Seminars in Ophthalmology

ISSN: 0882-0538 (Print) 1744-5205 (Online) Journal homepage: https://www.tandfonline.com/loi/isio20

Ranibizumab (Lucentis) versus Bevacizumab

(Avastin) for the Treatment of Age-Related Macular
Degeneration: An Economic Disparity of Eye
Health

Tomas A. Moreno & Stephen J. Kim

To cite this article: Tomas A. Moreno & Stephen J. Kim (2016) Ranibizumab (Lucentis)
versus Bevacizumab (Avastin) for the Treatment of Age-Related Macular Degeneration:
An Economic Disparity of Eye Health, Seminars in Ophthalmology, 31:4, 378-384, DOI:
10.3109/08820538.2016.1154174

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Published online: 26 Apr 2016.

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Seminars in Ophthalmology, 2016; 31(4): 378–384
© Taylor & Francis
ISSN: 0882-0538 print / 1744-5205 online
DOI: 10.3109/08820538.2016.1154174

REVIEW

Ranibizumab (Lucentis) versus Bevacizumab

(Avastin) for the Treatment of Age-Related Macular
Degeneration: An Economic Disparity of Eye Health
Tomas A. Moreno and Stephen J. Kim

Department of Ophthalmology, Vanderbilt Eye Institute, Nashville, TN, USA

ABSTRACT
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the advent of anti-
vascular endothelial growth factor agents (VEGF) has revolutionized treatment for neovascular AMD. Two of the
most popular anti-VEGF agents, ranibizumab (Lucentis; Genentech/Roche) and bevacizumab (Avastin;
Genentech/Roche), effectively treat neovascular AMD but have a substantial difference in price. Multiple level
1 trials have demonstrated that bevacizumab is noninferior to ranibizumab in the treatment of neovascular AMD
and that both have similar safety profiles. The decision to use one drug over the other is multifactorial with
influences from industry as well as individual physician biases. However, the additional billions spent on
ranibizumab result in a large economic disparity that is not rationalized by cost effectiveness models.
Keywords: Anti-VEGF, Avastin, economic disparity, Lucentis, macular degeneration

INTRODUCTION have demonstrated that ranibizumab and bevacizu-

mab are equally effective for the treatment of
Age-related macular degeneration (AMD) is the lead- neovascular AMD.9
ing cause of blindness in the elderly in the United A study by the Office of Inspector General found that,
States and estimated to increase by 50% by 2020.1 in 2010, combined Medicare Part B expenditures for rani-
Multiple randomized controlled clinical trials have bizumab and bevacizumab totaled nearly $2 billion, one-
demonstrated the effectiveness of anti-vascular sixth of the total Medicare Part B budget, with most of the
endothelial growth factor (VEGF) agents in the treat- expenditures arising from the high price of ranibizumab.8
ment of neovascular AMD.2–5 Two of the most popular The purpose of this review is to give a comprehensive
anti-VEGF agents are ranibizumab (Lucentis; analysis of the literature with the primary intent to explore
Genentech/Roche) and bevacizumab (Avastin; potential factors that influence the decision of physicians
Genentech/Roche).6,7 While both drugs are made by to choose one drug over the other.
the same parent company, ranibizumab has US Food
and Drug Administration (FDA) approval for the
treatment of neovascular AMD, whereas bevacizumab BEVACIZUMAB (AVASTIN) HISTORY
does not. Bevacizumab is currently FDA-approved for
treatment of systemic cancers but is used off-label to Bevacizumab is a 149 kd recombinant humanized
treat AMD. The economic disparity arises from the monoclonal antibody targeted at all isoforms of
striking cost difference between the two drugs. VEGF A.10 Both bevacizumab and ranibizumab are
Medicare reimburses approximately $2,023 per dose manufactured by the Swiss pharmaceutical company
of ranibizumab and only $55 per dose of Roche, and were created by its US subsidiary,
bevacizumab.8 This cost difference is amplified by the Genentech. Bevacizumab was first FDA-approved
fact that these drugs are dosed as often as monthly. for the treatment of metastatic colon cancer in 2004
Additionally, recent large randomized clinical trials and was first used for the off-label treatment of

