL ISSUES. 2020; 22(C):23–26

Introduction vitrectomy, intraocular steroids, and approved anti-VEGF thera-

Pathologies that affect the retinal endothelial cells are classi-
fied as retinal vascular diseases, such as diabetic retinopathy and
diabetic macular edema (DME), and choroid vascular diseases,
such as age-related macular degeneration (AMD).1 DME is the
accumulation of fluid in the central point of the retina due to
extensive capillary leakage.2 AMD is a chronic degenerative eye
disease that causes pathological changes in the macular region of
the retina leading to progressive loss of vision; AMD can be clas-
sified into nonexudative (dry) or neovascular (wet) forms.3,4
The global prevalence of AMD and DME is 8.69% and 6.1%,
respectively.5,6 According to Z Alotaibi,7 the major causes of
blindness in Saudi people are AMD (5.7%) and diabetic retinopathy
(15.7%). Several factors influence DME and AMD development,
such as vascular endothelial growth factor (VEGF). Currently, there
are different options of care for treating such cases, such as laser,
pies.2 Anti-VEGF therapy is the standard-of-care treatment for
AMD and DME; it inhibits blood vessel proliferation and
reduces macular edema or swelling.3 The US Food and Drug
Administration–approved anti-VEGF therapies include ranibizu-
mab (Lucentis®, Genentech/Novartis) or aflibercept (Eylea®,
Regeneron Pharmaceuticals/Bayer).8,9 Ranibizumab is a fully hu-
manized antigen-binding portion of an anti-VEGFA monoclonal
antibody (Fab) administered by intravitreal injection.10 Aflibercept
is an anti-VEGFA–placental growth factor fusion protein that tar-
gets all VEGFA isoforms and placental growth factor.11
Aflibercept and ranibizumab have the same clinical outcome
and safety profile for treating AMD.3,12-14 The therapeutic equiv-
alency between aflibercept and ranibizumab in DME has been
confirmed in a 2016 US study15 and in a 2016 Denmark study.16
Cost-minimization analysis (CMA) can be used to compare in-
terventions if they are therapeutically equivalent.17 Therefore, the

Conflict of interest: The authors have indicated that they have no conflicts of interest with regard to the content of this article.
* Address correspondence to: Faris El-Dahiyat, PhD, College of Pharmacy, Al Ain University, PO Box 64141, Al Ain, United Arab Emirates. Email: faris.dahiyat@aau.ac.ae
2212-1099/$36.00 - see front matter ª 2019 ISPOR–The professional society for health economics and outcomes research. Published by Elsevier Inc.
https://doi.org/10.1016/j.vhri.2019.09.007
24 VALUE IN HEALTH REGIONAL ISSUES SEPTEMBER 2020

present study used this pharmacoeconomic evaluation to identify
the intervention with the lowest cost.
The Saudi Arabia Ministry of Health is responsible for only 60%
of healthcare services, whereas the remaining 40% is funded by
private and other sectors. Therefore, the high cost of a healthcare
intervention may impose considerable pressure on the national
budget and patients.18
The main challenge for the Saudi Arabia healthcare system and
other Gulf Corporation Council countries is the high cost of drugs,
which increases over time because of new drug design technolo-
gies, manufacturing of biotechnology drugs, and high research and
development costs in the pharmaceutical industry.18 Moreover,
the market share of generic drugs that are considered cost-
containment tools is very small.19 To overcome the challenge of
the high cost of medication, the Gulf Corporation Council coun-
tries have established a “group purchasing” program.18
The objective of this study is to perform a CMA to determine
whether aflibercept or ranibizumab is the most cost-saving option
for treating patients with vision loss owing to AMD or DME to be
used by public and private healthcare providers in Saudi Arabia.
Methods
Estimation of the Cost
Here, we used the perspective of the patient as a third-party
payer. The time horizon of the study was 2 years, as this is the
longest treatment duration found in the literature. The cost was
estimated based on treatment regimens identified from the liter-
ature search,3,12-16 and we included the current prices of ranibi-
zumab and aflibercept in Saudi Arabia and the direct medical
costs. The US dollar (USD) to Saudi Riyal (SR) yearly average ex-
change rate was approximately 3.75 in 2018.20 The retail price of
ranibizumab (brand name, Lucentis, 10 mg/mL intravitreal injec-
tion) is $1879.55 (7048.3 SR) per vial, and that of aflibercept
(brand name, Eylea, 40 mg/mL intravitreal injection) is $968.83
(3633.1 SR) per vial.21 The annual average treatment cost was
calculated based on these prices.
Based on current clinical practice and the literature, the fre-
quency of doctor’s visits for diagnosis and follow-up for both
drugs and other costs such as diagnostic cost are equivalent, as
both drugs are considered anti-VEGF intravitreal injections and
have similar treatment efficacy, adverse reactions, and tolerance
but differing frequencies of administration.3,12-16 The costs of 2-
year treatment with aflibercept and ranibizumab were calcu-
lated by adding the price per dose to the cost of the injection
procedure and then multiplying the result by the average number
of doses per patient expected over a 2-year period. The medication
costs were obtained from the Saudi Food and Drug Authority
based on 2018 prices and are expressed in SR. The estimated cost
of 1 injection procedure was $1213.3 (4550 SR) per eye and was
based on a market survey of more than 20 clinics and hospitals
specializing in ophthalmology. Costs that occurred beyond 1 year
were discounted at a rate of 2.1% as per the Saudi Arabia monetary
authority for June 2018 and were considered the second-year
discounted rate (DR).22
Base-Case Identification
There are different treatment regimens for managing macular
edema in patients with AMD or DME using ranibizumab or afli-
bercept.15 Medication-use data and average dosage were based on
previous literature, which compared the treatment effect of rani-
bizumab and aflibercept directly and showed that they have
equivalent efficacy in the overall population (a single 0.05-mL
dose containing 0.5 mg ranibizumab vs a single 50-mL dose con-
taining 2 mg aflibercept).3,12-16 The base-case scenario assumed
that both aflibercept and ranibizumab groups of patients with
DME would follow the same monthly treatment protocol with the
same follow-up and treatment regimen for 2 years.
Sensitivity Analysis
Here, several different clinical scenarios were used to illustrate
potential clinical situations. Moreover, they were used to analyze
the difference in annual average treatment costs for ranibizumab
and aflibercept. These scenarios were adopted from previous
studies,14,23,24 where different treatment regimens and injection

