Journal of Medical Economics

ISSN: 1369-6998 (Print) 1941-837X (Online) Journal homepage: http://www.tandfonline.com/loi/ijme20

Cost-efficiency analyses for the US of biosimilar

filgrastim-sndz, reference filgrastim, pegfilgrastim,
and pegfilgrastim with on-body injector in the
prophylaxis of chemotherapy-induced (febrile)
neutropenia

Ali McBride, Kim Campbell, Mohan Bikkina, Karen MacDonald, Ivo Abraham
& Sanjeev Balu

To cite this article: Ali McBride, Kim Campbell, Mohan Bikkina, Karen MacDonald, Ivo
Abraham & Sanjeev Balu (2017): Cost-efficiency analyses for the US of biosimilar filgrastim-
sndz, reference filgrastim, pegfilgrastim, and pegfilgrastim with on-body injector in the
prophylaxis of chemotherapy-induced (febrile) neutropenia, Journal of Medical Economics, DOI:
10.1080/13696998.2017.1358173

To link to this article: http://dx.doi.org/10.1080/13696998.2017.1358173

Accepted author version posted online: 19

Jul 2017.

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Cost-efficiency analyses for the US of biosimilar filgrastim-sndz, reference filgrastim, pegfilgrastim,
and pegfilgrastim with on-body injector in the prophylaxis of chemotherapy-induced (febrile)
neutropenia

Ali McBridea,b,c, Kim Campbelld, Mohan Bikkinad, Karen MacDonalde, Ivo Abrahamb,c,e,f,g, Sanjeev Balud
a
Banner University Medical Center, Tucson, AZ, USA
b
University of Arizona Cancer Center, Tucson, AZ, USA
c
Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, AZ,
USA
d
Sandoz, Princeton, NJ, USA

t
e
Matrix45, Tucson, AZ, USA

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f
Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, AZ, USA
g
Department of Family and Community Medicine, College of Medicine–Tucson, University of Arizona,

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Tucson, AZ, USA

Correspondence: Ivo Abraham, Center for Health Outcomes and PharmacoEconomic Research,

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University of Arizona, Drachman Hall B-306H, 1295 N. Martin Avenue, Tucson, AZ 85721, USA, email:
abraham@pharmacy.arizona.edu

TRANSPARENCY
Declaration of funding
an
This work was sponsored by Sandoz, Inc.
M
Declaration of financial/other interests
AM serves on a Speakers Bureau and Steering Committee for Sandoz, Inc. He was subcontracted by
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Matrix45 for work on this project. KC, MB, and SB are employees of Sandoz, Inc., the study sponsor. IA
and KM are employees of Matrix45, which was contracted by Sandoz, Inc. to conduct the simulations.
e

By company policy, employees are prohibited from owning equity in client organizations (except
through mutual funds or other independently administered collective investment instruments) or
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contracting independently with client organizations. Matrix45 provides similar services to those
described in this article to other biopharmaceutical companies on a non-exclusivity basis. Peer reviewers
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on this manuscript have received an honorarium from JME for their review work, but have no other
relevant financial relationships to disclose.
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Author contributions
All authors met ICMJE and COPE criteria and contributed substantively to the study as follows: IA, KC,
KM, MB, and SB contributed to study concept. AM, IA, KC, KM, MB, and SB contributed to study design
and reviewed and interpreted results. IA and KM designed the model, performed the simulations, and
developed the manuscript. AM, KC, MB, and SB reviewed the manuscript for intellectual content.

Previous presentations
This study was presented as a poster at the Annual Meeting of the Multinational Association of
Supportive Care in Cancer, 22-24 June 2017 in Washington, DC.
ABSTRACT
Aims: Guidelines recommend prophylaxis with granulocyte colony-stimulating factor for chemotherapy-
induced (febrile) neutropenia (CIN/FN) based on regimen myelotoxicity and patient-related risk factors.
Our aim was to conduct a cost-efficiency analysis for the US of the direct acquisition and administration
costs of the recently approved biosimilar filgrastim-sndz (Zarxio® EP2006) with reference filgrastim
(Neupogen®), pegfilgrastim (Neulasta®), and pegfilgrastim injection device (Neulasta Onpro®; hereafter
pegfilgrastim-injector) for CIN/FN prophylaxis.

Methods: A cost-efficiency analysis of the prophylaxis of one patient during one chemotherapy cycle
under 1–14 days’ time horizon was conducted using the unit dose average selling price (ASP) and
Current Procedural Terminology (CPT) codes for subcutaneous prophylactic injection under four
scenarios: cost of medication only (COSTMED), patient self-administration (SELFADMIN), health-care

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provider (HCP) initiating administration followed by self-administration (HCPSTART), and HCP providing

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full administration (HCPALL). Two case studies were created to illustrate real-world clinical implications.
The analyses were replicated using wholesale acquisition cost (WAC).

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Results: Using ASP+CPT, cost savings achieved with filgrastim-sndz relative to reference filgrastim
ranged from $65 (1 day) to $916 (14 days) across all scenarios. Relative to pegfilgrastim, savings with

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filgrastim-sndz ranged from $834 (14 days) up to $3,666 (1 day) under the COSTMED, SELFADMIN, and
HPOSTART scenarios; and from $284 (14 days) up to $3,666 (1 day) under the HPOALL scenario. Similar
to the cost-savings compared to pegfilgrastim, filgrastim-sndz achieved savings relative to pegfilgrastim-
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injector: from $834 (14 days) to $3,666 (1 day) under the COSTMED scenario, from $859 (14 days) to
$3,692 (1 day) under SELFADMIN, from $817 (14 days) to $3,649 (1 day) under HPOSTART, and from
$267 (14 days) to $3,649 (1 day) under HPOALL. Cost savings of filgrastim-sndz using WAC+CPT were
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even greater under all scenarios.