Received 20 November 2015; accepted 10 February 2016; published online 21 April 2016
Correspondence: Stephen J. Kim, Vanderbilt Eye Institute, Department of Ophthalmology, 2311 Pierce Ave., Nashville, TN 37232, USA.
E-mail: [email protected]

378
 Ranibizumab versus Bevacizumab for AMD 379

AMD by Dr. Philip Rosenfeld in 2005.11 from the circulatory system 100-fold faster.18–20
Dr. Rosenfeld was a lead investigator in the clinical These characteristics were used to support the argu-
trials evaluating the efficacy of ranibizumab when he ment by Genentech that ranibizumab was more
realized that bevacizumab and ranibizumab were effective with less potential for systemic adverse
derived from the same antibody and thus possibly effects than bevacizumab.21 However, the large
functionally equivalent.12 In a university-approved price differential between the two drugs, physician
research program in which Rosenfeld was a co- favorable experiences using off-label bevacizumab,
author, intravenous bevacizumab was found to and necessary off-label use of bevacizumab for the
improve visual acuity, optical coherence tomography treatment (at that time) of diabetic macular edema
(OCT), and angiographic outcomes in patients with and macular edema due to vein occlusions
subfoveal choroidal neovascularization.13 With his prompted its continued off-label use for the treat-
knowledge of the similarity between bevacizumab ment of AMD.
and ranibizumab and the promising results intravi-
treal ranibizumab had in preliminary trials,14
Dr. Rosenfeld then used a much smaller dose of COST
bevacizumab as an intravitreal injection in a patient
losing vision from neovascular AMD not responsive Medicare reimbursement of ranibizumab, and thus
to the best current management at that time.11 the cost of ranibizumab to Medicare, is approxi-
Results revealed resolution of subretinal fluid by mately $2,023 per dose, while bevacizumab is
week one and the improved macular appearance approximately $55 per dose.8 Both drugs are still
was maintained for at least four weeks.11 The under patent by the same parent company,
patient’s vision remained stable and no adverse Genentech. The large price discrepancy arises from
events were reported.11 Dr. Rosenfeld presented the fact that bevacizumab is FDA-approved for
these results at the American Society of Retina metastatic colon cancer and comes in 100 mg or
Specialist meeting and, soon afterwards, bevacizu- 400 mg vials. These formulations are much larger
mab gained widespread popularity for the treatment than what is needed for intravitreal use and are
of neovascular AMD despite the lack of large rando- compounded by pharmacies to produce multiple
