PharmacoEconomics - Open (2023) 7:3–36

https://doi.org/10.1007/s41669-022-00361-3

SYSTEMATIC REVIEW

A Systematic Review of Time and Resource Use Costs of Subcutaneous

Versus Intravenous Administration of Oncology Biologics in a Hospital
Setting
Conor McCloskey1 · María Toboso Ortega2 · Sunita Nair3 · Maria João Garcia4 · Federico Manevy4

Accepted: 19 July 2022 / Published online: 23 August 2022

© The Author(s) 2022

Abstract
Background The introduction of human epidermal growth factor receptor 2 (HER2)-targeted treatment options, including
dual HER2 blockade, has improved the prognosis for patients with HER2-positive breast cancer (BC) substantially. However,
most of these treatments are administered via the intravenous (IV) route, which can present many challenges, such as long
infusion and observation times, issues associated with repeated IV access, and increased strain on time and resources of
medical centers and healthcare professionals. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous
(SC) injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (­ PHESGO®, F. Hoffmann-La Roche Ltd, Basel, Switzer-
land; PH FDC SC)) has been approved for use alongside chemotherapy for early-stage and metastatic HER2-positive BC.
Objectives This systematic literature review was performed to identify evidence relating to time/resource use and resulting
cost differences between SC and IV administration of oncology biologics in a hospital setting, and, ultimately, to inform
economic modeling and associated health technology assessment of PH FDC SC.
Methods Electronic databases (Embase, MEDLINE, and EconLit) were searched on 9 April 2020. Additional hand searches
were performed to identify publications not captured in the electronic database search. Publication screening and data
extraction (study characteristics, participants, interventions, costs, and time/resource use) were carried out per the standard
Cochrane review methodology. The quality of economic evidence of cost analyses was assessed using the 36-item checklist
of the National Institute for Health and Care Excellence Single Technology Appraisal Specification for submission of evi-
dence (January 2015).
Results The database search identified 2,740 records, of which 237 underwent full text screening. Full text screening,
prioritization of publications about patients with a cancer diagnosis, and the addition of four citations identified during
the hand search resulted in 72 final included publications, relating to 71 unique studies. This included 40 publications that
described the time/resource use and/or costs associated with SC versus IV trastuzumab administration for the treatment of
HER2-positive BC, and 28 publications that described time/resource use and/or costs associated with rituximab SC versus
IV administration for the treatment of non-Hodgkin’s lymphoma/follicular lymphoma and diffuse large B-cell lymphoma.
The majority of publications showed substantial time savings for preparation and administration of SC versus IV therapy,
and cost savings associated with reductions in healthcare professional time and resource use for SC administration.
Limitations There was a lack of consensus between publications regarding time and cost measurements. In addition, the
search was limited to publications related to anticancer drugs; the majority of the studies included were performed in Euro-
pean countries.
Conclusions and implications This review indicated a substantial body of evidence showing time/resource and cost savings
of SC versus IV administration of oncology biologics in a hospital setting, which can be used to inform economic evalua-
tions of PH FDC SC.

Extended author information available on the last page of the article

Vol.:(0123456789)
4 C. McCloskey et al.

response), and the potential risks associated with indwell-

Key Points for Decision Makers ing venous access (e.g., catheter-associated pain/discomfort,
thrombosis, or risk of systemic infections) [25–28]. Moreo-
Most of the publications identified in this systematic ver, the increasing use of IV administered agents in oncol-
review showed time/resource and cost savings associated ogy has placed a strain on medical centers and healthcare
with subcutaneous versus intravenous administration of professionals (HCPs) with respect to the time and resources
anticancer biologics in a hospital setting. required to prepare and administer infusions [25, 29].
This evidence can provide relevant inputs for economic A subcutaneous (SC) formulation has previously been
evaluations of the fixed-dose combination of pertuzumab developed for trastuzumab ­(Herceptin® SC or Herceptin
and trastuzumab for subcutaneous injection (pertuzumab, ­HylectaTM, F. Hoffmann-La Roche Ltd) [11, 30]. The Han-
trastuzumab, and hyaluronidase-zzxf ­(PHESGO®, F. naH study (NCT00950300) compared the pharmacokinet-
Hoffmann-La Roche Ltd; PH FDC SC)). ics, efficacy, and safety of SC trastuzumab with IV trastu-
zumab. SC trastuzumab was shown to be non-inferior to
IV, for both co-primary endpoints (serum trough concentra-
tion at pre-dose cycle 8 and pathologic complete response
rates), demonstrating that the SC formulation is a valid treat-
1 Introduction ment alternative to IV [31–34]. Further to this, the safety
and efficacy profiles for SC trastuzumab in combination
Breast cancer (BC) is the most prevalent form of invasive with IV pertuzumab and docetaxel as a first-line treatment
cancer among women, with over 2.2 million cases and for patients with HER2-positive MBC in the MetaPHER
almost 700,000 deaths worldwide in 2020 [1, 2]. Approxi- study (NCT02402712) was found to be consistent with
mately 20% of BC cases are human epidermal growth factor those observed for IV trastuzumab in combination with
receptor 2 (HER2)-positive, a subtype defined by amplifica- IV pertuzumab and docetaxel in the CLEOPATRA study
tion of the HER2 oncogene and overexpression of the HER2 (NCT00567190) [21, 35–38].
transmembrane receptor protein on the surface of tumor The PrefHer study (NCT01401166), in which patients
cells. HER2 interacts with other HER family proteins as with EBC were randomized to receive four cycles of SC
part of signal transduction pathways, mediating cell growth, trastuzumab followed by four cycles of IV trastuzumab, or
survival, and differentiation [3]. HER2-positive BC is asso- vice versa, demonstrated a strong patient preference and
ciated with poor prognosis, arising from increased tumor increased HCP satisfaction with SC over IV administration
aggressiveness, higher rates of recurrence, and increased [39, 40]. These results were also confirmed in the metastatic
mortality [3, 4]. setting in the MetaspHer study (NCT01810393) [41]. The
Trastuzumab ­(Herceptin®, F. Hoffmann-La Roche Ltd, approval of a fixed-dose combination of pertuzumab and
Basel, Switzerland), the first approved HER2-targeted mon- trastuzumab for SC injection (pertuzumab, trastuzumab, and
oclonal antibody, transformed the treatment and prognosis hyaluronidase-zzxf ­(PHESGO®, F. Hoffmann-La Roche Ltd;
of patients with HER2-positive BC in both the early and the PH FDC SC)) [42] presents an opportunity for an option that
metastatic settings [5–15]. This has led to the development is preferred by patients and can potentially provide time-
of dual anti-HER2 blockade with pertuzumab plus trastu- saving benefits to patients and HCPs versus IV adminis-
zumab ­(PERJETA® and H ­ erceptin®, F. Hoffmann-La Roche tration, according to patient and HCP questionnaires in the
Ltd; standard of care in first-line HER2-positive metastatic PHranceSCa study (NCT03674112) [43].
BC (MBC) and high-risk early BC (EBC)) [13–21] and the This systematic literature review (SLR) was performed to
anti-HER2 antibody-drug conjugate ado-trastuzumab emtan- identify evidence relating to differences in time/resource use
sine ­(Kadcyla®, F. Hoffmann-La Roche Ltd; used in second- and the resulting cost differences between SC and IV admin-
line HER2-positive MBC and in EBC for the treatment of istration (but not differences in the drug costs themselves).
residual invasive disease following neoadjuvant therapy The rationale for performing the SLR was as preliminary
and surgery) [13–16, 22–24]. These treatment options have work that will ultimately inform economic modeling and
improved the prognosis for patients with HER2-positive BC associated health technology assessment of PH FDC SC.
substantially. The most analogous evidence was likely to be data relating
However, intravenous (IV) administration of anticancer to the time/resource use and cost differences for SC versus
biologics can present multiple challenges for many patients, IV administration of trastuzumab for the treatment of BC,
including long infusion and observation times, the need for or of rituximab ­(Rituxan® or ­MabThera®, F. Hoffmann-
repeated, invasive IV access (sometimes over long peri- La Roche Ltd) for treatment of non-Hodgkin’s lymphoma
ods of time in cases where there is evidence of a treatment (NHL)/follicular lymphoma (FL) and diffuse large B-cell
lymphoma (DLBCL). Thus, the SLR initially sought to
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 5

identify cost analyses as well as time-and-motion analy- eligible publications, a higher number than anticipated due
ses for any indication where patients’ treatment requires to broad eligibility criteria. Prioritization was therefore
IV or SC administration in a hospital setting, and was then given to publications of patients with a cancer diagnosis,
restricted to oncology biologics. as noted in Table 1, given the target population for PH FDC
SC, resulting in exclusion of 74 non-oncology publications.
Hand searching identified a further four citations that met
2 Methods the revised eligibility criteria, resulting in 72 final included
publications, relating to 71 unique studies. The PRISMA
A systematic search was conducted via the Ovid platform diagram is presented in Fig. 1.
(Wolters Kluwer, Alphen aan den Rijn, Netherlands) on
9 April 2020 using a predefined search strategy within the 3.1 Characteristics of Included Studies
Embase (1980–present), MEDLINE (1946–present), and
EconLit (1961–present) electronic databases. The database Table 2 summarizes the characteristics of all included stud-
search strings identified all relevant studies (full papers or ies. In total, 40 publications were identified that described
abstracts from any conferences) indexed in Embase, and were the time/resource use and/or costs associated with SC versus
modified for performing searches in MEDLINE and EconLit IV trastuzumab administration for the treatment of HER2-
to account for differences in syntax and thesaurus headings. positive BC. Of these, 22 publications [25, 48–68] (13 full
Searches included terms for free text and Medical Subject papers [25, 51–55, 59, 62–67] and nine abstracts [48–50,
Heading (MeSH) terms. The search strategies used and details 56–58, 61, 68]) reported time/resource use for administra-
of any additional hand searches that were carried out to iden- tion of SC versus IV trastuzumab (Fig. 2). This included
tify publications not captured in the electronic database search two publications related to PrefHer, a multinational study
are provided in the Online Supplemental Material, Resource 1. conducted in eight countries (Canada, France, Switzerland,
Details on the study eligibility criteria are presented in Table 1. Denmark, Italy, Russia, Spain, and Turkey), 18 publications
The SLR followed the standard Cochrane review meth- that reported studies that were conducted in at least 12 indi-
odology [44] and included double screenings by two inde- vidual European countries (the country was not stated in one
pendent reviewers. Relevant data from included publica- of the publications) [48–54, 57–61, 63–68], one publica-
tions were extracted by a reviewer and verified by a second tion that reported a study in Hong Kong [56], and one that
independent reviewer; any disputes were resolved through reported a study in New Zealand [62]. A total of 24 publi-
discussion. The types of data to be collected were predefined cations reported on the costs of SC versus IV trastuzumab
and included: study country, study design, industry sponsor, administration. Of these, 19 reported data for at least 13
inclusion/exclusion criteria, target population, study aims, individual European countries (the country was not stated in
data source, intervention, study limitations, and conclusions. one of the publications) [48–51, 53, 54, 57, 59–61, 63–65,
Cost and time/resource use outcomes were also captured 67]. The other five were in Canada, Chile, Singapore, Hong
and stratified by disease and route of administration. Qual- Kong, and New Zealand [56, 62, 69–71]. Budget impacts of
ity assessments of the studies in the included publications introducing SC trastuzumab were reported by five publica-
were conducted by a single analyst and verified by a sec- tions (Arabia, Ecuador, Canada, Brazil, Spain) [69, 72–75].
ond analyst or project lead. The quality of economic evi- Six other publications described costs related to SC trastu-
dence reported in the included cost analysis publications zumab: three compared SC trastuzumab with an IV trastu-
were assessed using the 36-item checklist of the National zumab biosimilar [76–78], two described cost minimization
Institute for Health and Care Excellence Single Technology analyses for SC versus IV administration [79, 80], and one
Appraisal Specification for manufacturer/sponsor submis- reported on cost savings for the administration of the SC
sion of evidence (January 2015), adapted from Drummond route over 18 months compared with a combination of SC
and Jefferson [45]. The methodologic limitations of publica- and IV [81].
tions reporting on time/resource use and costs were assessed A total of 28 publications were identified that described
based on a model described by Drummond et al. [46] and time/resource use and/or costs associated with rituximab SC
adapted to cost of illness by Molinier et al. [47]. versus IV administration for the treatment of NHL/FL or
DLBCL. Nineteen of these publications reported on time/
resource use, 11 of which also described related costs. There
3 Results were an additional seven publications that reported only
on costs, to give 18 publications with cost-related analy-
This search identified 2,740 records, of which 237 under- ses. The remaining three publications described the likely
went full-text screening. Ninety-five publications were budget impact of introducing the rituximab SC formulation
excluded during full-text screening, leaving 142 potentially for the treatment of NHL or DLBCL, and provided limited
6 C. McCloskey et al.