Conclusions: Prophylaxis with filgrastim-sndz, a biosimilar filgrastim, was associated consistently with
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significant cost-savings over prophylaxis with reference filgrastim, pegfilgrastim, and pegfilgrastim-
injector, and this across various administration scenarios.
e

Keywords: filgrastim; pegfilgrastim; biosimilars; GCSF; neutropenia; febrile neutropenia; cost-efficiency

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Introduction
Depending on the myelotoxicity of a given regimen, cancer patients undergoing chemotherapy may be
at significant risk of developing chemotherapy-induced (febrile) neutropenia (CIN/FN), a potentially life-
threatening complication [1,2,3,4,5]. Febrile neutropenia can often lead to ambulatory and emergency
room visits and, in severe cases, hospitalization [5]. Consequently, the chemotherapy regimen may be
switched to a less myelotoxic one or subsequent cycles of chemotherapy may be reduced in dose,
delayed, or discontinued, which reduces the relative dose intensity (RDI) of the chemotherapy
treatment [6]. In turn, this may interfere with tumor response to treatment and impair clinical outcomes
[6,7]. The impact of (febrile) neutropenia on quality of life is significant because of anxiety, depression,
symptom burden, and impairment in functional status and activity [8,9].

Recombinant granulocyte-colony stimulating factors (GCSF) such as filgrastim (Neupogen®, Amgen,

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Thousand Oaks, CA, USA) and its pegylated formulation pegfilgrastim (Neulasta®, Amgen, Thousand

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Oaks, CA, USA) are biological growth factors that promote the production of neutrophils in the bone
marrow [10]. The product label advises that filgrastim be administered daily for a maximum of 14 days,

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starting no sooner than 24 hours following the end of myelosuppressive chemotherapy [11].
Pegfilgrastim includes a single subcutaneous injection per chemotherapy cycle, also administered no
sooner than 24 hours after chemotherapy [12]. International best practice guidelines for CIN/FN

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prophylaxis recommend GCSF initiation with filgrastim or pegfilgrastim no sooner than 24 hours but also
no later than 3 [13] or 4 days [14] following the completion of a chemotherapy infusion. Recently, an on-
body injector device (Neulasta Onpro®, Amgen, Thousand Oaks, CA, USA) was approved, which is applied
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the day of chemotherapy to administer pegfilgrastim approximately 27 hours later [12]. Following the
patent expirations for reference filgrastim, the biosimilar agent filgrastim-sndz was approved in Europe
in 2008 and in the US in 2015. It has since been marketed in Europe as Zarzio® and in the US as Zarxio®.
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A meta-analysis of 17 randomized controlled trials showed convincingly that, as a class, GCSFs reduce
the risk of febrile neutropenia, infection-related mortality, and all-cause mortality; and improve the RDI
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of the chemotherapy regimens compared to placebo or untreated controls [3]. In contrast, there has
been debate as to the potential superiority of pegfilgrastim over reference filgrastim, as pegfilgrastim
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was approved on the basis of two non-inferiority trials comparing it to reference filgrastim [15,16]. A
pooled analysis of these two pivotal trials suggested potential superiority [17], however each of the
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individual trials was adequately powered to begin with. Three meta-analyses attempted to document
the relative superiority of pegfilgrastim over filgrastim [18,19,20]. However, they are methodologically
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compromised by the limited number of studies included [21], the inordinate weight of one study
suggesting superiority when other adequately powered studies indicate no differential efficacy between
both agents, and selectivity in the endpoints included. One publication reported on analyses of four
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serially introduced regimens of CIN/FN prophylaxis in four sequential non-randomized cohorts of breast
cancer patients: ciproflaxin, daily filgrastim, pegfilgrastim, and pegfilgrastim in combination with
ciproflaxin. Pegfilgrastim with or without ciproflaxin was found to be more effective; even though a
filgrastim regimen was not compared to pegfilgrastim contemporaneously and under randomized
conditions (and neither was any other combination of the four treatments) [22]. As Klastersky and Awad
point out [21], pegfilgrastim “is definitely not inferior to classical” filgrastim, but “whether it might be
more superior and more cost-effective cannot be derived from the presently available data, but it seems
unlikely that major differences do exist”.

This is important from the vantage point of comparative economic evaluations of GCSFs, especially now
that a biosimilar version of filgrastim is available in the US and biosimilars are reimbursed under
Medicare Part B, are allowed as a formulary enhancement in Part D prescription drug plans, and are
allowed under the Medicaid Drug Treatment Program. Assuming that filgrastim (including the approved
biosimilars) and pegfilgrastim can be considered similar in efficacy based on randomized controlled trials
and related pivotal approval studies, the choice of agent may be driven by the economic efficiencies
achieved - specifically the reductions in the cost of prophylaxis - rather than the clinical benefits of
superior efficacy.

Aapro et al. [23] performed a comparative cost-efficiency analysis of filgrastim, filgrastim-sndz, and
pegfilgrastim for the five largest countries (G5) in the European Union (Germany, France, United
Kingdom, Italy, and Spain [EU]). Evaluating only the cost of medication for one cycle of chemotherapy,
they estimated the cost-efficiency achieved through prophylaxis with filgrastim-sndz instead of
filgrastim in regimens from 1 to 14 days; and prophylaxis with 1 to14 day regimens of filgrastim or
filgrastim-sndz instead of single-administration pegfilgrastim. While pegfilgrastim was found to turn

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cost-saving at 12 days of prophylaxis with filgrastim, at no point over the 14-day period did pegfilgrastim

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yield a savings benefit over filgrastim-sndz.