mized control trials evaluating its efficacy or safety doses per vial, thereby drastically reducing the
for intraocular use.6 price. Ranibizumab is sold in single-use, one-dose
Bevacizumab is bought in quantities much larger vials.
than necessary for intravitreal use and compounded In 2008, Medicare Part B spent more than
by pharmacies. As a result, Medicare reimbursement $536 million for ranibizumab, while only spending
to physicians or, in other words, the cost of bevacizu- about $20 million on bevacizumab.6 During this same
mab to Medicare is approximately $55 per dose.8 time, 140,000 more injections of bevacizumab were
Ranibizumab at this time was in phase II and phase performed than injections of ranibizumab.6 In the
III trials for FDA approval, which it received years of 2008 and 2009, Medicare Part B spent a total
in June 2006. of $40 million for 936,382 bevacizumab treatments and
$1.1 billion for 696,927 ranibizumab treatments.22 In
2010, Medicare and its beneficiaries spent $1.1 billion
RANIBIZUMAB HISTORY for ranibizumab and only $27 million for
bevacizumab.8
Ranibizumab is a 48 kd recombinant humanized A September 2011 audit report by the Office of
monoclonal antibody fragment that targets all iso- Inspector General found that if Medicare reimburse-
forms of VEGF A. It gained FDA approval for the ment for all beneficiaries treated with bevacizumab or
use of neovascular AMD in June 2006 and in Europe ranibizumab for neovascular AMD during the
in 2007. Several clinical trials have shown its efficacy in calendar year of 2008 and 2009 had been paid at the
stabilizing or improving visual acuity in 95% of rate of ranibizumab, Medicare Part B would have
patients and that these results persisted for two increased spending by approximately $1.5 billion and
years.15,16 Monthly intravitreal injections are recom- beneficiaries would have paid approximately
mended, but a review concluded that three consecu- $370 million more in copayment.22 Conversely, if
tive monthly injections, followed by maintenance these beneficiaries had been paid at the bevacizumab
comprising of regular monthly visits with clinician- rate during the same time period, Medicare Part B
determined retreatment, may be the most appropriate would have saved over $1 billion.22 This same study
regimen.17 Genentech/Roche set the price of ranibizu- calculated that the average beneficiary copayment
mab at about $2000 per single-use vial. (coinsurance and/or deductible) was $11 for bevacizu-
Ranibizumab is one-third the size of bevacizumab mab and $406 for ranibizumab.22
(which may facilitate penetration into the retina), A 2014 study by Hutton et al. used modelling meth-
has higher binding affinity to VEGF, and clears ods to predict 10-year (2010–2020) population-level