Table 1  Eligibility criteria for the systematic literature review

Description Inclusion criteria Exclusion criteria

Population Any patients receiving treatment in a hospital ­settinga Patients treated exclusively at home
Intervention/comparator Studies comparing any IV- versus SC-administered interventions Studies not comparing IV- versus SC-
administered interventions
Outcomes Costs and time/resource use Clinical outcomes
Direct medical costs:
Port versus PICC versus CVC costs
Direct non-medical costs:
Transportation
Childcare costs
Additional caregiver costs
Indirect/societal costs:
Productivity losses
Absenteeism
Presenteeism
Withdrawal from labor force
Estimates of time/resource use including:
Hospitalization and length of stay
Pharmacist time
Nurse time
Drug wastage
Cost drivers
Time-and-motion outcomes including:
Patient waiting time
Drug preparation time
Administration time
Monitoring/observation time
Nurse set-up time
AE management time
Study design/setting Cost and time/resource use studies: Systematic literature ­reviewsb
Any studies reporting original cost and/or time/resource use data Studies based on animal models
Preclinical and biologic studies
Narrative reviews, editorials, opinions
Language of publication Not restricted NA
Date of publication Full publications: 2­ 012c to present Full publications prior to 2012
Conference abstracts: 2017 to ­presentd Conference abstracts prior to 2017
Countries Not restricted NA

AE adverse event, CVC central venous catheter, IV intravenous, NA not applicable, PICC peripherally inserted central catheter, SC subcutaneous,
SLR systematic literature review
a
As a result of the deliberately inclusive eligibility criteria originally designed for this SLR, a larger than anticipated number of potentially eli-
gible studies were identified after the completion of first pass screening. A decision was taken to deprioritize any study that did not focus on a
population of patients with a cancer diagnosis
b
Relevant systematic literature reviews were reference checked before being excluded
c
Year of approval of SC trastuzumab
d
Conference abstracts that were superseded by a full publication were excluded unless the abstract reported some unique data

evidence relating to the comparative costs of rituximab SC paucity of studies reporting individual outcomes, it was not
and administrations. feasible to categorize the studies according to risk. Although
the study designs of the economic evaluations were gener-
3.2 Quality Assessment Results ally well described, reporting of data collection methods and
of analysis and interpretation of the results was inconsistent
A quality assessment of all full publications was conducted. between studies. For example, time horizons of costs and
Overall, the studies were considered to be of adequate qual- benefits, discount rates, and sensitivity analyses were only
ity. However, due to the wide range of study designs and the discussed in a small proportion of the publications.
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 7

Fig. 1  PRISMA diagram: Study Identification of studies via databases and registers Identification of studies via other methods
flow of included and excluded
publications. PRISMA Preferred
Reporting Items for Systematic Records identified from

Identification
databases (N = 2740): Records removed Reports identified through
Reviews and Meta-Analyses before screening: hand searching (n = 4):
Embase (n = 2254)
MEDLINE (n = 410) Duplicate records Conference searching (n = 3)
Cochrane (n = 67) removed (n = 385) Citation searching (n = 1)
EconLit (n = 9)

Records excluded
(n = 2118):
Records screened Intervention (n = 1291)
(n = 2355) Review/editorial (n = 447)
Study design (n = 346)
Duplicate (n = 24)
Population (n = 10)

Reports sought for retrieval Reports not retrieved

Screening

(n = 237) (n = 0)

Reports assessed for eligibility Reports excluded (n = 95):

(n = 237) Duplicate (n = 6)
Intervention (n = 20)
Outcomes (n = 49)
Review/editorial (n = 4)
Study design (n = 5)
Superseded (n = 11)

Additional exclusion criteria used

to deprioritise non-oncology
studies (n = 74)
Studies included in review
Included

(n = 71)
Reports of included studies
(n = 72)

3.3 Time/Resource Use With IV Versus SC the average HCP time required for administration based on
Administration of Trastuzumab this. Another publication [53] only reported active HCP
times for preparation and administration, obtained from
Of the 22 publications reporting data regarding time detailed case reports and stopwatch time measurements for
required, or the difference in time required, for administra- all nurse activities for a subgroup of observed cases.
tion of SC versus IV trastuzumab for the treatment of BC, 16
reported data either from time-and-motion studies or stud- 3.3.1 Preparation Time
ies where the time for each specific procedure was directly
measured. Some reported single-center studies, while others Preparation time for trastuzumab was reported in seven pub-
reported studies involving up to 16 centers. Two publications lications, including two where only the difference in prepa-
reported studies that estimated time based on information ration time between SC and IV was reported. Within these,
provided by drug preparation/administration software [51, preparation time was directly measured [25, 49, 53, 62] or
68]; one publication reported a study that estimated time estimated from software records [51, 68] or HCP question-
from a survey of HCPs [66], and three publications did not naires [66]. HCP estimates were consistent with publications
report the manner in which time was estimated [52, 56, 58]. from studies in which time was measured directly. Preparation
HCP time includes drug preparation and administration of IV trastuzumab for administration was reported to require
times, and may be reported according to specific roles (e.g., 14–21 min, compared with 0–11 min for SC trastuzumab. The
pharmacists, nurses, nursing assistants), or as an average of time difference between SC and IV was 3–14 min per prepa-
the HCP times. Variation in the description of the elements ration [25, 49, 51, 53, 62, 66, 68]. An additional publication
involved in preparation and administration of trastuzumab reported preparation time for the loading dose to be 8 versus
may limit comparison between publications. For example, 2 min, for IV and SC trastuzumab, respectively. Nursing time
one time-and-motion study publication [63] described the was reported as 16 versus 7 min, and was deemed likely to
measured time for each step involved in preparation and relate to preparation rather than administration of the dose,
administration, including involvement of the pharmacist, giving a total time of 24 versus 9 min [61].
staff nurse, and clinical nurse specialist, and then provided
 8

Table 2  Summary of all publications included in this systematic literature review

Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Trastuzumab—full publications
De Cock 2016 [25] Canada, France, Switzerland, Prospective, observational Multiple centers across dif- HER2-positive BC (NR) – Treatment room time, 17.9
Denmark, Italy, Russia, time-and-motion study ferent countries 1) SC trastuzumab (single- versus 9.8–11.2 min, Prepa-
Spain, Turkey (PrefHer; NCT01401166) use injection device or ration, 13.9 versus 5.0–7.6
to quantify patient chair handheld syringe) min
time and active HCP time 2) IV trastuzumab Total time, 31.8 versus
associated with SC and IV 14.8–18.8 min, i.e. 13–17
­trastuzumaba min shorter
Chair time, 55–57 min shorter;
77.8 versus 20.9–22.6 min,
p<0.0001
Farolfi 2017 [51] Italy Retrospective cohort study Time/resource utilization EBC (n = 114) Direct costs, €13,655 versus Preparation, 14.1 versus 10.7
to compare the time/ retrieved from Institutional 1) SC trastuzumab €14,154/patient/year min
resource utilization of SC medical record database 2) IV trastuzumab €14,233 versus €14,273/ Administration, 90 versus
and IV trastuzumab and (Log80); unit patient/year (including 5 min (loading dose); 30
to conduct an economic costs for healthcare profes- indirect costs) versus 5 min (maintenance
­evaluationa sionals retrieved from the Preparation, dose)
Italian National Contract €92.60 versus €57.50/
patient/year
Day hospital cost, €575.82
versus €61.51/patient/year
Hedayati 2019 [54] Sweden Retrospective study to Karolinska University HER2-positive BC (n = Savings for cohort over 1 Administration, 90 versus
estimate the economic Hospital 178) year: 10 min (first session; 30
efficiency of SC trastu- 1) IV trastuzumab Avoiding surgery to implant versus 10 min (subsequent
zumab by assessing the 2) SC trastuzumab catheters, €419,012 sessions)
economic benefits of actual Preparation time, €167,087
SC-driven process changes Consumables, €17,389
at one single Swedish Direct cost saving, €603,488
healthcare ­institutiona (for cohort over 1 year)
Jackisch 2015 [55] Canada, Denmark, France, Prospective study to provide NR HER2-positive BC (n = – Active HCP time:
Russia, Spain, Switzerland an overview of the study 415) Denmark 7.2 versus 4.9 min
data on SC trastuzumab 1) IV trastuzumab France, 9 versus 5.7
and summarizes and 2) SC trastuzumab Canada, 11.8 versus 6.3
evaluates the experience of Russia, 9.9 versus 5.2
7 German centers over 18 Spain, 8.2 versus 4.0
months of administering Switzerland, 10.5 versus 7.2
SC trastuzumab in routine Chair time:
clinical ­practicea Denmark, 57 versus 24 min
France, 85 versus 27
Canada, 67 versus 24
Russia, 47 versus 13
Spain, 100 versus 20
Switzerland, 133 versus 38
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Lopez-Vivanco 2017 [59] Spain Prospective observational NR HER2-positive BC (n = 10) Preparation and administra- Active HCP time,
study to describe HCP and 1) IV trastuzumab tion, €12.76 versus €6.01 27.2 versus 13.2 min
patient time and related 2) SC trastuzumab Consumables, €8.64 versus [Nursing time,
costs associated with IV €2.39 21.8 versus 11.2 min
and SC trastuzumab in Costs per 18 cycles: Pharmacist time,
patients with HER2-posi- HPC, €230 versus €108 4.2 versus 1.2 min
tive early ­BCa Consumables, €155 versus Nursing assistant time, 1.1
€43 versus 0.8 min]
Drug costs, €29,046 versus Chair time, 101 versus 20 min
€28,301 Treatment room time. 120
Direct costs, €29,432 versus versus 30 min
€28,452 (for 18 cycles) Hospital time, 205 versus
€29,635 versus €28,503 115 min
(for 18 cycles including
indirect costs)
Lost productivity, €204 ver-
sus 51 (for 18 cycles)
North 2015 [62] New Zealand Noninterventional, descrip- Auckland City Hospital (IV HER2-positive BC (n = 18) Total, NZD 76.94 Pharmacist time, 20.5 versus
tive study to determine trastuzumab) and Tauranga 1) IV trastuzumab For administration and 0 min
medical time/resource Hospital (SC and IV 2) SC trastuzumab preparation, NZD 61,67 Administration, 37.6 versus
utilization associated trastuzumab) [Chair time, NZD 40.03 5.7 min
with administration of SC HCP nurse time, NZD 4.59 HCP (nurse) time, 13.0 versus
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

trastuzumab injection via Total pharmacist time, NZD 6.9 min

handheld syringe versus 17.05] Chair time, 47.4 versus 10.5
IV trastuzumab infusion in Consumables, NZD 15.27 min
patients with HER2-posi-
tive BC in New ­Zealanda
O’Brien 2019 [63] Ireland Prospective observational Two large acute Irish Uni- HER2-positive BC (NR) Consumables, €56.28 versus HCP time, 74.7 versus 15.4
study to analyze which versity teaching hospitals 1) IV trastuzumab €25.91 min
route of trastuzumab within the south/southwest 2) SC trastuzumab Preparation and administra-
administration, for the tion time, €44.93 versus €9
treatment of HER2- Direct costs, for 17-cycle
positive BC, was more treatment
cost-effective and time- €36,619 versus €35,010
saving in relation to active €36,863 versus €35,077
HCP ­timea (including indirect costs)
Societal costs, for 17-cycle
treatment
€243.74 versus €67.15
9
 10