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With the entry of filgrastim-sndz onto the US market, we aimed to replicate and extend the Aapro et al.
[23] European analysis with cost-efficiency analyses specific to the US. Instead of comparing only to
pegfilgrastim injections, we also included pegfilgrastim-injector. In addition to a base-case scenario that

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evaluates only the cost of medication, we introduce three additional scenarios that vary in the role of
the patient and provider in the administration of filgrastim-sndz, reference filgrastim, pegfilgrastim and
the application of pegfilgrastim-injector. We complement primary cost-efficiency analyses based on the
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Average Selling Price (ASP) with secondary analyses based on the Wholesale Acquisition Cost (WAC). To
translate the implications of these analyses to the clinic, we illustrate the economic results with two
hypothetical case studies in the oncological (solid tumor) and hematological setting. The intent of our
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analyses was to assess the affordability of GCSF prophylaxis with filgrastim-sndz versus prophylaxis with
reference filgrastim, pegfilgrastim, and pegfilgrastim-injector because of the cost-efficiencies enabled by
prophylaxis with filgrastim-sndz [24].
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Methods
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Scenarios
We defined four cost scenarios as shown in Table 1, including a base-case medication cost scenario and
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three clinical scenarios that, given demographic, geographic, and financial factors influencing access to
and utilization of cancer services, are representative of cancer care in the US. The base-case COSTMED
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scenario considers only the cost of medication and, in the case of pegfilgrastim-injector, the body
injector device. The SELFADMIN scenario assumes that patients self-administer their GCSF injections,
whether daily filgrastim or single-dose pegfilgrastim, initiating prophylaxis within the recommended
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time window following the end of chemotherapy. However, in this scenario, for patients receiving
prophylaxis with pegfilgrastim-injector, the application of the device is assumed to be done by staff in
clinics and infusion centers at the healthcare provider organization (HPO) in a session on the day of
completion of the chemotherapy cycle. In the HPOSTART scenario, prophylaxis is initiated in a single
session at the HPO, whether the first injection of filgrastim-sndz or reference filgrastim, the only
injection of pegfilgrastim, or the application of the pegfilgrastim-injector device. Lastly, the HPOALL
scenario assumes that all GCSF administrations are done at the HPO: injection of pegfilgrastim or
application of the pegfilgrastim-injector device in a single session, and filgrastim injections in daily
sessions up to the number of days of prophylaxis prescribed (possible range 1-14 days).
Cost Model
Following Aapro et al. [23], our cost-efficiency analyses focused on the direct costs a buyer or payer
would incur when purchasing or covering prophylaxis with any of the four agents (filgrastim-sndz,
reference filgrastim, pegfilgrastim, pegfilgrastim-injector) in one patient during one chemotherapy cycle.
Indirect costs were not included. Thus, our model included the cost to buyer or payer of the acquisition
and, depending on the scenario, the administration of filgrastim-sndz 300μg or reference filgrastim
300μg from 1-14 days, and pegfilgrastim 6mg as single-injection or as single-administration through the
pegfilgrastim-injector on-body injector. Filgrastim is also available in 480μg for patients weighing 65kg or
more or as per institutional preferences, however the 300μg dose was the unit of reference in the Aapro
et al. cost-efficiency analysis [23] and in a US cost-effectiveness study [25].

Assumptions

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The following assumptions governed the analyses.

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1. All estimates are expressed in 2016 US dollars (USD) rounded to the nearest integer.

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2. The intent of this analysis was to evaluate the cost-efficiency of prophylaxis with daily (self-)
administered subcutaneous injections of filgrastim-sndz for up to 14 days relative to a similar
regimen of reference filgrastim , single-injection pegfilgrastim, and pegfilgrastim-injector

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administered through a single-use on-body injector.

3. Prophylaxis options were considered to be similar to each other in efficacy considering the evidence
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from the pivotal pegfilgrastim vs. filgrastim non-inferiority trials. Hence, we estimated the absolute
cost of the various prophylaxis regimens and scenarios. We did not adjust cost estimates for
differential efficacy as none was assumed. We excluded expenses related to the management of
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(febrile) neutropenia, clinician fees, administrative fees, evaluation-and-management fees, and
(actual or opportunity) costs of associated reductions, delays, or cancellations of chemotherapy
administrations. Our analyses focused on cost-efficiency, not on cost-effectiveness or cost-utility.
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4. Prophylaxis was assumed to be initiated per major European and US guideline recommendations
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[13,14].
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5. Medication costs were for medications provided through infusion centers or through hospital
outpatient services, not through specialty pharmacies. In the primary analysis, the cost estimate of
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medication was the average selling price (ASP) for the third quarter (Oct – Dec) of 2016 (3Q16), as it
was derived from the first quarter 2017 (1Q17) Medicare Part B drug payment limit data published
by the US Centers for Medicare and Medicaid Services (CMS) [26]. Using the CMS methodology [27],
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and considering the six-month time lag before payment limits are calculated, 3Q16 ASP was
computed retroactively as the CMS 1Q17 payment limit minus 6 percent; except for biosimilars
where, per CMS methodology, the ASP is calculated as the payment limit of the biosimilar minus 6
percent of the ASP of the reference product. The secondary analysis (included as Supplemental
Materials) used the wholesale acquisition cost (WAC) for the same period [28].

6. Medication administration costs were defined as the reimbursement received for the applicable
2016 Current Procedural Terminology (CPT) codes [29]. The reimbursement amount is considered to
be the true cost.

7. Reflecting standard clinical practice to teach patients about their medications, patient education
costs were assumed to be covered by the cost of medication administration.
8. Excluded were visit costs, patient co-pays, costs associated with patient self-administration, and
other patient costs (travel, lodging, meals and incidentals, time, etc.; and indirect, opportunity, or
intangible costs). Discounts and other adjustments in the purchasing or reimbursement process
were deemed confidential, variable from provider to providers, and undisclosed. They were not
considered in the analyses, nor were any other parameters of the time value of money.

9. Excluded also were cost drivers that were common to and fixed across all four regimens as these
would not be differentiators of cost outcomes.

10. No evaluation-and-management (E&M) costs were included because (1) injections/applications may
be part of a larger clinic visit and hence the applicable E&M-related HCPCS/CPT codes and

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associated reimbursements would vary, and this independently of prophylaxis; and (2) if E&M could

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be standardized, it would cease to be a potential cost differentiator.