Table 1. Clinical scenarios for different types of patients.

Scenario Patient’s Description Average number of

clinical injections/scenario
case
Aflibercept Ranibizumab
15
Base DME Both groups of patients followed monthly using a protocol-specific follow-up, as they 14.8 14.2
visit a physician every 4 weeks in the first year and every 4 to 16 weeks in the second
year according to treatment course. At each visit, the patient is assessed for injection
based on visual acuity and optical coherence tomography.
One14 AMD One group of patients starts 1 injection every 4 weeks as a loading dose for 3 16 16.5
consecutive injections and then 1 injection every 4 weeks as needed for the first year
and 1 injection every 12 weeks as needed for the second year on ranibizumab; the
other group follows the same regimen on aflibercept.
Two14 AMD For ranibizumab, 1 group starts 1 injection every 4 weeks as a loading dose for 3 11.2 16.2
consecutive injections then 1 injection every 8 weeks as needed for the first year and in
the second year 1 injection every 12 weeks then as needed; the other group follows the
same regimen on aflibercept.
Three22,23 DME One group of patients receives 1 injection every 4 weeks for 3 consecutive injections as 9 7
a loading dose of ranibizumab and then follows a pro re nata (PRN) regimen until the
end of the first year. The other group receives 1 injection every 4 weeks for 5
consecutive injections as a loading dose of aflibercept and then follows a regimen of 1
injection every 8 weeks until the end of the first year.

AMD indicates age-related macular degeneration; DME, diabetic macular edema.

 ECONOMIC EVALUATION 25

Table 2. Annual treatment cost of ranibizumab and aflibercept in patients with AMD or DME in the base case and in scenario 1.*

Base case Scenario 1

First Second Second Cost of Annual First Second Second Cost of Annual
year year year (DR) 2 years cost year year year (DR) 2 years cost
Ranibizumab
Average No. 9.20 5.00 11.80 4.70
of injections
Total cost (SR) 106 704.36 57 991.5 56 773.67 163 478.03 81 739.01 136 859.94 54 512.01 53 367.25 190 277.19 95 113.59
Aflibercept
Average No. 9.40 5.40 11.90 4.10
of injections
Total cost (SR) 76 921.14 44 188.7 43 260.77 120 181.91 60 090.95 97 378.89 33 550.71 32 846.14 130 225.03 65 112.51
Cost difference 21 048.06 30 001.08
(SR)
Annual saving 25.75% 31.54%

AMD indicates age-related macular degeneration; DR, discounted rate; DME, diabetic macular edema; SR, Saudi Riyal.
*Yearly cost = (cost of surgery 1 cost of 1 vial) 3 average no. of injection; second year (DR) = total cost of second year/(1 1 0.02145); total cost of 2 years = total cost of
first year 1 total cost of second year (DR); annual cost = cost of 2 years/2; cost difference = annual cost of ranibizumab – annual cost of aflibercept; saving in annual
cost = ([annual cost of ranibizumab – annual cost of aflibercept]/annual cost of ranibizumab) 3 100.