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Olofsson 2016 [64] Sweden Observational study to Five oncology clinics HER2-positive BC (n = Direct costs, First visit, HCP time, 44 versus 26 min
estimate the societal value 195) €2695 versus €1938 (first treatment)
of trastuzumab adminis- 1) IV trastuzumab €2976 versus €2079 (includ- 30 versus 16 (subsequent treat-
tered through SC injection 2) SC trastuzumab ing indirect costs) ment), p < 0.01 for both
compared to IV ­infusionb Subsequent visits, €2033 Hospital time:
versus €1933 414 versus 313 min (first treat-
€2099 versus €1983 (includ- ment), p < 0.05;
ing indirect costs) 90 versus 67 min, p < 0.01
First visit: (subsequent treatment)
Consumables, €53 versus €1
Nurse time, €22 versus €13
Drug costs, €2616 versus
€1920
Subsequent visits:
Consumables, €53 versus €1
Nurse time, €15 versus €8
Drug costs, €1962 versus
€1920
First visit:
Lost productivity, €94 versus
€16
Lost leisure time, €187 ver-
sus €125 (includes patient
and accompanying kin)
Subsequent visits
Lost productivity, €26 versus
€16
Lost leisure time, €40 versus
€34
Olsen 2018 [65] Denmark Study design NR. To Seven departments located at HER2-positive BC (NR) Non-drug costs excluding HCP time, 92 versus 30 min
estimate the costs of regional hospitals and five 1) IV trastuzumab patient’s time: (first cycle), subsequent
administration of IV and at university hospitals 2) SC trastuzumab 1st cycle, €171 versus €60 therapy, 56 versus 30 min
SC trastuzumab t­reatmenta 4+ cycle, €103 versus €52 Direct contact, 111 versus 13
Non-drug costs including min (first cycle), 51 versus
patient’s time: 13 min (subsequent cycle)
1st cycle, €290 versus €153 Observation time, same for
4+ cycle, €112 versus €55 first cycle; second cycle, 61
versus 93 min
Tjalma 2018 [67] Belgium Observational, non–inter- LEAN day care oncology HER2-positive BC (n = Administration, €224.48 Total time in center, 173
ventional, prospective, unit of the Antwerp Uni- 130) versus €10.60 versus 51 min
monocentric time, motion versity Hospital 1) SC trastuzumab HCP time, €37.4 versus €7.9 HCP time, 68 versus 14 min
and cost assessment study 2) IV trastuzumab Consumables, €23.60 versus Chair time, 137 versus 10.6
to determine and compare €2.70 min
the time and costs of SC Drug wastage, €139.00
versus IV trastuzumab versus 0
administration in patients Overall saving per admin-
with HER2-positive ­BCa istration excluding drug
costs, €212.93
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Rojas 2020 [71] Chile Cost-minimization analysis Nuestra Señora de la HER2-positive BC (n = Direct costs, per treatment –
to compare the direct and Esperanza Cancer Center, 100) (18 doses) including
indirect medical and non- Red de Salud UC-Christus 1) IV trastuzumab indirect costs, US$83,309
medical costs associated network 2) SC trastuzumab versus US$77,068
with SC trastuzumab and Per treatment (18 doses):
IV trastuzumab in patients Preparation, US$78,076
with HER2+ early BC in versus US$73,225
a private health center in Administration, US$3485
­Chileb versus US$2005
Aes, US$1574 versus
US$1715
Societal costs, per treatment
(18 doses)
Indirect costs, US$173
versus US$1216
De La Vega Zamorano Spain Retrospective observational Hospital de la Ribera. Alzira. HER2-positive EBC or
2017 [81] study to evaluate and Valencia MBC (n = 28)
quantify the ­economica 1) SC trastuzumab
impact of SC presentation 2) IV trastuzumab
of trastuzumab
Lazaro Cebas 2017 [82] Spain Cross-sectional question- Oncology outpatient hospital HER2-positive BC (n = 76) Direct costs, annual saving, –
naire-based study to inves- (Hospital Universitario 12 1) IV trastuzumab €35,332
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

tigate patient satisfaction de Octubre, Madrid) 2) SC trastuzumab

and preferences regarding
SC versus IV trastu-
zumab and to evaluate the
financial impact derived
from the use of the SC
­formulationa
Mylonas 2017 [86] Greece Economic analysis to NR HER2-positive BC (NR) Direct costs, €23,118 versus –
conduct an economic 1) IV trastuzumab €21,870 per therapy
evaluation comparing 2) SC trastuzumab Administration, €266.94
SC trastuzumab with versus €64.41
IV trastuzumab, in the CVAD, €289.80 versus 0
treatment of patients with Overhead,
HER2-positive early and €249.94 versus €67.19
metastatic BC (EBC- Drug cost, €22,311 versus
MBC), in the Greek health €21,738
care ­settinga
11
 12

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified
Trastuzumab—abstracts

Andrade 2013 [48] Portugal Study design NR. To deter- Five public and two private HER2-positive BC €43.22 versus €3.18 –
mine the costs associated hospitals; official sources (mean: n = 12 patients/
with the preparation and or price tables provided by week)
administration of HER2- manufacturer 1) IV trastuzumab
positive BC treatment 2) SC trastuzumab
with IV trastuzumab and
to estimate the differ-
ence compared with SC
­trastuzumaba
Blein 2018 [49] France Observational study to Nine healthcare facilities HER2-positive BC (n = Consumables, €11.07 lower Preparation, 12 min shorter
evaluate the organizational 411) Administration, 107 min
and economic impacts 1) SC trastuzumab shorter
generated by the admin- 2) IV trastuzumab
istration of SC versus IV
­trastuzumaba
De Cock 2014 [50] Russia Prospective, time-and- Three centers HER2-positive BC (NR) HCP time, 1175 roubles HCP time, 38.7 versus 20.1
motion study to quantify 1) IV trastuzumab saved for 18 sessions min, 18.6 min shorter
HCP time and patient chair 2) SC trastuzumab Chair time, 6314 roubles Chair time, 67.1 versus 7.6
time related to trastuzumab saved for 18 sessions min, 59.5 min shorter
treatment to estimate
potential time and cost sav-
ings with a transition from
IV to ­SCa
Lee 2018 [56] Hong Kong Cost-minimization analysis NR HER2-positive BC (NR) Saving for 18-cycle treat- Nursing time, 0.18 FTE per
to investigate the cost 1) IV trastuzumab ment: week saved
differences between IV 2) SC trastuzumab HCP time costs, HKD 4416 Pharmacist time, 0.14 FTE
and SC trastuzumab in Drug costs: HKD 73,720 saved per week
Hong Kong by applying
the medical time/resources
utilization data in other
­countriesa
Lewis 2017 [57] UK Retrospective study to Royal United Hospital, Bath BC (NR) Saving for given year: HCP time, 15 min saved
evaluate the impact of SC 1) SC trastuzumab Consumables, £2220 Chair time, 38 min saved
trastuzumab on out-patient 2) IV trastuzumab Drug costs £94,327
BC services at the Royal
United Hospital, Bath and
to determine the necessity
for prolonged observation
after its ­administrationa
Lopez 2017 [58] NR Retrospective study to NR HER2-positive BC (n = 74) – Chair time, 6-fold reduction
evaluate the impact on 1) IV trastuzumab over 1 year
drug costs, patient chair 2) SC trastuzumab
time and safety profile of
switching from IV to SC
­trastuzumaba
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Nestorovska 2015 [60] Republic of Macedonia Cost-minimization analysis Data from prior prospective EBC (n = 169) Direct costs, €30,500 versus Preparation and administra-
to compare the total time-motion study; unit 1) SC trastuzumab €30,102 per treatment tion, 47 min saved
cost of SC trastuzumab costs obtained utilizing 2) IV trastuzumab course
versus IV trastuzumab for official (government and Non-drug costs, €196 versus
HER2-positive BC patients hospital pharmacy) pub- €4.20
from the Republic of licly available data
­Macedoniaa
Nierenberger 2017 [61] France Time-motion study to com- Hospital HER2 positive BC (NR) Consumables, 655 versus Preparation, 8.3 versus 2 min
pare times (preparation, 1) SC trastuzumab €240 (first dose); 6.5 versus 2 min
nurse and medical) and 2) IV trastuzumab Nurse time, 15.7 versus (subsequent doses)
costs of IV trastuzumab 7.0 min
and SC ­trastuzumaba
Coombes 2019 [69] Canada Cost-minimization analysis NR HER2-positive BC (NR) Savings of Can$11,943 per –
to estimate the incremental 1) IV trastuzumab treatment course
costs/savings associated 2) SC trastuzumab BIM savings
with the use of SC trastu- Year 1, Can$15.8 million
zumab for the treatment Year 2, Can$19.4 million
of HER2-positive BC if Year 3, Can$23.0 million
reimbursed with the same
provincial funding criteria
as IV trastuzumab in
Ontario, ­Canadaa
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

Ali 2017 [72] Kingdom of Saudi Arabia Budget impact model to esti- Clinical and cost inputs HER2-positive EBC (NR) BIM, total savings over –
mate financial impact of were obtained through 1) SC trastuzumab 3 years: 7.2–9.4% and
introducing fixed dose SC discussion with medical 2) IV trastuzumab 12.4–16.6% (assuming
trastuzumab for treatment oncologists and hematolo- 25% and 50% reductions in
of HER2-positive EBC in gists; outputs from budget non-drug costs)
a
­KSA impact model
Kashiura 2018 [73] Brazil Economic analysis to esti- Data from National Regula- HER2 positive BC (n = BIM savings over 5 years, –
mate the budgetary impact tory Agency for Private 31,909) 948.2 million BRL
of SC trastuzumab, com- Health Insurance and 1) SC trastuzumab
pared with IV trastuzumab, Plans; data from Survey 2) IV trastuzumab
in the Brazilian Private performed with 28 HMOs
Healthcare System, to
treat early and metastatic
HER-2 positive ­BCa
Poquet-Jornet 2018 [74] Spain Economic analysis to assess RWD from Hospital Marina HER2-positive BC (n = 58) BIM, current scenario (66% –
the hospital budget impact Salud de Denia and elec- 1) IV trastuzumab receiving iv), €466,480
of only SC trastuzumab tronic records 2) SC trastuzumab All patients receiving IV,
against IV + SC trastu- €393,654
zumab for patients with
­BCa
13
 14

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Calvache 2017 [75] Ecuador Economic analysis to con- NR HER2-positive BC (n = BIM, IV, year 1, –
duct an economic analysis 515) US$15,711,000
for decision making 1) IV Trastuzumab IV, year 2, US$15,199,000
between IV and SC tras- 2) SC Trastuzumab SC, year 1/2, US$14,842,000
tuzumab for the treatment Saving over 5 years,
of HER2-positive BC in US$2,296,000
­Ecuadora
Agirrezabal 2018 [76] Italy Cost-saving study to analyze Official, public drug prices HER2-positive BC and – Preparation and administra-
the per-patient costs gastric cancer (NR) tion, 79 versus 18 min
and potential savings of 1) ­KANJINTI® IV
­KANJINTI® compared 2) ­Herceptin® IV
with originator ­Herceptin® 3) ­Herceptin® SC
and other trastuzumab
biosimilars (IV) in HER2-
positive EBC and MBC
and MGC in ­Italya
D’Arpino 2019 [77] Italy Study design NR. To A single hospital institution HER2-positive EBC or
compare the total medical MBC and metastatic
costs for a hospital of gastric cancer (NR)
treatment with subcutane- 1) ­Herceptin® SC
ously injected H
­ erceptin® 2) ­KANJINTI® IV
and intravenously infused
­KANJINTI®a
Todorovic 2017 [79] Montenegro Economic analysis to Oncology Department at HER2-positive BC (n = 55)
compare the total cost of Clinical Center of Mon- 1) IV trastuzumab
SC trastuzumab versus IV tenegro 2) SC trastuzumab
trastuzumab (IV-TRA) for
HER2-positive patients
with BC at the Oncology
Department at Clinical
Center of ­Montenegroa
Villarreal-Garza 2019 [80] Mexico Economic analysis to Tertiary healthcare facility at HER2-positive BC (NR)
estimate the cost savings of TecSalud 1) SC trastuzumab
the use of SC trastuzumab 2) IV trastuzumab
compared with IV trastu-
zumab according to patient
weight, and calculate
the infusion time of SC
trastuzumab in a tertiary
healthcare facility at Tec-
Salud from Feb 2018–Jan
­2019a
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Kulikov 2015 [83] Russia Economic analysis to NR BC (NR) Direct costs, €25,016 versus –
determine the preferable 1) IV trastuzumab €21,863
treatment scheme for BC 2) SC trastuzumab Saving of €3153 per treat-
from the pharmacoeco- ment course
nomic perspective by the
comparison of SC and IV
­administrationa
Martin 2017 [84] Panama Cost minimization study to Instituto Oncológico NR (NR) Drug costs, 17% saving –
carry out a cost minimiza- Nacional 1) IV trastuzumab Nursing supplies, 87%
tion study considering 2) SC trastuzumab saving
the cost of the treatment, Pharmacy supplies, 47%
the supplies and the time saving
utilized by Pharmacy Nursing time costs, 91%
and Nursing to prepare saving
and administer it (IV, SC Pharmacy time costs, 69%
trastuzumab)a saving
Direct costs, US$5985/
patient/year (18-cycles)
Mitchell 2019 [85] UK Economic analysis to The Christie NHS Founda- HER2-positive BC (n = – Nursing time, £105 versus £26
compare and determine tion Trust 116) Preparation, £78 versus £14
the experience of patients 1) SC trastuzumab Drug cost, £1500 versus £1223
receiving all of their trastu- 2) IV trastuzumab Direct costs, £3629 versus
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

zumab treatment via the IV 1263 per administration

route versus the SC ­routea (including insertion of port
for IV administration)
Trastuzumab/rituximab—full publications
Favier 2018 [52] France Observational study to 36 day hospitals Patients with cancer (NR) – Chair time trastuzumab,
evaluate the medical and 1) IV trastuzumab/rituximab reduced by 56%
economic consequences 2) SC trastuzumab/rituximab Chair time rituximab, reduced
of switching to SC trastu- by 74%
zumab and SC ­rituximaba
15
 16