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Cost inputs
Table 2 presents the ASP medication costs as well as the applicable administration costs for the CPT
code 96372 (therapeutic, prophylactic, or diagnostic injection; subcutaneous or intramuscular). The

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administration costs were $42.31 for reference filgrastim, filgrastim-sndz, and pegfilgrastim as hospital
outpatient injections, but $25.44 for pegfilgrastim-injector as the device is applied in physician clinics
and therefore falls under the Physician Fee Schedule; for a difference of $16.87. Note that pegfilgrastim
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and pegfilgrastim-injector are priced the same. WAC medication costs are listed in Table S1.

Cost-efficiency analyses
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For each scenario and following Aapro et al. [23], we calculated the total cost (defined as the required
medications plus, as applicable, administration costs) of prophylaxis with each option (filgrastim-sndz,
reference filgrastim, pegfilgrastim, pegfilgrastim-injector) per that scenario’s specifications. Total cost of
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filgrastim-sndz and reference filgrastim prophylaxis were estimated cumulatively from 1 to 14 daily
injections compared to the constant and time-independent cost of pegfilgrastim and pegfilgrastim-
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injector. From this, we determined the cumulative savings or loss of prophylaxis with filgrastim-sndz
over reference filgrastim; and the cost differentials between single-administration pegfilgrastim or
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pegfilgrastim-injector prophylaxis versus 1-14 injections with filgrastim-sndz or reference filgrastim. We

included the full range from 1-14 days for analytical completeness.
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We also generated two graphics for each scenario [23]. The first (panel A in each figure) plots the cost
evolution from 1 to 14 days of prophylaxis with reference filgrastim or filgrastim-sndz against the
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constant cost of pegfilgrastim or pegfilgrastim-injector prophylaxis for the same period. The day at
which reference filgrastim or filgrastim-sndz lines intersect with the pegfilgrastim or pegfilgrastim-
injector lines is the point where savings with the standard filgrastim agents cease and prophylaxis with
the pegfilgrastim options become cost-saving. The second graphic (panel B) shows the evolution over
14 days in relative savings achieved from filgrastim-sndz versus reference filgrastim prophylaxis. It also
displays the evolution in cost-savings when using reference filgrastim or filgrastim-sndz versus
pegfilgrastim or pegfilgrastim-injector. The day at which the line for either daily agent intersects with
the zero dollar ($0) line on the Y-axis is the point at which using pegfilgrastim or pegfilgrastim-injector
translates into cost-savings. Note that the pegfilgrastim and pegfilgrastim-injector lines virtually overlap
because the only cost differential between both is the difference of $16.87 in their respective
administration costs.
Case studies
To translate the cost-efficiency results to the clinic, we developed two hypothetical case studies, one in
the oncology and one in the hematology setting. Both case studies assume that all GCSF administrations
are done by and at the HPO (i.e., HPOALL scenario).

The first case concerns a 43-year-old Caucasian female, newly diagnosed with stage II breast cancer that
is negative for human epidermal growth factor receptor 2 (HER2) and beginning treatment with TAC
(docetaxel, doxorubicin, cyclophosphamide) for 6 cycles. The patient has an otherwise unremarkable
medical history and no comorbidities. Primary prophylaxis is initiated in cycle 1 due to the high
chemotherapy-related risk for neutropenia (>20%) and continued through all 6 cycles. The local protocol
for GCSF support for TAC is either single-injection pegfilgrastim or 11 days of either reference filgrastim
or filgrastim-sndz.

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The second case involves a 57-year-old African-American male, newly diagnosed with diffuse large B-cell
lymphoma (DLBCL) and undergoing treatment with R-CHOP-21 (cyclophosphamide, doxorubicin,

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vincristine, prednisone, rituximab) for 6 cycles. The patient has a past history of hypercholesterolemia
and hypertension. The patient did not have growth factor added to his treatment regimen as R-CHOP-21
is at an intermediate neutropenia risk level (10-20%) and the patient lacked other risk factors such as

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prior history of CIN, anemia, or being 65 years or older. The patient presented to the emergency
department with fever and chills 5 days after his second cycle of R-CHOP-21. He had a temperature of 41
degrees Celsius, heart rate of 120 beats per minute, and blood pressure of 80/63. The patient was
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admitted to the medical oncology service and started on antibiotics, and was an inpatient for 7 days
until the fever subsided. Cultures were negative throughout the course of treatment. The patient had
pegfilgrastim added to his chemotherapy regimen for the remaining 4 chemotherapy cycles, however
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the insurance company asked to switch the patient to filgrastim-sndz 300g and authorized 7 days of
prophylaxis.
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Results
Cost-efficiency analyses
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Tables 3 through 6 and Figures 1 through 4 present the results for the primary ASP analyses for,
respectively, the COSTMED, SELFADMIN, HPOSTART and HPOALL scenarios. Each Table details the
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cumulative variable cost of treatment with filgrastim-sndz or reference filgrastim against the fixed cost
of pegfilgrastim or pegfilgrastim-injector without (COSTMED) and with (other scenarios) the
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corresponding administration costs, the cumulative cost-savings of using filgrastim-sndz over reference
filgrastim, and the cost differential of pegfilgrastim or pegfilgrastim-injector prophylaxis relative to
reference filgrastim or filgrastim-sndz treatment over up to 14 days.
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In the COSTMED scenario (Table 3; Figure 1), the cumulative cost of prophylaxis with reference
filgrastim evolves from its unit cost of $283 (1 day) to $3,966 (14 days), compared to $218 to $3,051 for
filgrastim-sndz, for cost-savings with filgrastim-sndz ranging from $65 for a 1-day to $916 for a 14-day
regimen. When comparing reference filgrastim to pegfilgrastim or pegfilgrastim-injector, both single-
dose prophylaxis options only turn cost-saving by $82 at 14 days of reference filgrastim treatment. At no
point over a treatment regimen of up to 14 daily filgrastim-sndz injections do pegfilgrastim and
pegfilgrastim-injector yield a savings benefit. Filgrastim-sndz retains marginal savings of $834 at 14 days
but may save $3,666 if only 1 day of filgrastim-sndz prophylaxis is administered.