© 2016 Taylor & Francis

380 T. A. Moreno and S. J. Kim

costs and health benefits of using bevacizumab and proportion of patients with fluid on OCT in the bev-
ranibizumab in both neovascular AMD and diabetic acizumab group compared to ranibizumab, but this
macular edema. The study projected that, over those was not significant. 24
10 years, Centers for Medicare and Medicaid Services
(CMS) will spend $20 billion and patients will spend
$5 billion on bevacizumab and ranibizumab.23 These SAFETY
projections assume two-thirds of patients receive bev-
acizumab and one-third receive ranibizumab, which is The systemic and ocular adverse events for both
similar to current practice. Hutton et al. reported that if bevacizumab and ranibizumab have also been eval-
all patients switched to bevacizumab, the CMS would uated in randomized controlled trials. In the one-
only spend $2 billion (saving $18 billion) over the 10 year and two-year results of the CATT trial, there
years and patients would only spend $420 million were no differences seen in the rates of endophthal-
(saving nearly $5 billion).23 Alternatively, if all patients mitis, death, or arteriothrombotic events comparing
switched to ranibizumab, spending would increase to bevacizumab and ranibizumab.9 Both studies
$57 billion and $14 billion respectively.23 showed a significant difference in “one or more ser-
ious adverse events” with ranibizumab having less
events than bevacizumab (24.1% vs. 19.0% in year
CLINICAL TRIALS COMPARING EFFICACY one, p-value = 0.04 and 39.9% vs 31.7% in year two,
p-value = 0.004). A serious adverse event was
Multiple randomized controlled clinical trials around defined as death from any cause, arteriothrombotic
the world were conducted comparing bevacizumab to event, nonfatal myocardial infarction, nonfatal
ranibizumab. These studies included, but were not stroke, death from vascular causes, venous thrombo-
limited to, Comparison of Age-Related Macular tic event, transient ischemic attack, and
Degeneration Treatment Trials (CATT) in the USA, hypertension.9 In the one-year and two-year results
the Inhibition of VEGF in Age-related choroidal for the IVAN study, there was no difference in the
Neovascularization (IVAN) in the UK, Multicenter proportion experiencing a serious adverse event.24,29
Anti-VEGF Trial (MANTA) in Austria, French It is important to note that these studies were not
Evaluation Group Avastin Versus Lucentis (GEFAL), powered to determine differences in adverse events.
and Lucentis compared to Avastin (LUCAS).9,24–27 A Cochrane review published in September 2014
These studies enrolled more than 3000 participants concluded that no difference could be determined
and all trials showed that bevacizumab was non- between intravitreal bevacizumab and ranibizumab
inferior to ranibizumab when using the same dosing for deaths, all serious systemic adverse events, or
method. specific subsets of serious systemic adverse events
The largest study conducted was the CATT trial, with the exception of gastrointestinal disorders.30
which enrolled 1208 patients in 44 institutions with The study included data from nine non-industry
neovascular AMD. Both one-year and two-year results supported studies (3665 participants), including six
have been published. The trial consisted of four treat- published (2745 participants) and three unpublished
ment groups defined by drug (bevacizumab or ranibi- (920 participants). The study reported that at the
zumab) and dosing (monthly or as needed).9 Both the maximum follow-up (one or two years), the risk of
one-year and two-year results for the CATT trial death with ranibizumab was 3.4%, and with bevaci-
showed no difference in the mean gain in visual acuity zumab was 3.7% (95% CI 2.7% to 5.3%).30 The esti-
between both drugs.4,9 The two-year data for the mated risk ratio for all serious systemic adverse
CATT trial showed that the mean gain in visual acuity events with bevacizumab compared to ranibizumab
was greater in the monthly rather than as-needed was 1.08 (95% CI 0.90 to 1.31, p-value = 0.41). The
groups. The one-year results showed that monthly absolute risk of any serious systemic adverse event
ranibizumab showed a greater decrease in central ret- with ranibizumab was 22.2%, and with bevacizumab
inal thickness compared to the other groups. The two- was 24.0% (95% CI 20.0% to 29.1%).30
year results showed the proportion of patients without However, several small but devastating outbreaks
fluid was greater in the monthly groups compared to of endophthalmitis have been reported with the use of
the as-needed groups and greater in those treated with bevacizumab. One outbreak in South Florida involved
ranibizumab compared to bevacizumab.9 12 patients with endophthalmitis following bevacizu-
A meta-analysis published in 2014, including five mab injection compounded by the same pharmacy.31
randomized control trials, confirmed the non- In addition, seven unused syringes of bevacizumab
inferiority of bevacizumab compared to ranibizumab prepared by the compounding pharmacy were posi-
and also reported better anatomical results with tive for the same bacteria that were isolated in the
ranibizumab.28 The IVAN two-year results reported affected patients.31 Similar outbreaks were reported
no difference in final visual acuity comparing bevaci- in Nashville, both at a Veterans Affairs (VA) hospital
zumab to ranibizumab and reported a slightly higher and in the community, in Minneapolis, and in Los