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Franken 2018 [53] The Netherlands Observational noninter- NR HER2-positive EBC or Trastuzumab Preparation, 17.1 versus 8.4
ventional micro costing MBC or NHL (n = 126) Direct costs, €1856 versus min
study to investigate time/ 1) SC trastuzumab/rituximab €1763 Administration, 97.4 versus
resource use for hospitals 2) IV trastuzumab/rituximab Total direct costs excluding 6.6 min
and patients and compared drug costs, €118 versus Active HCP time, 44.5 versus
healthcare and societal €50 29.7 min
costs for IV and SC admin- [Preparation:
istration of trastuzumab Active HCP time, €9.02
and ­rituximabb versus €2.94
Consumables, €5.19 versus
€1.83
Administration:
Active HCP time cost,
€20.27 versus €17.40
Consumables, €8.92 versus
€0.46]
Societal costs, €48.60 versus
€26.39
Rituximab
Drug costs, €2000 versus
1828
Administration, €146 versus
€76
[Day care unit costs, €96
versus €38
Consumables, €12 saving
HCP time, €9 saving]
Societal cost, €26 saving
Cicchetti 2018 [105] Italy Economic analysis to pro- NR Patients with cancer (NR) Direct costs, €4050 saving –
vide a multidimensional 1) IV trastuzumab/rituximab per patient per year
assessment of the impact 2) SC trastuzumab/rituximab
of SC rituximab and tras-
tuzumab compared with
IV, providing a particular
focus on expected social
and economic benefits for
the ­patientb
Trastuzumab/rituximab—abstracts
Vangheluwe 2018 [68] France Cost analysis study to Data obtained from chemo- Patients with cancer (NR) – Preparation, 8.9 min saved
evaluate the realized and therapy prescription soft- 1) IV trastuzumab/rituximab HCP, 6.8 min saved
potential medico-economic ware, Medical Information 2) SC trastuzumab/rituximab Chair time, 3 versus 2 hours
benefits in OCUs induced System 2016, patient
by the use of SC rituximab satisfaction surveys and
a
and SC ­trastuzumab interviews with hematolo-
gists, oncologists, nurses
and pharmacists
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Ghosh 2018 [70] Singapore Cost-minimization analysis NR EBC or MBC (NR) Non-drug savings, –
to analyze cost-differences 1) SC trastuzumab/rituximab US$22,449 versus
between SC versus IV 2) IV trastuzumab/rituximab US$4036, 17% of total
trastuzumab for EBC and savings for 26 cycles
MBC in S ­ ingaporea
Jang 2018 [78] UK Economic analysis to assess Drug acquisition and admin- Rheumatoid arthritis,
the budget impact of istration costs obtained chronic lymphocytic leu-
adopting IV biosimilar from national tariffs kemia, NHL, granuloma-
rituximab and IV biosimi- tosis with polyangiitis and
lar trastuzumab compared microscopic polyangiitis,
with SC and IV originators BC and MGC (NR)
from the perspective of 1) SC trastuzumab/rituximab
the UK National Health 2) IV trastuzumab/rituximab
­Servicec
Rituximab—full publications
Ponzetti 2016 [66] Italy Systematic survey to analyze Nineteen centers across six NHL and BC (NR) – Patients time, 4.81 versus 1.45
the time/resource and cost regions: Emilia Romagna, 1) Rituximab SC h, 200 min saving
implications from differ- Lazio, Liguria, Piemont, 2) Rituximab IV HCP preparation time: 23
ent perspectives (patient, Toscana, Umbria versus 10 min
medical staff) in the real
­worlda
De Cock 2016b [88] Austria, Brazil, France, Italy, Prospective time-and- Eight countries and 30 day iNHL (NR) – Patient time, treatment room
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

Russia, Slovenia, Spain, motion study (MabCute; oncology units 1) Rituximab SC time, 281.8 versus 95.9 min
UK NCT01461928) to quantify 2) Rituximab IV Active HCP time, 35.0 versus
active HCP time as well 23.7 min
as chair time associated Treatment room time,
with rituximab IV and SC 12.2–40.6 min versus
administrations in patients 7.8–19.9 min
with iNHL, and to estimate Preparation time, 3.7–38.9 min
the potential time savings versus 1.6–33.3 min; pooled
with a conversion from data, 35.0 versus 23.7 min
rituximab IV to SC, for a 262.1 versus 67.3 min
single administration ses- Chair time, infusion duration,
sion and for the first year 180.9 versus 8.3 min
of ­treatmenta Increase in time for first infu-
sion, 83.1 min
Lugtenburg 2017 [89] The Netherlands, Turkey, Randomized, open-label 151 centers DLBCL (n = 576) – 2.6–3.0 h versus 6 min (infu-
Spain, Switzerland, study to examine the 1) R-CHOP with rituximab sion duration)
Germany efficacy and safety of SC
rituximab SC versus the 2) R-CHOP with rituximab
IV formulation as part of a IV
R-CHOP regimen. Patient
satisfaction with treatment
was also ­assesseda
17
 18

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Mihajlovic 2017 [90] The Netherlands Prospective, observational, Isala Clinics, Medical Center DLBCL (NR) Total direct cost saving Nursing: 16.5 versus 13.7 min
bottom-up micro costing Leeuwarden (MCL), AZC 1) Rituximab SC €265.17 (€2176.77 versus Pharmacy: 4.0 versus 3.7 min,
study to identify and Dordrecht, MCAl-kmaar, 2) Rituximab IV €1911.09) 16 s shorter for SC
compare all direct costs of OMC Sittard-Geleen, Drug cost saving €85.34
intravenous and subcutane- Maasstad Hospital Labour cost saving, €1.24
ous rituximab given to
patients with diffuse large
B-cell lymphoma in the
­Netherlandsa
Fargier 2018 [91] France Observational cross- Three teaching hospitals in Follicular lymphoma (n Direct costs, €1897.40 Pharmacist, 9.1 versus 3.5 min
sectional to evaluate the Lyon, Nantes, and Tours = 73) versus €1788.10/cycle Nurse, 23.7 versus 11.8 min
economic impact of using 1) Rituximab IV Cost difference of €109.20
SC rituximab as mainte- 2) Rituximab SC Rituximab €1863 versus
nance therapy compared €1777
with usual patient care for Pre-medication, €1.10 versus
follicular lymphoma, and €0.20
to investigate HRQoL, Consumables, €21 versus
patients’ and nurses’ €0.51
perceptions and prefer- Active HCP time, €21.90
ences, in the context of the versus €9.90
French health ­servicea
Rule 2014 [92] UK Prospective, observational, Plymouth, London, Oxford NHL (n = 700) Mean staff cost savings: Treatment room time, 264
time-and-motion study to 1) Rituximab SC £115.17 (£146.43 versus versus 70 min
investigate the staff time 2) Rituximab IV £31.26) Hospital time, 304 versus
and costs associated with £575.85 per course (5 ses- 110 min
administration of SC and sions per year) Total HCP, 223 versus 48.5
IV ­rituximaba min, saving 174.8 min per
infusion
Chair time, 239 versus 46
min, 193.1 min saving per
infusion
Rituximab—abstracts
Ben Lakhal 2019 [93] Tunisia Cost-minimization analysis Hospital Aziza Othmana B NHL (NR) TND 545 versus TND 330 Annual saving of nursing time,
and budget impact model 1) Rituximab SC per patient 22.13 days
to evaluate cost and time/ 2) Rituximab IV Chair time annual saving,
resource use impact associ- 193.5 days
ated with the administra-
tion of rituximab SC and
IV administrations on the
Tunisian health system
over 3 ­yearsa
Chansung 2018 [94] Thailand Randomized controlled trial NR DLBCL and FL (n = 30) Productivity loss Infusion time, 212.4 versus
to evaluate preference, 1) Rituximab SC THB 291.28 versus 8.66 6.3 min
satisfaction of patients, 2) Rituximab IV
efficacy and economic
burden between rituximab
IV versus rituximab ­SCb
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Delgado-Sánchez 2019 [95] Spain Retrospective study to Son Espases University Adult patients with lym- Direct cost, €1955.94 versus HCP time, day care unit time,
compare the direct costs Hospital, the third-level phoma (n = 105) €1460.01, saving of €496 4 versus 1 h (standard prac-
associated with the use of reference hospital of 1) Rituximab IV (€1729 for IV biosimilar) tice times)
IV and SC rituximab, not Balearic Islands (database 2) Rituximab SC Drug costs, €1458 versus
only considering the drug of the Pharmacy Depart- €1335
price but also the costs of ment, O­ ncosafety®-AVIDA Preparation, €4.49 versus
pharmacy handling, place software) €2.24 per cycle
occupation and administra- Day care unit cost, €493
tion in the day care unit. versus €123
To determine whether the
results could be modified
with the availability of
the new IV biosimilar of
rituximab and develop an
exploratory analysis in a
nonlymphoma ­groupa
Di Rocco 2017 [96] Italy Prospective study to evalu- Department of Cellular DLBCL (n = 71) Direct costs, €472,227 ver- Chair time, 240 versus 135
ate the costs of the two Biotechnologies and 1) Rituximab SC sus €449,870 for 35 and 36 min
different formulations of Haematology, University 2) Rituximab IV patients, respectively
rituximab (IV versus SC) of Rome Sapienza
combined with CHOP and
the efficacy in terms of
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

complete response rates

and ­toxicitya
Fisher 2017 [97] USA Prospective, observational, NR FL, DLBCL and CLL – Time at infusion center, 319
time-and-motion study to patients (n = 40) min
understanding the patient 1) Rituximab SC Time in infusion chair, 212
perspective regarding 2) Rituximab IV min
rituximab administration
to make decisions between
intravenous (IV) and SC
methods of ­administrationa
Irwin 2017 [98] UK Observational study to inves- University Hospital of Wales NHL and DLBCL (NR) – Rituximab maintenance: 150
tigate cost savings and 1) Rituximab SC versus 11 min
reduction in chair times 2) Rituximab IV (R-CHOP: 260 versus
for patients treated with 130 min
chemotherapy regimens R-CVP: 135 versus 50 min)
containing SC rituximab
therapy compared to IV
rituximab therapy in a
single center in the U
­ Ka
19
 20