In the SELFADMIN scenario (Table 4; Figure 2) and similar to the COSTMED scenario, the cumulative cost
of prophylaxis with reference filgrastim ranges from $283 (1 day) to $3,966 (14 days), compared to $218
to $3,051 for filgrastim-sndz, yielding cost-savings with filgrastim-sndz from $65 for a 1-day to $916 for a
14-day regimen. Both pegfilgrastim and pegfilgrastim-injector turn cost-saving only at 14 days of
reference filgrastim prophylaxis by $82 and $57, respectively. Here too, at no point over a treatment
regimen of up to 14 daily filgrastim-sndz injections do pegfilgrastim or pegfilgrastim-injector yield a
savings benefit. Filgrastim-sndz retains marginal savings of $834 over pegfilgrastim and $859 over
pegfilgrastim-injector at 14 days but may save $3,666 and $3,692, respectively, if only 1 day of
filgrastim-sndz prophylaxis is prescribed.

In the HPOSTART scenario (Table 5; Figure 3), the cumulative cost of prophylaxis with reference
filgrastim progresses from $326 (1 day) to $4,009 (14 days), compared to $260 to $3,093 for filgrastim-
sndz, yielding cost-savings with filgrastim-sndz from $65 for a 1-day to $916 for a 14-day regimen. Both
pegfilgrastim and pegfilgrastim-injector turn cost-saving by, respectively, $82 and $99 at 14 days of

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reference filgrastim prophylaxis. Again, at no point over a prophylaxis regimen of up to 14 daily

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filgrastim-sndz injections do pegfilgrastim or pegfilgrastim-injector yield a savings benefit. Filgrastim-
sndz retains marginal savings of $834 over pegfilgrastim and $817 over pegfilgrastim-injector at 14 days

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but may save $3,666 and $3,649, respectively, if only 1 day of filgrastim-sndz prophylaxis is given.

Lastly, in the HPOALL scenario (Table 6; Figure 4), the cumulative cost of reference filgrastim

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prophylaxis increases from $326 (1 day) to $4,559 (14 days), compared to $260 to $3,643 for filgrastim-
sndz, yielding cost-savings with filgrastim-sndz from $65 for a 1-day to $916 for a 14-day regimen. Both
pegfilgrastim ($306 to $632) and pegfilgrastim-injector ($323 to $649) are cost-saving from 13 days of
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reference filgrastim prophylaxis. At no point over up to 14 daily filgrastim-sndz injections do
pegfilgrastim or pegfilgrastim-injector yield a savings benefit. Filgrastim-sndz retains marginal savings of
$284 over pegfilgrastim and $267 over pegfilgrastim-injector at 14 days but may save $3,666 and
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$3,649, respectively, if only 1 day of filgrastim-sndz prophylaxis is prescribed.

Results of the above ASP-based analyses but using the WAC instead are included in the Supplementary
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Materials as Tables S1, S2, S3, S4, S5, and S6, and Figures S1, S2, S3, and S4.
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Case studies
In the case of the patient with HER2-negative breast cancer treated with 6 cycles of TAC and receiving
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GCSF support for all cycles with either pegfilgrastim or 11 days of filgrastim-sndz or reference filgrastim,
the costs of prophylaxis as prescribed range from $2,862 for filgrastim-sndz to $3,582 for pegfilgrastim
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(Table 7). Prophylaxis with filgrastim-sndz yields savings over reference filgrastim of $719 per cycle and
$4,316 over 6 cycles; savings over pegfilgrastim of $1,064 per cycle and $6,385 over 6 cycles; and savings
over pegfilgrastim-injector of $1,047 per cycle and $6,284 over 6 cycles.
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In the case of the patient with DLBCL receiving GCSF support for the remaining 4 cycles of his R-CHOP-21
regimen following hospitalization for febrile neutropenia, and whose insurance company authorized 7
days of standard filgrastim while denying single-administration pegfilgrastim per cycle, the total
prophylaxis costs per cycle were $1,821 for filgrastim-sndz versus $2,279 for reference filgrastim, for
savings of $458 per cycle and $1,831 over 4 cycles (Table 7). The insurer denial of pegfilgrastim and the
use of filgrastim-sndz instead, resulted in savings of $2,105 per cycle and $8,420 over 4 cycles. The
corresponding savings over pegfilgrastim-injector prophylaxis were $2,088 and $8,353.
Discussion
The economic analyses for the US reported here shows consistently that filgrastim-sndz is the least
expensive and therefore economically the most cost-efficient method of prophylaxis for cancer patients
at risk for developing (febrile) neutropenia due to the myelotoxicity of their chemotherapy regimen.
Filgrastim-sndz yields cost-savings of $65 per injection over reference filgrastim, whether one only
considers the cost of drug or also the cost of administration, whether patients self-administer filgrastim,
whether prophylaxis is initiated at the HPO, or whether all injections are given at the HPO. Filgrastim-
sndz also yields significant cost-savings relative to single-administration pegfilgrastim and pegfilgrastim-
injector, though these are a function of the number of filgrastim-sndz administrations. The cost of
prophylaxis with filgrastim-sndz stays significantly below that of prophylaxis with pegfilgrastim or
pegfilgrastim-injector regardless of administration scenario and the number of days of filgrastim
prophylaxis prescribed. Thus, in the 5 to 7 day filgrastim regimens that seem to have become common

t
practice across many tumor types [30,31], substituting filgrastim-sndz for reference filgrastim yields

ip
cost-savings between $327 to $458 per chemotherapy cycle while using filgrastim-sndz instead of
pegfilgrastim generates savings between $2,105 and $2,795 per cycle (the corresponding figures for

cr
pegfilgrastim-injector are $2,088 and $2,821). Considering the therapeutic similarity of filgrastim and
pegfilgrastim, filgrastim-sndz offers the most economical option in the prophylaxis of (febrile)
neutropenia in cancer patients undergoing myelotoxic chemotherapy.