Seminars in Ophthalmology
 Ranibizumab versus Bevacizumab for AMD 381

Angeles at another VA hospital.32,33 These outbreaks utility of loss of vision, etc.) was simultaneously varied
of endophthalmitis highlighted the increased risk of in a probabilistic sensitivity analysis (creating 10,000
contamination associated with the extra measure of simulation iterations or different scenarios), as-needed
compounding bevacizumab for intraocular use. bevacizumab was the preferred treatment option in
Nevertheless, despite the potential for increased risk nearly two-thirds of the simulations and monthly bev-
of contamination with bevacizumab, Medicare data acizumab was the preferred alternative in 18% to 20%
show no significant difference in endophthalmitis of the simulations.36 The authors concluded that
rates between bevacizumab and ranibizumab.34 insurers and health policy makers should consider
endorsing the use of intravitreal bevacizumab over
other treatment alternatives as first-line therapy for
COST-EFFECTIVENESS neovascular AMD, as this might curtail some of the
rapidly rising costs of managing patients with this
Before the CATT study and other randomized con- condition.36
trolled trials comparing bevacizumab to ranibizumab
were published, a paper modelling the cost effective-
ness of bevacizumab versus ranibizumab reported USAGE
that ranibizumab would have to be 2.5 times as effi-
cacious as bevacizumab to be the preferred, cost- A study analyzing the 2008 Medicare Fee-For-Service
effective treatment.35 The trial reported that monthly claims in 2008 showed that of the 222,886 unique
injections of ranibizumab for predominantly classic beneficiaries, 146,276 (64.4%) received bevacizumab
and occult choroidal neovascularization came at a and 80,929 (35.6%) received ranibizumab.6 This study
cost per quality adjusted life year (QALY) of more also showed that there was a geographic variation in
than £100,000 (~$150,000) when compared to the proportion of bevacizumab to ranibizumab used in
monthly injections of bevacizumab. The research the United States. The study reported that 11 of the 50
also reported that doubling the rate for serious ocular states had higher rates of ranibizumab use than
adverse events for bevacizumab had little effect on bevacizumab use.6 These states included Florida,
cost per QALY.35 The main limitation to this study Maine, Vermont, Connecticut, Pennsylvania, New
was that no head-to-head randomized controlled trial Jersey, Tennessee, Iowa, North Dakota, Nebraska,
comparing bevacizumab to ranibizumab had been and Kansas. In a separate study of the 456,237
completed at the time of publication. Therefore, the beneficiaries initiated on anti-VEGF treatment for
authors had to make several assumptions about the neovascular AMD between January 1, 2006,
efficacy and safety of bevacizumab and ranibizumab. and December 2010, the initial anti-VEGF treatment
Stein et al. published a similar study in 2013 medication was bevacizumab in 66% of the patients
modelling the cost-effectiveness of bevacizumab and and ranibizumab in 33% of the patients.7
ranibizumab. The study used the high-quality data on A study by Jeng et al. published in 2014 (notably
safety, efficacy, and difference in outcomes from both after the high-profile CATT and IVAN trials had been
the one- and two-year results of the CATT trial.36 The published) randomly selected two samples of retina
study concluded that both the as-needed and monthly specialists regarding their treatment and dosing regi-
bevacizumab injections were far more cost-effective men choices among bevacizumab, ranibizumab, and
than monthly ranibizumab injections. In this study, aflibercept (Eylea, Regeneron Pharmaceuticals,
they calculated that monthly ranibizumab gains an Tarrytown, NY). One group was asked to provide
additional 0.02 QALY versus monthly bevacizumab recommendations on a hypothetical patient with neo-
at an incremental cost-effectiveness ratio of more vascular AMD and the other group was asked to
than $10 million per QALY. This amount is consider- provide recommendations as if they themselves were
able given that the study’s cut-off for effectiveness was the standardized patient with neovascular AMD.38
$100,000 per QALY, which is a well-established value Two hundred and twenty-six (28.3%) of the 800 retinal
used in several other cost-effectiveness analyses in specialists completed the survey and were distributed
medicine.36,37 In a sensitivity analysis, the risk of ser- equally between the survey groups. When recom-
ious vascular events (including myocardial infarction, mending treatment for a hypothetical patient, 52.2%
cerebrovascular event, and venous thrombotic event) of retina specialists recommended bevacizumab while
would have to be 2.5 times greater with bevacizumab 27.4% and 20.4% recommended ranibizumab and
than ranibizumab for as-needed ranibizumab to be the aflibercept, respectively.38 The choice of medication
preferred treatment option.36 The authors also was influenced by geographical location (p=0.005),
concluded that, even if the risk of endophthalmitis with respondents in the Northeast being equally likely
for bevacizumab was 10 times the risk reported in to choose each of the three drugs while the South,
the CATT trial, as-needed bevacizumab would have Midwest, and West were more likely to choose beva-
the best value. When each parameter in the study cizumab. The percent of respondents recommending
(including rates of adverse events, life expectancy, bevacizumab by location in the Northeast, South,