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Lebas 2018 [99] France Retrospective study to Alpes Leman Hospital Patients who had been Annual hospital saving Annual total hospital infusion
review the issues intro- provided Rituximab €49,372 time saving
duced by a switch from (Mabthera) (n = 52) 101 h
Rituximab ­(Mabthera®) to 1) Mabthera IV/SC
its biosimilar product and 2) Truxima IV/SC
quantify what cost savings
can be ­expecteda
McBride 2018b [100] USA Economic model to perform Simulation study NHL (NR) Direct incremental costs: Chair time, administration
(linked with McBride a time and cost simulation 1) Rituximab SC US$4261 higher if BSA, time saving 2 h 9 min–2
2018a [102]) of reference IV, SC, and 2) Rituximab IV-S 1.62 m2 h 23 min per infusion
biosimilar IV rituxi- 3) Rituximab IV-R90 US$27 higher if BSA 1.85 versus standard IV infusion
mab from the US payer m2 (depending on BSA)
­perspectived US$4,208 saving if BSA
2.1 ­m2
McBride 2018c [101] USA Economic model to conduct Simulation study FL (NR) Direct costs savings over 2 Chair time, administration
a time and cost simulation 1) Rituximab SC years: US$1120–19,331 time saving 2 h 10 min–2 h
of RITUX single agent 2) Rituximab IV-S depending on BSA 24 min per infusion (depend-
maintenance therapy for 3) Rituximab IV-R90 1.62–2.1 ­m2 ing on BSA)
FL comparing SC RITUX,
rRITUX, and bRITUX
from the U.S. payer
perspective following
initiation ­therapyd
McBride 2018a [102] USA Economic model to perform Simulation study NHL (NR) Direct costs savings of Chair time, administration
(linked with McBride a time and cost simulation 1) Rituximab SC US$104–4012 depending time saving 2 h 10 min–2 h
2018b [100]) of SC RITUX, rRITUX 2) Rituximab IV-S on BSA (1.62–2.1 ­m2) 24 min per infusion (depend-
and bRITUX from the US 3) Rituximab IV-R90 ing on BSA)
payer ­perspectived
Nikolov 2017 [103] Macedonia Cost-minimization analysis Stem Cell Transplantation NHL (n = 220) Total direct cost saving, €75 Chair time, 6 h 12 min versus
to identify and compare the Unit, Outpatient Clinic, 1) Rituximab SC (€1621 versus 1546) 10 min
total costs of subcutaneous Clinical Department, 2) Rituximab IV Savings: €12.86 for HCP
versus intravenous admin- University Clinic of Hema- time (€14.62 versus €1.76)
istration of rituximab for tology, Skopje €8.9 for chair occupying cost
the treatment of NHL (€10.10 versus €1.20)
patients in the Republic of
­Macedoniaa
Tomarchio 2017 [104] Italy Economic analysis to NR DLBCL and FL (n = 40) Total direct cost saving: Patient time, total saving per
evaluate, in patients with 1) Rituximab IV €274.49 eight-cycle course 17.5 h
DLBCL and FL, the eco- 2) Rituximab SC Drug cost saving €156.27 Nursing: 144 versus 111 min
nomic and social impact per patient Pharmacy, 40 versus 19 min
of subcutaneous rituximab
­administrationa
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Chansung 2018b [106] Thailand Retrospective study of rituxi- CHI of Thailand; HER DLBCL (n = 1011) THB 562 saving per cycle –
mab SC and rituximab 1) Rituximab SC
IV to investigate whether 2) Rituximab IV
adopting rituximab SC
would yield cost saving in
payers’ ­perspectived
Annibali 2017 [107] Italy Cross-sectional study to NR DLBCL €274.49/patient saving –
evaluate in DLBCL and FL (n = 45 patients; n = 45
the economic and social caregivers)
impact of SC ­Rituximaba 1) Rituximab SC
2) Rituximab IV
Gomes 2017 [108] Brazil Economic analysis to Hospital Geral de Curitiba FL and DLBCL patients Total savings: –
compare the total cost of (NR) FL: 12,091.66 BRL
rituximab IV versus SC in 1) Rituximab SC DLBCL: 4454.82 BRL
both indications approved 2) Rituximab IV
by ANVISA for rituximab
SC: FL first line and
maintenance and DLBCL
first ­linea
Kashiura 2018b [109] Brazil Economic analysis to Data from National Regula- NHL (n = 5783) BIM, savings over 5 years, –
estimate the budgetary tory Agency for Private 1) Rituximab SC 344.7 million BRL for
impact of the introduction Health Insurance and 2) Rituximab IV large health maintenance
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

of subcutaneous rituximab, Plans; data from Survey organization, (0.4 million

compared with intravenous performed with 28 HMOs beneficiaries)
rituximab, in the Brazilian
Private Healthcare System,
to treat diffuse large B-cell
and follicular CD-20+
patients with N­ HLa
Rauf 2017 [110] Kingdom of Saudi Arabia Economic analysis to Clinical and cost inputs NHL (NR) BIM, total budget reduction –
investigate the economic were obtained through 1) Mabthera IV Year 1: 1.6–4.4%
implications of using discussion with medical 2) Mabthera SC Year 2: 3.3–8.8%
rituximab SC compared oncologists and hematolo- Year 3: 4.9–13.2%
to IV formulation in KSA gists; other data came from
for ­NHLa budget impact model
Stewart 2018 [111] Canada Economic analysis to Time-and-motion data from FL and DLBCL (NR) BIM, over 3 years: –
estimate the effect (on UK based study; key input 1) Rituximab SC 128,715 systemic therapy
systemic therapy suite time parameters of the model 2) Rituximab IV suite hours saved
and on the costs of drug were based on literature Approximately Can$40
acquisition and administra- and chart review data; million saved in drug and
tion) of implementing SC data outputs from authors’ administration costs
rituximab in the initial model
chemoimmunotherapy
for FL and DLBCL over
3 years in the Canadian
­marketa
21
 22

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Other agents—full publications

Cristino 2017 [112] Czech Republic Cost analysis to assess deno- Unit cost inputs for the Prostate cancer, BC and Denosumab SC, CZK186.20 –
sumab versus zoledronic model taken from multiple patients with other solid Zoledronic acid IV,
acid in the prevention of sources tumors (NR) CZK409.17
SREs in adults with bone 1) Denosumab SC
metastases from prostate 2) Zoledronic acid IV
cancer, BC, and OST
(excluding hematologi-
cal malignancies) from a
national payer perspective
in the Czech ­Republicd
Li 2019 [113] China Randomized controlled trial Cancer Hospital of China Malignant melanoma (n = Total direct cost/patient –
to treat Chinese patients Medical University 250) IFN-α SC, ¥105,345
with malignant melanoma 1) INF-α SC IL-2 IV, ¥95,656; p < 0.0001
using a high dose of subcu- 2) Continuous IL-2 IV
taneous IFN-α or continu-
ous intravenous IL-2 for
4 months. The secondary
end point of the trial was
to compare the efficacy
and safety of IFN-α
therapy with IL-2 therapy
and to do the research that
Chinese guidelines are
inadequate when it comes
to using of IFN-α as a
cancer ­treatmenta
Raje 2018 [114] USA Cost analysis to estimate the Unit costs for the model Multiple myeloma (NR) Denosumab SC administra- –
incremental cost ratio and taken from multiple 1) Denosumab SC tion, US$42.18
the net monetary benefit sources 2) Zoledronic acid IV Zoledronic acid IV,
of denosumab versus zole- US$184.17
dronic acid in patients with US$ 2017
MM, from the perspectives
of both society and ­payersd
C. McCloskey et al.
Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Stopeck 2012 [115] USA Cost analysis to assess Unit costs for the model Castration-resistant prostate Denosumab SC administra- –
denosumab relative to taken from multiple source cancer, BC, and non- tion, US$35.42
zoledronic acid for the small-cell lung cancer, and Zoledronic acid IV adminis-
prevention of SREs bone metastases (NR) tration, US$154.64
among patients with bone 1) Denosumab SC US$ 2011
metastases secondary to 2) Zoledronic acid IV
castration-resistant prostate
cancer, BC, or non-small
cell lung cancer, based on
a lifetime Markov cohort
model from a US managed
care perspective. Authors
aimed to obtain incremen-
tal cost ratios including
cost per quality-adjusted
life year gained and cost
per SRE ­avoidede
Zhang 2018 [116] Australia, Belgium, Brazil, Cost analysis of DVd, Vd Multiple centers across dif- RRMM (n = 569 [POL- Cost per administration:
Canada, Czech Republic, (both including SC bort- ferent countries LUX]; n = 498 [CAS- DRd: $134
Germany, Hungary, Den- ezomib) and DRd (all IV) TOR]) DVd: $203
mark, Italy, Spain, France, in patients with RRMM 1) Lenalidomide and dexa- Vd: $69
Great Britain, Greece, using data from two phase methasone
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics

Israel, Japan, Korea, 3 trials (CASTOR and 2) Lenalidomide, dexameth-

Mexico, The Netherlands, POLLUX)a asone and daratumumab
Turkey, Ukraine, Poland, OR
Russia, Sweden, Taiwan, 1) Bortezomib and dexa-
USA methasone
2) Bortezomib, dexametha-
sone and daratumumab
Body 2017 [117] Belgium, Germany, Italy Observational time-and- Ten day-oncology units Bone metastases secondary – Zoledronic acid IV versus
motion study to estimate across Belgium, Germany, to a solid tumor (n = 189) denosumab SC
total task time and total and Italy 1) Denosumab SC Total time per administration,
active healthcare profes- 2) Zoledronic 44.2 versus 8.4 min
sional time for predefined acid IV Administration time, 25.1
tasks associated with deno- versus 1.5 min
sumab and zoledronic acid Active HCP time, 12.2 versus
monotherapy administra- 6.9 min
tion. Secondary objectives Chair time, 44.7 versus 7.3
included estimating patient min
time in the DOU, time in Treatment room time, 46.7
the treatment unit, and versus 12.3 min
time in the treatment chair Patient time in hospital, 103
or on the examination versus 69 min
­tablea
23
 24

Table 2  (continued)
Publication Study country Study design and aim Data source Patient population and Cost outcomes identified Time/resource-use outcomes
intervention identified

Despiau 2017 [118] France Observational study to assess Institut universitaire du can- Patients with cancer (n = 48) – Duration of outpatient stay, 1
the consequences of this cer Toulouse–Oncopole 1) SC h shorter for SC versus IV
new route of administra- 2) IV administration
tion on the organization Reflects 82% decrease in treat-
of a day hospital in real ment duration
conditions, at the oncology Waiting times before treatment
day hospital of the Tou- did not differ
louse University Cancer
Institute ­Oncopolea
Other agents—abstracts
Mateos 2019 [119] Sweden, Poland, Czech Randomized, open-label, NR RRMM (n = 522) – Median duration for adminis-
Republic, Ukraine, non-inferiority, phase 3 1) Daratumumab SC tration:
Canada, UK, Japan, USA study. Study aim N­ Ra 2) Daratumumab IV IV: 421/255/205 min for the
first/second/subsequent
infusions
SC: 5 min

BIM budget impact model, BRL Brazilian real, BSA body surface area, CVAD, central venous access device; CHI, Center Office of Healthcare Information; CZK, Czech Republic Koruna;
DLBCL, diffuse large B-cell lymphoma; DRd, daratumumab; DVd, bortezomib, daratumumab and dexamethasone; FL, follicular lymphoma; h hour, FTE full-time equivalents, HCP healthcare
professional, HKD Hong Kong dollar, IFN-α interferon-alpha, IL-2 interleukin-2, IV intravenous, MBC metastatic breast cancer, MGC metastatic gastric cancer, min minute, NHL non-Hodg-
kin’s lymphoma, NHS National Health Service, NR not reported, NZD New Zealand dollar, R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, R-CVP, rituximab,
cyclophosphamide, vincristine sulfate and prednisone, RCT​z controlled trial, SC subcutaneous, SLR systematic literature review, THB Thai Bhat
a
The perspective of this study was not explicitly stated in the publication
b
This study was conducted from the societal perspective
c
This study was conducted from the perspective of the UK NHS
d
This study was conducted from the payer perspective
e
This study was conducted from the US managed care perspective
C. McCloskey et al.
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 25

Fig. 2  Numbers of publications Full publications Abstracts

25
reporting time/resource use and
costs for each agent/indication

20

Number of publications
9 12
15
12

10 15

13 12
5 0
7
1 5
3 2
0
Trastuzumab Trastuzumab Rituximab Rituximab Other Other
resource costs resource costs agents agents
use use resource use cost

Fig. 3  HCP time as reported HCP TIME

across included studies. HCP IV (mins) SC (mins)
healthcare professional, IV
intravenous, mins min, SC sub- 92 30 62 (67%) DENMARK [65]
75 15.4 59 (79%) IRELAND [63]
cutaneous. Δ, difference in HCP
68 14 54 (79%) BELGIUM [67]
time between IV and SC admin- 45 29.7 15 (33%) THE NETHERLANDS [53]
istration presented in min and as 44 26 18 (41%) SWEDEN [64]
a percentage of total time 39 20.1 19 (48%) RUSSIA [50]
34 6.9 27 (79%) NEW ZEALAND [62]
27 13.2 14 (51%) SPAIN [59]
12 6.3 6 (47%) CANADA [55]
11 7.2 3 (31%) SWITZERLAND [55]
10 5.2 5 (47%) RUSSIA [55]
9 5.7 3 (37%) FRANCE [55]
8 4 4 (51%) SPAIN [55]
7 4.9 2 (32%) DENMARK [55]

3.3.2 Administration Time SC trastuzumab, for combined preparation and administra-

tion times.
Administration time for trastuzumab was reported in five
publications, of which four directly measured time [49, 53, 3.3.3 Active Healthcare Professional (HCP) Time
54, 62]; one publication reported estimated time from drug
delivery software [51], which was found to be consistent Active HCP time, and time savings with SC versus IV
with the other four publications. Administration times of 90 trastuzumab, were reported in nine publications and are
and 30 min were reported for IV trastuzumab loading and shown in Fig. 3. Based on direct measurements, active
subsequent doses, respectively, in two of the publications HCP time was 13–92 min (IV) versus 7–30 min (SC);
[51, 54]. A further two publications reported times of 38 and a difference of 6–62 min [50, 53, 59, 62–65, 67]. Two
97 min for IV trastuzumab administration [53, 62]. In con- publications reported a longer administration time for the
trast, the reported times for SC trastuzumab administration loading dose of IV trastuzumab (92 and 44 min); here, the
ranged from 5 to 10 min, with no difference between loading time differences between the loading dose of IV and SC
and subsequent doses. The differences in administration time were 62 and 18 min [64, 65]. One publication reported
between IV and SC were 80–85 (loading dose) and 20–25 only on the time difference (15 min) between IV and SC
min (subsequent doses) [51, 54], and 32–107 min in the [57]. One other publication reported only the difference
three publications in which loading/subsequent doses were in HCP time (7 min), which was estimated based on drug
not specified [49, 53, 62]. Additionally, two publications preparation software [68]. One report of active HCP time
reported time savings of 47 min [60] and 61 min [48] with included a range of 7–12 min (IV) versus 4–7 min (SC)
26 C. McCloskey et al.