us
As in Europe [23], the cost-savings that can be achieved with filgrastim-sndz in the US are significant,
which is critical considering the concerns about rising drug costs and the debates about strategies to
an
reduce spending on pharmaceuticals. The market adoption signals from Europe are encouraging.
According to QuintilesIMS, biosimilars accounted for about a quarter of sales of all biologics with expired
EU patents in 2013, with significant country-to-country variation pointing at sustained growth
M
opportunities for biosimilar products [32,33,34]. Biosimilar filgrastim has reached market shares upward
of 60% across European countries. It constitutes a large proportion of the US$490 million spent on
biosimilars in the EU G5 in 2015 [32,35].
d

These are potentially encouraging trends for biosimilar filgrastim in the US. Adopting filgrastim-sndz, for
e

instance, will translate into considerable cost-savings without compromising the effectiveness and
safety of prophylaxis. The US indeed has one of the highest generic adoption rates among high-income
pt

countries and this is likely to extend into biosimilars. In 2014, 88% of the 4.3 billion prescriptions in the
US were filled with generics, resulting in $254 billion in savings, and accounting for only 28% of total
ce

drug spending that year [36]. Consider in this regard the Oncology Care Model currently being evaluated
by the Centers for Medicare and Medicaid Services [37]. In this episode-based payment model,
providers are paid on the basis of performance and financial accountability [38], thus incentivizing
Ac

quality and cost to deliver value. Thus, with filgrastim-sndz and reference filgrastim therapeutically
similar, the same quality of prophylaxis can be assured with filgrastim-sndz and the lower cost achieves
both efficiency and value.

In addition to the direct cost-savings that can be achieved with prophylaxis with filgrastim-sndz, there is
another equation that is likely to be impacted favorably. As pegfilgrastim is non-inferior to reference
filgrastim, and filgrastim-sndz was shown to yield similar efficacy and safety outcomes as filgrastim, it
follows that filgrastim-sndz can be considered to be as efficacious as all three originator alternatives.
Further, the real-world effectiveness of filgrastim-sndz was demonstrated in the MONITOR-GCSF study
[31]. Hence the pharmacotherapeutic benefit of filgrastim-sndz should be considered similar to that of
originator alternatives. In the context of value-based formulary decision-making, whether at the payer
or at the provider level, the cost per benefits achieved should be lower. Thus, using filgrastim-sndz
instead of daily reference filgrastim or single-administration pegfilgrastim or pegfilgrastim-injector
meets the triple evidence criteria of effectiveness, cost of treatment, and clinical benefits, resulting in a
lower cost/benefit ratio.

The need to balance savings and outcomes is underscored by the anecdotal evidence from cancer clinics
of some US payers denying GCSF support with pegfilgrastim and authorizing up to 7 days of filgrastim
instead. Per our analyses, prophylaxis for 7 days with reference filgrastim in lieu of pegfilgrastim would
yield savings of $1,647 per cycle in the HPOALL scenario and $1,901 per cycle in the remaining scenarios.
Moreover, using filgrastim-sndz instead of reference filgrastim would generate an additional $458 in
savings in all scenarios evaluated.

Cost-savings from prophylaxis with filgrastim-sndz bring two additional, budget-neutral benefits to

t
payers and buyers. The savings can be applied to provide more patients with access to GCSF support

ip
with filgrastim-sndz. Similarly, the savings can provide expanded access to high-cost curative cancer
treatments on a budget-neutral basis, as Sun et al. [39] showed for rituximab and trastuzumab in a EU

cr
G5 simulation for a panel of 10,000 patients converted from reference filgrastim to filgrastim-sndz.

We considered various durations of filgrastim prophylaxis. The standard recommendation is to treat for

us
up to 14 days or through the absolute neutrophil nadir induced by chemotherapy until the count has
reached 10,000/mm3. On the other hand, prophylaxis patterns observed in routine clinical practice
cluster around 4 to 7 days of filgrastim support [30, 31]. Further, the European MONITOR-GCSF study
an
found that the conventional algorithm of providing growth factor support to patients treated with
myelotoxic regimens with >20% febrile neutropenia risk or to high-risk patients receiving regimens with
10-20% risk may not be adhered to in routine clinical practice [31,40]. In fact, 26% of patients were over-
M
prophylacted relative to the EORTC [13] guidelines, 57% were correctly-prophylacted, and 17% under-
prophylacted. Over-prophylaxis was consistently associated with and predictive of better outcomes
[41,42]. It is evident that a quarter century of clinical experience with filgrastim has led to a maturity in
d

treatment patterns that may be inconsistent with the initial evidence from randomized controlled trials
and with practice guidelines based this evidence. While shorter courses of filgrastim prophylaxis may
e

generate cost-savings, they have been linked to an increase in the risk of hospitalization, which may
offset or exceed any savings achieved. Conversely, each additional day of filgrastim prophylaxis reduced
pt

the risk of hospitalization by 8% to 23% depending on tumor type [30].

ce

We assumed similar efficacy and safety of filgrastim-sndz, reference filgrastim, and pegfilgrastim, and
this on the basis of evidence of the non-inferiority trials of filgrastim and pegfilgrastim [15,16], the
equivalence of filgrastim-sndz and reference filgrastim as evidenced in the European registration studies
Ac

[43,44,45], and triangulating filgrastim-sndz to pegfilgrastim. The assumption of similarity of reference

filgrastim and pegfilgrastim has been challenged based on non-controlled post-approval studies and
meta-analyses sponsored by the manufacturer. Understandable from a strategic point of view, if
marketing authorization can be obtained on the basis of the non-inferiority trials of pegfilgrastim to
filgrastim, this approach might be preferable over the risk of a superiority trial failing or an equivalence
trial falling outside the pre-sepcified margin. For the same reasons manufacturers are disinclined to
sponsor head-to-head trials post-approval. Notwithstanding, they will look for (the appearance of)
superiority from non-controlled retrospective or prospective studies or from meta-analyses when the
only direct RCT evidence is from the pivotal non-inferiority trials. Our position taken in the analyses
reported herein is that RCT-level evidence is the only evidence permitting inferences of causality. In the
absence of RCT-level superiority data, all that is established is that pegfilgrastim is non-inferior to
filgrastim; and by triangulation to filgrastim-sndz.
Our analyses build upon but also extend the Aapro et al. findings [23] to the more heterogeneous payer
market in the US. In addition to the cost-of-drug analyses (COSTMED) for the US, we added scenarios
that varied the role of patient and provider to enhance the applicability of our analyses to clinical
practice. Though the incremental cost implications are minimal, we included pegfilgrastim-injector,
which was approved in 2015. We illustrate our analyses with two hypothetical case studies to increase
the relevance of our analyses to the clinical setting and enhance the accessibility of our analyses to
practicing clinicians.