frequencies are used to model different clinical conditions that
may reflect real-world usage patterns. Table 1 presents the 3 main
clinical scenarios identified.
Results
Annual Average Treatment Cost of Ranibizumab and
Aflibercept for the Base Case
Base-case cost analysis showed that the annual treatment cost
of ranibizumab was $21 797.07 (81 739.01 SR), whereas that of
aflibercept was $16 024.25 (60 090.95 SR). Under the same con-
dition, aflibercept could achieve yearly cost savings of 25.75%
compared with ranibizumab (Table 2).
Annual Average Treatment Cost of Ranibizumab and
Aflibercept in Different Scenarios
In 2 of the 3 scenarios (scenarios 1 and 2) in which AMD
cases were involved, the annual treatment cost of aflibercept
ranged from $12 123.86 to $17 363.34 (45 464.48 SR to 65 112.51
SR), and that of ranibizumab ranged from $24 895.21 to $25
363.62 (93 357.03 SR to 95 113.59 SR). The use of aflibercept also
minimized the cost in both scenarios regardless of changes in the
frequency of doctor’s visits or other costs, yielding cost savings of
31.54% to 51.3% (Tables 2 and 3).
In scenario 3, which involved DME cases, the annual treatment
cost of aflibercept and ranibizumab was $19 639.44 and $21 650.16
(73 647.9 SR and 81 188.1 SR), respectively. The use of
aflibercept instead of ranibizumab yielded cost savings of 9.28%
(Tables 2 and 3).
Discussion
We examined the costs of ranibizumab and aflibercept for
treating patients with AMD and DME. The analysis showed that
aflibercept is more cost-saving than ranibizumab, demonstrating
lower costs for Saudi patients over 2 years. The primary driver of

Table 3. Annual treatment cost of ranibizumab and aflibercept in patients with AMD or DME in scenario 2 and scenario 3.*

Scenario 2 Scenario 3
First Second Second Cost of Annual First Second Second Cost of Annual
year year year (DR) 2 years cost year year year (DR) 2 years cost
Ranibizumab
Average No. 11.60 4.60 7.00
of injections
Total cost (SR) 134 482.28 53 352.18 52 231.78 186 714.06 93 357.03 81 188.1 81 188.1
Aflibercept
Average No. 7.00 4.20 9.00
of injections
Total cost (SR) 57 281.70 34 369.02 33 647.27 90 928.97 45 464.48 73 647.90 73 647.90
Cost difference 47 892.55 7 540.2
(SR)
Annual saving 51.30% 9.28%

AMD indicates age-related macular degeneration; DR, discounted rate; DME, diabetic macular edema; SR, Saudi Riyal.
*Yearly cost = (cost of surgery 1 cost of 1 vial) 3 average no. of injections; second year (DR) = total cost of second year/(1 1 0.02145); total cost of 2 years = total cost of
first year 1 total cost of second year (DR); annual cost = cost of 2 years/2; cost difference = annual cost of ranibizumab – annual cost of aflibercept; saving in annual cost
= ([annual cost of ranibizumab – annual cost of aflibercept]/annual cost of ranibizumab) 3 100.
26 VALUE IN HEALTH REGIONAL ISSUES
this result was the 48.45% lower price of the aflibercept vial versus
that of ranibizumab. CMA has been used under the hypotheses
that the critical clinical outcomes and adverse effects of both
drugs are effectively equivalent, based on the results of previous
studies.3,12-16
In economic evaluation, it is difficult to measure the study
variables accurately, and each medication therapy may incur
different treatment costs when applied among diverse pop-
ulations or medical institutions25; therefore, we developed 3
scenarios in sensitivity analyses to mirror the real-life cost profile,
and validating the effect of several assumptions on the study re-
sults is essential. All sensitivity analysis results were consistent
with the base-case analysis, corroborating the finding that afli-
bercept is more cost-saving than ranibizumab. The results, how-
ever, may represent an advantage for aflibercept only if differences
in the price of medication were observed in an actual clinical
practice. A notable finding was that aflibercept remained cost-
saving compared with ranibizumab if the frequency of afli-
bercept injection was assumed to be the same as that of
ranibizumab.
The present study results match the results of other cost-
effectiveness studies.25 For example, Hernandez et al26 reported
that aflibercept is more cost-effective than ranibizumab in AMD.
On the other hand, the result of the present study was contrary to
the findings of a previous study in the United Kingdom, which
reported that ranibizumab was more cost-effective than afli-
bercept for treating DME.27 This could be justified by the afli-
bercept price per vial being higher than that of ranibizumab, with
the same frequency of injections.
Although the European Society of Retina Specialists (EUR-
ETINA) recommends anti-VEGF therapy as first-line therapy, it
does not specify which anti-VEGF should be used first. Therefore,
economic evaluation analysis should be conducted to derive a
rational decision regarding medications with the same efficacy
and safety profiles.2
The present study has some limitations. It was conducted from
a third-party payer’s perspective, and the indirect cost related to
the AMD or DME treatment was not considered, as there are no
reference data. Moreover, we considered only a single mono-
therapy; however, because of the complexity of some cases, laser
combination therapy is commonly used in clinical practice, and
patients may switch between drugs, which may affect the cost
over a more extended period.28 Therefore, we included in the
study different regimens for different cases to reduce the burden
of this limitation.
Thus, more studies from different perspectives and more types
of cost are needed to understand the overall annual costs to
provide disease burden information. Regardless of these limita-
tions, the exceptional strength of the present study that it is the
first CMA study in the Middle East region to compare aflibercept
and ranibizumab.
Conclusions
The present study results indicate that, from the third-party
payer perspective, aflibercept is a cost-containment option that
provides substantial savings over ranibizumab for treating Saudi
patients with AMD and DME without compromising health
outcome results.
Acknowledgments
This work did not receive any funding.
SEPTEMBER 2020
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