Fig. 4  Patient chair time CHAIR TIME

reported across included stud- IV (mins) SC (mins)
ies. IV intravenous, mins min,
SC subcutaneous. Δ, difference 180 120 60 (33%) FRANCE [68]
137 10.6 126 (92%) BELGIUM [67]
in chair time between IV and
133 38 95 (71%) SWITZERLAND [55]
SC administration presented 101 20 81 (80%) SPAIN [59]
in min and as a percentage of 100 20 80 (80%) SPAIN [55]
total time 85 27 58 (68%) FRANCE [55]
67 7.6 60 (89%) RUSSIA [50]
67 24 43 (64%) CANADA [5 ]
57 24 33 (58%) DENMARK [5 ]
47 10.5 37 (78%) NEW ZEALAND [62]
47 13 34 (72%) RUSSIA [5 ]

[55]; however, it is unclear what was included within the subsequent doses (following the loading dose) to be lower
time, and why the HCP times in this report were shorter (23-min difference: 90 min IV vs. 67 min SC) [64].
than those of other publications. Active time differ-
ences were also reported for different HCPs and were 3.4 Costs Associated with IV Versus SC
all in favor of SC versus IV administration: differences Administration of Trastuzumab
in nursing times were 6.1 min [62] and 10.6 min [59];
pharmacist and nursing assistant time differences were Costs for IV versus SC administration of trastuzumab were
3.0 min and 0.3 min, respectively [59]; and one publica- gathered from 24 publications with sufficient level of detail
tion reported time savings of 0.18 full-time equivalents to show how the costs were defined. Costs were reported per
(FTE) and 0.14 FTE with SC for nurses and pharmacists, administration, per treatment course, per patient per year, or
respectively [56]. for a particular cohort. Of these 24 publications, 18 reported
costs based on data from time-and-motion studies or studies
3.3.4 Patient Chair/Infusion Time in which the time for specific procedures was directly meas-
ured; one based estimates on information provided by drug
Chair time, where defined, was described consistently as preparation/administration software [51], one estimated time
the period between entry and exit from the infusion chair; from a survey of HCPs [70], and four did not report how
however, how the time was determined varied between time was estimated [56, 69, 82, 83]. Twelve of the publica-
publications, with some reporting studies that measured the tions were full publications, with the other 12 being congress
time directly [25, 59, 62, 67] and others reporting studies abstracts with limited detail (Fig. 2).
that estimated time from chemotherapy prescription soft- Thirteen publications covering ten countries reported
ware and HCP interviews [57, 68]. Differences in chair total direct medical costs for IV versus SC administration
time for trastuzumab administration were reported in 10 [51, 53, 54, 59, 60, 63, 64, 69, 82–86], which included non-
publications [25, 50, 52, 55, 57–59, 62, 67, 68], of which drug costs for preparation, administration, HCP time and
seven reported actual chair times and differences obtained consumables, and savings related to reduced drug wastage
through direct measurement; one publication estimated the or administered dose. All but four publications [51, 69, 82,
chair time based on drug delivery software [68] and was 83] indicated that time assessments were made directly.
consistent with the other seven publications. Chair time was Cost savings for SC compared with IV administration were
47–180 min (IV) versus 8–120 min (SC); the difference in reported in all but one publication, which reported data from
time was 33–126 min (Fig. 4). One publication reported a a study conducted in Italy that used time estimates from drug
sixfold decrease in chair time with SC administration [58], delivery software rather than direct time assessments [51].
with another describing a 56% reduction [52]. The PrefHer In this publication, total costs were numerically greater for
time-and-motion study reported chair time differences from SC administration; however, the difference was not statisti-
nine countries (Fig. 5), ranging from a difference of 47.1 min cally significant and was likely related to differences in drug
(Denmark) to 85.5 min (Spain) for administration with the acquisition costs as preparation and day hospital costs were
single-use injection device and 40.3 min (Italy) to 80.6 min shown to be significantly lower for SC administration [51].
(Spain) for administration with a hand-held syringe [25]. In seven of the publications, direct costs for SC admin-
Total time spent at the hospital was also reported, ranging istration were approximately 1.3–6% lower than those for
from 3–7 h (IV) to 1–5 h (SC), with a difference of 1.5–2 IV administration. One publication from a Russian study
h [59, 64, 67]. One publication reported the difference for reported a 12.6% decrease [83] and one from the UK
reported a 2.8-fold decrease [85] in direct costs with SC
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 27

Fig. 5  Differences in chair time IV-SID difference, min IV-HHS difference, min
for IV and SC administration Canada 52.3 (–68.2%) –
for countries included in the France 56.8 (–67.6%) 49.1 (–58.5%)
PrefHer time-and-motion study. Switzerland 72.0 (–65.6%) 78.6 (–71.6%)
Denmark 47.1 (–66.4%) 55.8 (–78.7%)
HHS hand-held syringe, IV HHS chair time for injection
SID chair time for injection Italy – 40.3 (–62.9%)
intravenous, SC subcutaneous, Russia 47.5 (–78.5%) 50.6 (–83.6%)
IV post-infusion
SID single-use injection device. Spain 85.5 (–80.7%) 80.6 (–76.1%)
IV infusion
Source: De Cock et al 2016 [25] IV pre-infusion
Turkey – 65.5 (–83.2%)
Pooled 56.9 (–73.1%) 55.2 (–71.0%)
120

14.4
100
28.1

80 10.9
9.5
12.6 12.5
69.1
14.1
Min

60 11.7 6.5
36.5

55.2
34.4
44.1
30.6 55.1
40
41.2 49.8

20 36.6
37.8
34.9
29.7 27.2 31.2 26.2
24.4 26.3 23.8 23.8 22.6 25.3 22.6
20.4 21.2 20.9
15.1 13.0 14.1 13.2
11.2 9.9
4.2
0
IV SID HHS IV SID HHS IV SID HHS IV SID HHS IV SID HHS IV SID HHS IV SID HHS IV SID HHS IV SID HHS
Canada France Switzerland Denmark Italy Russia Spain Turkey Case-based
(pooled)

versus IV administration. Twelve publications provided 3.5 Time/Resource Use with IV Versus SC

information on costs directly related to active HCP time, Administration of Rituximab
preparation and/or administration time, patients’ time,
or chair time [50, 53, 54, 56, 59, 62–65, 67, 84, 85]. All Nineteen publications (seven full publications [52, 66,
reported reduced time-related costs with SC versus IV 88–92] and 12 abstracts [93–104]) reported data on time
administration. required, or differences in time required, for IV versus
In the five publications reporting total costs including SC rituximab for the treatment of lymphoma (NHL/FL or
indirect costs, indirect costs were lower for patients who DLBCL in most publications) (Fig. 2). Of these, 12 reported
received SC versus IV trastuzumab [51, 59, 63, 64, 71]. SC data from time-and-motion studies or studies in which the
administration costs were also lower for consumables [49, time for specific procedures was directly measured, two esti-
53, 54, 57, 59, 61–64, 67], drug wastage [67], use of cen- mated time from a survey of HCPs [66, 93], and five did not
tral venous access devices [86], overheads [87], nursing and report how time was estimated [52, 89, 101].
pharmacy supplies [84], and avoiding catheter implantation
surgeries [54] compared with administration costs for IV in 3.5.1 Preparation Time
all publications that reported such information. One publica-
tion reported non-drug costs for the first and for subsequent Preparation time or pharmacist time per infusion of rituxi-
cycles of therapy; reported costs were higher for the first mab was reported in five publications and ranged from 4–40
cycle of therapy for both SC and IV administration [65]. One min (IV) to 2–20 min (SC) [66, 88, 90, 91, 104]. One of
publication reported the costs for management of adverse these publications reported a study that collected relevant
events, which were slightly higher for SC versus IV delivery data using a survey [66]; however, data were consistent
(US$1574 vs. US$1715 for 18 cycles) [71]. with those estimated from direct measurement. In all pub-
In addition to the 24 publications reporting cost-related lications, preparation/pharmacist time was shorter for SC
data, five further publications were identified that reported administration, with time savings of 5.6–21 min (in one
on the budget impact of introducing SC trastuzumab; all publication there was a marginal difference of 0.3 min (4.0
reported cost savings across varying time periods [69, vs. 3.7 min) [90]).
72–75].
28 C. McCloskey et al.

3.5.2 Active HCP Time reporting costs for rituximab maintenance therapy for FL
over 2 years [101] and one publication reporting costs of
Differences in HCP time per infusion of rituximab were rituximab as part of rituximab, cyclophosphamide, doxoru-
reported in five publications and directly measured [88, bicin, vincristine, and prednisolone therapy (R-CHOP) for
90–92, 104]. HCP times were 17–35 min (IV) compared patients with NHL [102] reported higher cost savings for
with 12–24 min (SC) in three publications, whereas two patients with higher body surface area (BSA). The other
publications reported longer times of 144 and 223 min (IV) publication, which also reported costs of rituximab as part
versus 111 and 49 min (SC). All five publications found that of R-CHOP therapy for NHL, reported the highest cost sav-
SC administration was associated with a time saving. A fur- ings for patients in the highest and lowest BSA categories,
ther publication reported annual savings of nurse time to be respectively [100]. However, the reason for this discrepancy
22 days for a single center in Tunisia [93] and one reported is unclear. Reductions in direct medical costs for SC versus
a time saving of 3 h in the day-care unit per infusion [95]. IV administration were reported in all nine of the publica-
tions reporting European studies, all but one [107] of which
3.5.3 Patient Chair/Infusion Time estimated time savings based on direct measurements, and
in four additional publications of studies from Tunisia (time
Chair time/infusion time for rituximab was reported in ten savings estimated by HCP survey) [93], Thailand [94, 106],
publications [88, 89, 92, 94, 96, 98, 100–103] and one fur- and Brazil [108]. In the European publications, non-drug-
ther publication reported the time for IV administration [97]. related cost savings included savings related to HCP time
For four of these publications, the method of time assess- [53, 91, 92, 103], consumables [53, 91], and day-care unit
ment was not reported; the remaining publications used costs [53, 95]. One of the publications from Thailand, which
direct time measurements. Chair time/infusion time was reported societal costs, reported a reduction in productivity
considerably shorter for SC versus IV administration in all loss with SC versus IV administration [94]. A further three
publications, ranging from 150–262 min (IV; one publica- congress abstracts describing the budget impact of introduc-
tion reported a time of 6 h and 12 min (372 min)) to 6–11 ing SC rituximab in Brazil, Saudi Arabia, and Canada were
min (46 and 135 min in two publications) for SC admin- identified, all of which reported cost savings at 1, 2, 3, or 5
istration. Time saved with SC administration ranged from years [109–111].
1 h 45 min to 3 h 26 min (a saving of 6 h in one publica-
tion with a particularly long time for IV administration). 3.7 Other Publications
A 74% reduction in chair time with SC administration was
reported in another publication [52], and annual time sav- In addition to the publications regarding trastuzumab and
ings per center of 101 h [99] and 193.5 days (administra- rituximab, eight other publications were identified that
tion time estimated using a survey) [93] were also reported. report relative time or cost information for IV versus SC
Time spent in the treatment room was directly measured and administration (Table 2) [112–119]:
ranged from 264–321 min (IV) to 70–105 min (SC). Time
savings with SC administration were ~200 min [66, 88, 92, • Three of four cost analysis publications were consid-
97]. One publication reported a time saving of 17.5 h per ered less relevant as they reported time and cost of sup-
eight-cycle course of treatment [104]. portive therapies (SC-administered denosumab vs. IV-
administered zoledronic acid) rather than treatment with
3.6 Costs Associated with IV Versus SC a targeted oncology drug [112, 114, 115]. The remaining
Administration of Rituximab cost analysis publication reported higher administration
costs for the regimens containing SC bortezomib, dara-
Costs for management of patients with NHL/FL or DLBCL tumumab, and dexamethasone than for those containing
receiving IV versus SC administration of rituximab were daratumumab, lenalidomide, and dexamethasone (all IV)
gathered from 18 publications. Of these, 11 reported costs in patients with relapsed/refractory multiple myeloma
based on direct assessment of HCP time, one estimated from two Phase III clinical trials [116].
time from a survey of HCPs [93], and six did not report • One publication from a randomized controlled trial at
how time was estimated [100–102, 105–107]. Only three a single Chinese hospital reported significantly (p <
of the publications were full papers; the rest were con- 0.0001) lower direct costs per patient for high-dose SC
gress abstracts (Fig. 2). Three simulation analysis study interferon-alpha compared with continuous IV interleu-
publications conducted in the USA report cost savings for kin-2 administration in patients with malignant myeloma
SC versus IV administration incrementally according to [113].
patient body surface area [100–102], which is used to cal- • Three publications reported directly measured time
culate the IV dose (the SC dose is fixed). One publication assessments for various oncology therapies; all of these
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 29