Even though the data look similar, there are differences between the COSTMED and SELFADMIN
scenarios. Under COSTMED, pegfilgrastim and pegfilgrastim-injector are analyzed as one because these
two options are priced the same. Under SELF-ADMIN, pegfilgrastim-injector cannot be self-administered

t
and must be applied by a clinician, hence the cost differential. Relatedly, in the ASP analyses

ip
pegfilgrastim and pegfilgrastim-injector show cost-savings over reference filgrastim, but not filgrastim-
sndz, in the COSTMED, SELFADMIN, and HPOSTART scenarios relative to 14 doses of reference

cr
filgrastim, and in the HPOALL scenario relative to 13 doses of reference filgrastim. These savings for the
pegylated formulations do not appear in the WAC analyses. This is due to asymmetry in the WAC over
ASP ratios of the agents of interest. The reference filgrastim WAC price is 1.1447 over the ASP price,

us
while the pegfilgrastim WAC price is 1.3273 over ASP prices. Note also that in daily clinical practice,
reference filgrastim is infrequently prescribed for such durations.
an
The Supporting Materials feature a replication of our primary analyses, which used the ASP as cost base,
with analyses using the WAC. The WAC-based cost inputs were considerably higher than those based on
the ASP resulting in differences in price of 23.4% for filgrastim-sndz, 13.5% for reference filgrastim, and
M
28.1% for pegfilgrastim and pegfilgrastim-injector. This yielded significantly greater savings than those
seen in the ASP analyses.
d

While our analyses provide robust estimates of savings that can be achieved from conversion to –
filgrastim-sndz, several questions remain to be answered and should be the subject of future research. A
e

case could be made that the convenience of a single administration, whether economic in terms of
(direct) patient and provider costs or clinical in terms of reduced patient discomfort compared to
pt

multiple injections or infusions, should be incorporated in economic evaluations. It remains unknown

how many daily filgrastim injections are necessary to minimize the risk of adverse outcomes – whether
ce

these outcomes are severe or febrile neutropenia episodes, hospitalizations, or chemotherapy

disturbances – and the associated costs. We used publicly available cost inputs, which may not reflect all
the incentives that manufacturers may extend to buyers and the contracts that group purchasing
Ac

organizations may be able to secure on behalf of their members. The impact of bid-based or value-based
contracting in securing volume contracts and pitching biosimilar versus originator products in formulary
decisions remains to be studied as well. As our study was a cost-efficiency study based on established
similarity in efficacy and safety, the analyses did not consider these variables. Hence the cost of CIN and
FN episodes and CIN/FN-related hospitalizations or chemotherapy disturbances was not included as
these would be constant across treatment options. The focus being on the cost of medication and
administration, our analyses did not include indirect and other treatment-related costs. Data on
discounts and rebates are confidential and could not be integrated into the model; hence we had to rely
on front-end estimates such as the ASP for our primary and the WAC for our secondary analyses.
Conclusion
In these cost-efficiency analyses, (febrile) neutropenia prophylaxis in cancer patients undergoing
myelotoxic chemotherapy with filgrastim-sndz, a biosimilar filgrastim, was associated consistently with
significant cost-savings over prophylaxis with reference filgrastim, pegfilgrastim, and pegfilgrastim-
injector, and this across various administration scenarios. With filgrastim and pegfilgrastim being
pharmacotherapeutically similar, the analyses show that from a cost-efficiency perspective, there is no
compelling rationale for prophylaxis with reference filgrastim, pegfilgrastim, or pegfilgrastim-injector
compared to filgrastim-sndz.

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TABLES
Table 1. Scenarios and associated cost inputs
Scenarios
COSTMED Cost of medication only (incl. for pegfilgrastim-injector)
SELFADMI Patient self-administers all medication, but pegfilgrastim-injector device is
N applied by clinician
HPOSTAR Healthcare provider organization administers first (filgrastim-sndz or reference
T filgrastim) injection and patient self-administers subsequent injections; HPO
administers pegfilgrastim and pegfilgrastim-injector
HPOALL Healthcare provider organization administers all treatments
Cost filgrastim- reference pegfilgrasti pegfilgrastim-
inputs sndz filgrastim m injector

t
✔ ✔ ✔ ✔

ip
COSTMED Medication
Administrati
- - - -
on

cr
SELFADMI
Medication ✔ ✔ ✔ ✔
N

us
Administrati
- - - 1 session
on
HPOSTAR
Medication ✔ an ✔ ✔ ✔
T
Administrati
1 session 1 session 1 session 1 session
on
✔ ✔ ✔ ✔
M
HPOALL Medication
Administrati * *
X sessions X sessions 1 session 1 session
on
*
Number of sessions dependent on the number of injections
d

administered
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pt
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Table 2. Medication and administration costs (ASP)

Medication Administration Combined cost
Ac

filgrastim-sndz $217.90 $42.31 $260.21

reference filgrastim $283.30 $42.31 $325.61
pegfilgrastim $3,884.18 $42.31 $3,926.49
pegfilgrastim-injector $3,884.18 $25.44 $3,909.62
Source ASP CPT ASP + CPT
ASP, Average Selling Price; CPT, Current Procedural Terminology.
Table 3. Comparative cost analysis of prophylaxis options for the COSTMED scenario

All costs rounded to nearest dollar; COSTMED, Cost of medication only (incl. for pegfilgrastim-

t
injector).