© 2016 Taylor & Francis

382 T. A. Moreno and S. J. Kim

Midwest, and West was 33%, 44%, 52%, and 68%, ranibizumab. Some physicians have described the
respectively. Interestingly, in the scenario of the rebate as a “bribe” and others have commented on
respondent as the hypothetical patient, the percentages how it is a large conflict of interest.39,40 Several studies
of choice of treatment were roughly equal between the have shown that exposure to information from phar-
three drugs (32.7%, 32.7%, and 34.6% for bevacizu- maceutical companies can influence physician
mab, ranibizumab, and aflibercept respectively).38 decisions.41 Furthermore, it has also been reported
The choice of medication in this scenario was not that physicians that are paid by Genentech are
influenced by geography. among the highest users of ranibizumab.42
Interestingly, at the Vanderbilt Eye Institute, a large
academic practice where there is no financial incentive
FACTORS INFLUENCING DECISION to use ranibizumab, approximately 90% of patients
with neovascular AMD receive bevacizumab.
One study published in 2012 using data from Genentech defended the rebate program by stating
Medicare 2010 surveyed physicians on why they that rebate and discount programs are a common busi-
chose bevacizumab versus ranibizumab.8 Cost was ness practice and they “help reduce the cost of our
reported as the primary factor for choosing medicines for hospitals, pharmacies, and doctors.”39
bevacizumab (70%).8 Forty-five percent of physicians The implementation of this rebate came
cited efficacy/effectiveness as a reason to choose bev- in October 2010, just before the publication of the
acizumab over ranibizumab and 40% cited patient CATT trial results.
insurance coverage, as the patient is responsible for Genentech has maintained, throughout the debate,
20% of the cost of the chosen drug in either copay or that they believe ranibizumab is the safer and more
coinsurance. This study did not survey the physicians effective medication.43 In a statement in response to
who chose ranibizumab over bevacizumab.8 the CATT trial, Genentech highlighted that ranibizu-
Several studies have speculated why physicians mab is specially formulated for intraocular use, is
choose ranibizumab over bevacizumab. Two studies, FDA-approved, and has undergone rigorous testing
previously described in this review, showed a strong in 18 completed trials.43 Genentech has no plan to
geographical influence on the recommended treatment seek FDA approval for bevacizumab, stating that
for AMD.6,38 Both studies state that the proportion of they already have an effective, approved medication
patients that lack a secondary insurance to cover the for the current condition. They continue to provide
20% cost of ranibizumab (estimated at a cost of bevacizumab in vials of much larger quantities that
$406 per injection)22 was likely a large contributor to are needed for intraocular use, requiring physicians
this regional bias. to use compounding pharmacies to formulate bevaci-
Another potential contributing factor influencing zumab for intraocular use.12 In 2006, the year ranibi-
physician choice is reimbursement. Medicare pays 6% zumab was approved, Genentech approached the FDA
above the sale price of each drug. Consequently, pre- to change the bevacizumab labeling to explicitly state
scribing ranibizumab results in an additional reimbur- that bevacizumab is not intended for ophthalmic use.
sement of approximately $95 for each ranibizumab However, the FDA “felt at that time that there was no
dose, but only $29 for bevacizumab per injection,22 safety-related basis adequately justifying that labeling
an average difference of $66 per dose. As a hypothe- change,” according to an internal FDA e-mail.12,44 In
tical example, a medium-sized retina practice perform- 2007, Genentech tried to restrict sales to third-party
ing 20,000 injections per year would generate compounding pharmacies but were overcome by
approximately $1.9 million in additional revenue large opposition from both ophthalmologists and
using ranibizumab exclusively versus only $580,000 compounding pharmacies.45,46 Genentech has also
for using bevacizumab exclusively, a difference of introduced a program that will cover the co-pay or co-
over $1.3 million. insurance up to $5000 per year for individuals with
Furthermore, Genentech began a confidential rebate household income less than $100,000 and will cover up
program in 2010 directed towards physician practices to $1500 if household income is greater than
that use a certain amount of ranibizumab and an addi- $100,000.47
tional rebate to practices that increased their use of Jeng et al. reported that, for a theoretical patient
ranibizumab from one quarter to the next.39 with AMD, retina specialists were more likely to pre-
Physician practices meeting certain thresholds in scribe bevacizumab, but when the retina specialist was
usage could potentially qualify for an additional rebate the hypothetical patient, the retina specialists were
of up to 3% of the wholesale cost of ranibizumab for equally split in recommending bevacizumab, ranibizu-
prescribing ranibizumab over bevacizumab. Using the mab, and aflibercept.38 This study gives unique insight
previous hypothetical example (medium-size retina into the thought process of the prescribing physician.
practice performing 20,000 injections per year), an The change from bevacizumab when treating a
additional $1.2 million a year in direct payments hypothetical patient to more expensive options when
from Genentech could be received for using treating themselves is unlikely influenced by financial

Seminars in Ophthalmology
 Ranibizumab versus Bevacizumab for AMD 383

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