publications demonstrated reduced administration time reflect differences in time estimate methodologies, defini-
for therapies administered by the SC route versus the IV tions of time periods, and clinical practice/hospital setup
route [117–119]. between the different participating centers. Notably, the mul-
tinational PrefHer time-and-motion study reported time dif-
ferences between countries [25], despite presumably using
4 Discussion similar definitions for each time period across the different
centers involved in the study. Similar variations were also
4.1 Interpretation of Results seen with studies of rituximab [88]; however, a consistent
trend in favor of SC administration was observed across all
Global increases in yearly cancer rates have resulted in publications. During the COVID-19 pandemic, urgent can-
increased numbers of IV infusions of chemotherapies and cer referrals and chemotherapy attendances declined by up
anticancer biologics. This represents a growing burden for to 84.3% and 63.4%, respectively, which might have resulted
medical centers and HCPs, and has led to a shortage of in increased mortality rates in patients with cancer and mul-
chair time for patients with cancer. The substantially shorter timorbidity [121]. The time savings of SC administration
administration times of therapies administered subcutane- have the potential to help increase throughput of patients
ously has the potential to offer several advantages over IV now that cancer services have resumed. In addition to this,
administration, including shorter treatment times, a reduc- decreased hospital time for patients with cancer may help to
tion in healthcare resource use, increased convenience for reduce the risk of COVID-19 infection and the associated
patients, and greater patient preference [25, 39, 40, 120]. high probability of mortality in these patients [122].
In this SLR, we identified 72 publications reporting on As expected, there were also variations in costs for IV
the time/resource use and/or costs associated with IV versus and SC administration between publications that could be
SC administration of oncology biologics in a hospital setting compared based on use of the same currency. However, six
or on the budget impact of introducing an SC formulation. European publications reported similar percentage savings
The majority of reported publications were of studies con- in direct costs and most publications showed a trend for cost
ducted in single countries or even single centers; all studies saving with SC versus IV administration of trastuzumab.
were published between 2012 and 2020. Two of the rituximab publications that showed cost differ-
Overall, the results were largely consistent in demonstrat- ences for the SC and IV formulations incrementally based
ing the time savings associated with preparation and admin- on BSA reported that the largest cost savings occurred for
istration of SC therapies, across both oncology biologics and patients with higher BSA.
other supportive therapies. Moreover, reductions were seen The findings of this SLR are consistent with other pub-
in the HCP time and resource use (including non-drug con- lished SLRs that have reported on the time, resource, and
sumables and drug wastage) required for SC versus IV ther- cost savings associated with SC administration versus IV, for
apy administration. Patient hospital time was also shorter both oncology and non-oncology biologics [123–125]. How-
with SC versus IV administration, and additional cost sav- ever, cost reductions associated with time savings for HCPs
ings may be achieved at the society level due to a reduction may be difficult to measure and achieve in clinical practice
in the loss of productivity and leisure time associated with [126]. Therefore, methods of improving the transferability of
patients attending the hospital for treatment. However, these time-related cost savings to the clinic should be investigated.
improvements in patient productivity are likely to be greater The purpose of this SLR was to ultimately inform eco-
in patients receiving maintenance therapy than those receiv- nomic modeling and associated health technology assess-
ing SC-administered oncology biologics in combination ment of PH FDC SC. Recommendations for durations of
with chemotherapy, due to the increased patient chair time post-administration surveillance for SC and IV trastuzumab
required for chemotherapy administration. Cost savings due are identical, with 6 h of observation recommended after the
to reduced production and leisure time loss for SC versus IV first dose and 2 h of observation for all subsequent doses [42,
trastuzumab across five Swedish oncology clinics were €78 127–129]. Within the context of this SLR, observation times
and €62, respectively, for first-time patients and €10 and €6, for SC and IV cancel out (as they are the same). The effi-
respectively, for subsequent patients [64]. Similarly, a study cacy and safety profiles of SC and IV trastuzumab were also
conducted in six hospitals in the Netherlands reported lower assumed to be comparable in this study. However, real-world
societal costs (travel expenses and costs related to informal evidence suggests that target levels of trastuzumab may not
care and loss of productivity) for SC versus IV administra- be reached with the first SC administration in patients with
tion for both trastuzumab (cost saving of €22) and rituximab a high body weight and, although cardiotoxicity risk does
(cost saving of €28) [53]. not appear to be increased in patients with low body weight,
There was some variation in times reported for IV and SC Phase III trials have reported higher rates of adverse events
preparation and administration of trastuzumab, which may with SC vs. IV administration [130].
30 C. McCloskey et al.

It is important to note that the focus of this SLR was on included in this SLR can offer a chance of providing valu-
administration in the hospital setting only. However, similar able insights into the impact of the route of administration
to the benefits provided by other SC-administered oncol- on treatment costs.
ogy biologics [131–133], PH FDC SC is expected to offer The focus of this SLR was to identify potential time dif-
advantages with regard to reduced time/resource utilization, ferences associated with SC versus IV administration, as
improved patient quality of life, and the potential to be used well as differences in non-time-related cost elements such
in the future in a flexible care setting [43]. There is consider- as non-drug consumables. As a result, the drug costs of the
able evidence demonstrating that PH FDC SC is well suited treatments being administered were not considered. How-
to at-home administration by a HCP [134]. Providing at-home ever, it is important to acknowledge the need for decision
treatment requires planning, training, careful patient selection makers to take a holistic approach to healthcare resource
and technology to link patients, caregivers, and specialists in utilization, which accounts for both drug and non-drug costs,
oncology clinics, as well as innovative methods for treatment in order to ensure optimal management of resources.
delivery (e.g., mobile care units) [134]. A US expanded access In the future, more studies should address the economic
study (NCT04395508) investigating at-home administration benefits for different institutions of patients switching from
of PH FDC SC by a home health nursing provider is ongoing. IV to SC oncology biologics [54], rather than simply com-
This study focuses on patients with HER2-positive breast can- paring different patient populations treated via either IV or
cer previously treated with IV pertuzumab plus trastuzumab SC administration. Furthermore, as the current economic
and chemotherapy and currently receiving or due to receive assessments have mainly been performed in developed
maintenance therapy with pertuzumab plus trastuzumab alone. countries and there are concerns about the transferability
of SC versus IV benefits to less developed countries [126],
4.2 Strengths and Limitations more studies should be conducted in regions such as Eastern
Europe or Latin America to assess the applicability of our
One strength of this SLR is that it identified studies with findings there.
a range of designs, although some were described only as
economic analyses with no additional clearly defined design
details included. The inclusion of both clinical trials and 5 Conclusion
studies conducted in the real-world setting suggests that the
reported time and cost savings may be translated to SC versus This SLR indicates that there is a substantial body of evi-
IV oncology biologics administered during standard clinical dence demonstrating oncology biologics administered by the
practice. The publications included in this SLR also reported SC route in a hospital setting to be associated with impor-
several different methodologies for time assessments; how- tant time and resource use savings versus IV administration.
ever, results from the two studies that reported time estimates The identified evidence provides valuable inputs for eco-
from drug delivery software or based on HCP surveys were nomic evaluations of PH FDC SC, or for other SC oncology
largely consistent with those from studies that used direct treatments.
measurements from time-and-motion-type methodologies.
Although the majority of the trastuzumab and rituximab Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 41669-0​ 22-0​ 0361-3.
studies identified were performed in European countries,
full-text publications were identified for studies conducted Acknowledgements Support for third-party medical-writing assistance
in Canada, Chile, China, New Zealand, and the USA, and for this manuscript, furnished by Katie Wilson, PhD, and Brian Law,
abstracts identified for studies conducted in Ecuador, Hong PhD, of Health Interactions, was provided by F. Hoffmann-La Roche
Kong, Japan, Mexico, Panama, Singapore, Thailand, Tuni- Ltd.
sia, and Saudi Arabia. Despite the potentially limited gen-
eralizability of the conclusions due to country-specific dif- Declarations
ferences in approaches to healthcare, the consistency of the
Funding This research was supported by F. Hoffmann-La Roche Ltd.
evidence supporting SC-related time and cost savings com-
pared with IV administration presented in this SLR suggest
Conflict of interest All authors received research funding support in
that the findings are likely to be applicable across different the form of third-party medical writing support from F. Hoffmann-La
healthcare systems and countries. Roche Ltd. CM is an employee of Clarivate, which was commissioned
Due to the large number of potentially relevant publi- to perform this systematic review by F. Hoffmann-La Roche Ltd, and
cations comparing SC with IV administration, the deci- received travel expenses from F. Hoffmann-La Roche Ltd to attend a
project scoping meeting. MTO and SN are employees of Clarivate,
sion was made to focus the literature search on anticancer which was commissioned to perform this systematic review by F. Hoff-
drugs. Although this pragmatic approach could lead to rel- mann-La Roche Ltd. MJG and FM are employees of and hold shares in
evant data/insights being missed, the oncology publications F. Hoffmann-La Roche Ltd.
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 31