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cr
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Table 4. Comparative cost analysis of prophylaxis options for the SELFADMIN scenario

an
M
e d
pt

All costs rounded to nearest dollar; SELFADMIN, Patient self-administers all medication, but
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pegfilgrastim-injector device is applied by clinician.

Ac
Table 5. Comparative cost analysis of prophylaxis options for the HPOSTART scenario

t
ip
All costs rounded to nearest dollar; HPOSTART, Healthcare provider organization (HPO)
administers first (filgrastim-sndz or filgrastim) injection and patient self-administers subsequent

cr
injections, but HPO administers pegfilgrastim and pegfilgrastim-injector.

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Table 6. Comparative cost analysis of prophylaxis options for the HPOALL scenario
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e d
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All costs rounded to nearest dollar; HPOALL, Healthcare provider organization administers all
treatments.
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Table 7. Case studies using the HPOALL scenario
Tumor type HER2-negative breast DLBCL
Chemo regimen TAC R-CHOP-21
Cycles 6 4
Filgrastim injections per cycle 11 7
Prophylaxis cost per cycle
filgrastim-sndz $2,862 $1,821
reference filgrastim $3,582 $2,279
pegfilgrastim $3,926 $3,926
pegfilgrastim-injector $3,910 $3,910
Savings per cycle

t
filgrastim-sndz vs. reference

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filgrastim $719 $458
filgrastim-sndz vs. pegfilgrastim $1,064 $2,105
filgrastim-sndz vs. pegfilgrastim-

cr
injector $1,047 $2,088
Total savings over all cycles

us
filgrastim-sndz vs. reference
filgrastim $4,316 $1,831
filgrastim-sndz vs. pegfilgrastim an $6,385 $8,420
filgrastim-sndz vs. pegfilgrastim-
injector $6,284 $8,353
All costs rounded to nearest dollar; DLBCL, diffuse large B-cell lymphoma; HER2, human
M
epidermal growth factor receptor 2; R-CHOP-21, cyclophosphamide, doxorubicin, vincristine,
prednisone, rituximab; TAC, docetaxel, doxorubicin, cyclophosphamide.
e d
pt
ce
Ac
FIGURES
Figure 1. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the COSTMED scenario.

t
ip
cr
us
an
Figure 2. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the SELFADMIN scenario.
M
e d
pt
ce
Ac
Figure 3. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the HPOSTART scenario.

t
ip
cr
us
Figure 4. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the HPOALL scenario.

an
M
e d
pt
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Supplementary Material
Table S1. Medication and administration costs (WAC)
Medication Administration Combined cost
filgrastim-sndz $275.66 $42.31 $317.97
reference filgrastim $324.30 $42.31 $366.61
pegfilgrastim $5,155.65 $42.31 $5,197.96
pegfilgrastim-injector $5,155.65 $25.44 $5,181.09
Source WAC CPT WAC + CPT
WAC, Wholesale Acquisition Cost; CPT, Current Procedural Terminology.

t
ip
Table S2. Comparative cost analysis of prophylaxis options for the COSTMED scenario with WAC

cr
us
an
M
All costs rounded to nearest dollar; COSTMED, Cost of medication only (incl. for pegfilgrastim-
injector); WAC, Wholesale Acquisition Cost.
e d
pt
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Table S3. Comparative cost analysis of prophylaxis options for the SELFADMIN scenario with
WAC

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All costs rounded to nearest dollar; SELFADMIN, Patient self-administers all medication, but

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pegfilgrastim-injector device is applied by clinician; WAC, Wholesale Acquisition Cost.

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Table S4. Comparative cost analysis of prophylaxis options for the HPOSTART scenario with WAC
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All costs rounded to nearest dollar; HPOSTART, Healthcare provider organization administers
first (filgrastim-sndz or filgrastim) injection and patient self-administers subsequent injections,
but HPO administers pegfilgrastim and pegfilgrastim-injector; WAC, Wholesale Acquisition Cost.
Table S5. Comparative cost analysis of prophylaxis options for the HPOALL scenario with WAC

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ip
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All costs rounded to nearest dollar; HPOALL, Healthcare provider organization (HPO) administers
all treatments; WAC, Wholesale Acquisition Cost.

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Table S6. Case studies using the HPOALL scenario with WAC
Tumor type HER2-negative breast DLBCL
Chemo regimen TAC R-CHOP-21
Cycles 6 4
Filgrastim injections per cycle 11 7
Prophylaxis cost per cycle
filgrastim-sndz $3,498 $2,226
reference filgrastim $4,033 $2,566
pegfilgrastim $5,198 $5,198
pegfilgrastim-injector $5,181 $5,181
Savings per cycle

t
filgrastim-sndz vs. reference

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filgrastim $535 $340
filgrastim-sndz vs. pegfilgrastim $1,700 $2,972
filgrastim-sndz vs. pegfilgrastim-

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injector $1,683 $2,955
Total savings over all cycles

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filgrastim-sndz vs. reference
filgrastim $3,210 $1,362
filgrastim-sndz vs. pegfilgrastim an $10,202 $11,889
filgrastim-sndz vs. pegfilgrastim-
injector $10,101 $11,821
All costs rounded to nearest dollar; DLBCL, diffuse large B-cell lymphoma; HER2, human
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epidermal growth factor receptor 2; R-CHOP-21, cyclophosphamide, doxorubicin, vincristine,
prednisone, rituximab; TAC, docetaxel, doxorubicin, cyclophosphamide; WAC, Wholesale
Acquisition Cost.
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Figure S1. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the COSTMED scenario with WAC.

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Figure S2. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the SELFADMIN scenario with WAC.
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Figure S3. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the HPOSTART scenario with WAC.

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ip
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Figure S4. Comparative cost analysis by product over 14 days (panel A) and associated savings
(loss) by product pairs (panel B) for the HPOALL scenario with WAC.
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