Ethics approval Not applicable. This article is based on previously 4. Ménard S, Fortis S, Castiglioni F, Agresti R, Balsari A. HER2
conducted studies and does not contain any new studies with human as a prognostic factor in breast cancer. Oncology. 2001;61(Suppl
participants or animals performed by any of the authors. 2):67–72.
5. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Baja-
Consent to participate Not applicable. monde A, et al. Use of chemotherapy plus a monoclonal antibody
against HER2 for metastatic breast cancer that overexpresses
Consent for publication Not applicable. HER2. N Engl J Med. 2001;344(11):783–92.
6. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch
Availability of data and material The data supporting the findings of A, Untch M, Smith I, et al. Trastuzumab after adjuvant chem-
this study are available within the article or its supplementary materi- otherapy in HER2-positive breast cancer. N Engl J Med.
als. 2005;353(16):1659–72.
7. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr,
Code availability Not applicable. Davidson NE, et al. Trastuzumab plus adjuvant chemother-
apy for operable HER2-positive breast cancer. N Engl J Med.
Author contributions All authors were involved in the concept and 2005;353(16):1673–84.
design of this systematic literature review (SLR). The protocol for 8. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubi-
this SLR was designed by CM, MTO, and SN, and was reviewed and ana-Hulin M, et al. Randomized phase II trial of the efficacy and
approved by F. Hoffmann-La Roche Ltd. CM and MTO conducted the safety of trastuzumab combined with docetaxel in patients with
publication screening, data extraction, and quality assessments. SN human epidermal growth factor receptor 2-positive metastatic
was involved in quality control and offered strategic advice during all breast cancer administered as first-line treatment: The M77001
aspects of the project, including publication screening, data extrac- study group. J Clin Oncol. 2005;23(19):4265–74.
tion, and quality assessments. CM and SN prepared the SLR report. 9. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A,
All authors reviewed and critically revised the manuscript, approved Tjulandin S, et al. Neoadjuvant chemotherapy with trastuzumab
the final version of the manuscript, and agree to be accountable for all followed by adjuvant trastuzumab versus neoadjuvant chemo-
aspects of the work in ensuring that questions related to the accuracy therapy alone, in patients with HER2-positive locally advanced
or integrity of any part of the work are appropriately investigated and breast cancer (the NOAH trial): a randomised controlled superi-
resolved. ority trial with a parallel HER2-negative cohort. Lancet (London,
England). 2010;375(9712):377–84.
10. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M,
Open Access This article is licensed under a Creative Commons Attri- Press M, et al. Adjuvant trastuzumab in HER2-positive breast
bution-NonCommercial 4.0 International License, which permits any cancer. N Engl J Med. 2011;365(14):1273–83.
non-commercial use, sharing, adaptation, distribution and reproduction 11. Roche Registration Ltd. H ­ erceptin® (trastuzumab). Summary of
in any medium or format, as long as you give appropriate credit to the Product Characteristics. 2021. https://​www.​ema.​europa.​eu/​en/​
original author(s) and the source, provide a link to the Creative Com- docum​ents/​produ​ct-​infor ​mation/​herce​ptin-​epar-​produ​ct-​infor​
mons licence, and indicate if changes were made. The images or other mation_​en.​pdf. Accessed 1 June 2022.
third party material in this article are included in the article's Creative 12. Genentech Inc. H ­ ERCEPTIN® (trastuzumab). Prescribing Infor-
Commons licence, unless indicated otherwise in a credit line to the mation. 2018. https://​www.​acces​sdata.​fda.​gov/​drugs​atfda_​docs/​
material. If material is not included in the article's Creative Commons label/​2018/​10379​2s534​5lbl.​pdf. Accessed 1 June 2022.
licence and your intended use is not permitted by statutory regula- 13. National Comprehensive Cancer Network (NCCN). NCCN Clini-
tion or exceeds the permitted use, you will need to obtain permission cal Practice Guidelines in Oncology (NCCN ­Guidelines®): Breast
directly from the copyright holder. To view a copy of this licence, visit Cancer. Version 1.2022. https://​www.​nccn.​org/​profe​ssion​als/​
http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc/4.​0/. physi​cian_​gls/​pdf/​breast.​pdf. Accessed Dec 2021.
14. Arbeitsgemeinschaft Gynäkologische Onkologie (German
Gynecological Oncology Group A. Guidelines of the AGO
Breast Committee. 2022. https://​www.​ago-​online.​de/​en/​leitl​
References inien- ​ e mpfe ​ h lung​ e n/ ​ l eitl ​ i nien- ​ e mpfe ​ h lung​ e n/ ​ kommi ​ s sion-​
mamma. Accessed June 2022.
1. Ruiz-Fernández MD, Hernández-Padilla JM, Ortiz-Amo R, 15. Cardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro
Fernández-Sola C, Fernández-Medina IM, Granero-Molina MS, André F, et al. 5th ESO-ESMO international consensus
J. Predictor factors of perceived health in family caregivers of guidelines for advanced breast cancer (ABC 5). Ann Oncol.
people diagnosed with mild or moderate Alzheimer’s disease. 2020;31(12):1623–49.
Int J Environ Res Public Health. 2019;16(19):3762. 16. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans
2. Global Cancer Observatory. Estimated number of deaths in 2020, P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice
worldwide, females, all ages. 2021. https://​gco.​iarc.​fr/​today/​ Guidelines for diagnosis, treatment and follow-up. Ann Oncol.
online-a​ nalys​ is-p​ ie?v=2​ 020&m
​ ode=c​ ancer​ &m
​ ode_p​ opula​ tion=​ 2019;30(8):1194–220.
conti​nents​&​popul​ation=​900&​popul​ations=​900&​key=​total​&​ 17. Roche Registration Ltd. P ­ ERJETA® (pertuzumab). Summary
sex=​2&​cancer=​39&​type=​1&​stati​stic=​5&​preva​lence=​0&​popul​ of Product Characteristics. 2021. https://​www.​ema.​europa.​eu/​
ation_​g roup=​0&​ages_​g roup%​5B%​5D=​0&​ages_​g roup%​5B%​ en/​docum​ents/​produ​ct-​infor ​mation/​perje​ta-​epar-​produ​ct-​infor​
5D=​17&​nb_​items=​7&​g roup_​cancer=​1&​inclu​de_​nmsc=​1&​ mation_​en.​pdf. Accessed 1 June 2022.
inclu​de_​nmsc_​other=​1&​half_​pie=​0&​donut=0. Accessed Dec 18. Genentech Inc. P ­ ERJETA® (pertuzumab). Prescribing Informa-
2021. tion. 2020. https://​www.​acces​sdata.​fda.​gov/​drugs​atfda_​docs/​
3. Patel A, Unni N, Peng Y. The changing paradigm for the label/​2020/​12540​9s124​lbl.​pdf. Accessed 1 June 2022.
treatment of HER2-positive breast cancer. Cancers (Basel).
2020;12(8):2081.
32 C. McCloskey et al.

19. Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch 2017;78(4 Suppl):Abstract PD3-11 (and associated poster
A, et al. 5-year analysis of neoadjuvant pertuzumab and tras- presentation).
tuzumab in patients with locally advanced, inflammatory, or 34. Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B,
early-stage HER2-positive breast cancer (NeoSphere): a mul- Chen S-C, et al. Subcutaneous vs intravenous trastuzumab for
ticentre, open-label, phase 2 randomised trial. Lancet Oncol. patients with ERBB2-positive early breast cancer: Final analysis
2016;17(6):791–800. of the HannaH phase 3 randomized clinical trial. JAMA Oncol.
20. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, 2019;5(5): e190339.
Benyunes M, Viale G, et al. Adjuvant pertuzumab and trastu- 35. Kümmel S, Tondini CA, Abraham J, Nowecki Z, Itrych B, Hitre
zumab in early HER2-positive breast cancer. N Engl J Med. E, et al. Subcutaneous trastuzumab with pertuzumab and doc-
2017;377(2):122–31. etaxel in HER2-positive metastatic breast cancer: Final analysis
21. Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, of MetaPHER, a phase IIIb single-arm safety study. Breast Can
et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive Res Treat. 2021;187(2):467–76.
metastatic breast cancer (CLEOPATRA): End-of-study results 36. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Per-
from a double-blind, randomised, placebo-controlled, phase 3 tuzumab plus trastuzumab plus docetaxel for metastatic breast
study. Lancet Oncol. 2020;21:519–30. cancer. N Engl J Med. 2012;366(2):109–19.
22. Roche Registration Ltd. ­Kadcyla® (trastuzumab emtansine). 37. Swain SM, Kim S-B, Cortés J, Ro J, Semiglazov V, Campone M,
Summary of Product Characteristics. 2021. https://​www.​ema.​ et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive
europa.​eu/​en/​docum​ents/​produ​ct-​infor ​mation/​kadcy​la-​epar-​ metastatic breast cancer (CLEOPATRA study): overall survival
produ​ct-​infor​mation_​en.​pdf. Accessed June 2022. results from a randomised, double-blind, placebo-controlled,
23. Genentech Inc. ­KADCYLA® (ado-trastuzumab emtansine). phase 3 study. Lancet Oncol. 2013;14(6):461–71.
Prescribing Information. https://​www.​acces​sdata.​fda.​gov/​drugs​ 38. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M,
atfda_​docs/​label/​2020/​12542​7s108​lbl.​pdf. Accessed June 2022. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive
24. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamou- metastatic breast cancer. N Engl J Med. 2015;372(8):724–34.
nas EP, Untch M, et al. Trastuzumab emtansine for resid- 39. Pivot X, Gligorov J, Müller V, Barrett-Lee P, Verma S, Knoop
ual invasive HER2-positive breast cancer. N Engl J Med. A, et al. Preference for subcutaneous or intravenous administra-
2019;380(7):617–28. tion of trastuzumab in patients with HER2-positive early breast
25. De Cock E, Pivot X, Hauser N, Verma S, Kritikou P, Millar D, cancer (PrefHer): an open-label randomised study. Lancet Oncol.
et al. A time and motion study of subcutaneous versus intrave- 2013;14(10):962–70.
nous trastuzumab in patients with HER2-positive early breast 40. Pivot X, Gligorov J, Müller V, Curigliano G, Knoop A, Verma S,
cancer. Cancer Med. 2016;5(3):389–97. et al. Patients’ preferences for subcutaneous trastuzumab versus
26. Fallowfield L, Osborne S, Langridge C, Monson K, Kilkerr J, conventional intravenous infusion for the adjuvant treatment of
Jenkins V. Implications of subcutaneous or intravenous delivery HER2-positive early breast cancer: final analysis of 488 patients
of trastuzumab; further insight from patient interviews in the in the international, randomized, two-cohort PrefHer study. Ann
PrefHer study. Breast. 2015;24(2):166–70. Oncol. 2014;25(10):1979–87.
27. Jackisch C, Müller V, Maintz C, Hell S, Ataseven B. Subcu- 41. Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V,
taneous administration of monoclonal antibodies in oncology. et al. Patients’ preference of trastuzumab administration (subcu-
Geburtshilfe Frauenheilkd. 2014;74(4):343–9. taneous versus intravenous) in HER2-positive metastatic breast
28. Shivakumar SP, Anderson DR, Couban S. Catheter-associ- cancer: results of the randomised MetaspHer study. Eur J Cancer.
ated thrombosis in patients with malignancy. J Clin Oncol. 2017;82:230–6.
2009;27(29):4858–64. 42. Genentech Inc. PHESGO (pertuzumab, trastuzumab, and hya-
29. De Cock E, Semiglazov V, Lopez-Vivanco G, Verma S, Pivot luronidase-zzxf). Prescribing Information. 2020. https://​www.​
X, Gligorov J, et al. Time savings with trastuzumab subcutane- acces​sdata.​fda.​gov/​drugs​atfda_​docs/​label/​2020/​76117​0s000​lbl.​
ous vs. intravenous administration: a time and motion study. In: pdf. Accessed 1 June 2022.
Poster presentation at the 13th St Gallen International Breast 43. O’Shaughnessy J, Sousa S, Cruz J, Fallowfield L, Auvinen P,
Cancer Conference; 13–16 March 2013. Abstract XXX; St Pulido C, et al. Preference for the fixed-dose combination of
Gallen. pertuzumab and trastuzumab for subcutaneous injection in
30. Genentech Inc. Herceptin Hylecta™ (trastuzumab and hyaluro- patients with HER2-positive early breast cancer (PHranc-
nidase-oysk). Prescribing Information. 2019. https://​www.​acces​ eSCa): a randomised, open-label phase II study. Eur J Cancer.
sdata.​fda.​gov/​drugs​atfda_​docs/​label/​2019/​76110​6s000​lbl.​pdf. 2021;152:223–32.
Accessed Dec 2021. 44. Higgins J, Thomas J. Cochrane handbook for systematic reviews
31. Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim of interventions. Version 6.2. 2021. https://t​ raini​ ng.c​ ochra​ ne.o​ rg/​
SB, et al. Subcutaneous versus intravenous administration of handb​ook/​curre​nt. Accessed Dec 2021.
(neo)adjuvant trastuzumab in patients with HER2-positive, 45. Drummond MF, Jefferson TO. Guidelines for authors and peer
clinical stage I-III breast cancer (HannaH study): a phase reviewers of economic submissions to the BMJ. The BMJ Eco-
3, open-label, multicentre randomised trial. Lancet Oncol. nomic Evaluation Working Party. BMJ. 1996;313(7052):275–83.
2012;13(9):869–78. 46. Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ, Stod-
32. Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, dart GL. Methods for the exonomic evaluation of health care
Hillenbach C, et al. Subcutaneous versus intravenous formu- programmes. 3rd ed. Oxford: Oxford University Press; 2005.
lation of trastuzumab for HER2-positive early breast cancer: 47. Molinier L, Bauvin E, Combescure C, Castelli C, Rebillard
updated results from the phase III HannaH study. Ann Oncol. X, Soulié M, et al. Methodological considerations in cost of
2015;26(2):320–5. prostate cancer studies: a systematic review. Value Health.
33. Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen 2008;11(5):878–85.
SC, et al. Efficacy and safety of subcutaneous or intravenous 48. Andrade S, Santos A. Hospital resources consumption associated
trastuzumab in patients with HER2-positive early breast cancer with trastuzumab treatment in breast cancer in Portugal. Value
after 5 years’ treatment-free follow-up: final analysis from the Health. 2013;16(7):Abstract PCN147.
phase III, open-label, randomized HannaH study. Cancer Res.
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 33

49. Blein C, bernard Marty C, Priou V, Borg MC, mouret-Reynier M, HER2-positive breast cancer—an observational study prospec-
Lebozec G, et al. A multicentric evaluation of consumables and tively recording resource utilization in a Swedish healthcare set-
transports cost of breast cancer patient’s treated by trastuzumab ting. Breast. 2016;29:140–6.
according to the administration form (IV versus SC). Value 65. Olsen J, Jensen KF, Olesen DS, Knoop A. Costs of subcutaneous
Health. 2018;21(Suppl 3):Abstract PCN95. and intravenous administration of trastuzumab for patients with
50. De Cock E, Pan YI, Tao S, Baidin P. Time savings with tran- HER2-positive breast cancer. J Comp Eff Res. 2018;7(5):411–9.
stuzumab subcutaneous (SC) injection verse trastuzumab intra- 66. Ponzetti C, Canciani M, Farina M, Era S, Walzer S. Potential
venous (IV) infusion: A time and motion study in 3 Russian resource and cost saving analysis of subcutaneous versus intra-
centers. Value Health. 2014;17(7):Abstract PCN221. venous administration for rituximab in non-Hodgkin’s lym-
51. Farolfi A, Silimbani P, Gallegati D, Petracci E, Schirone A, Altini phoma and for trastuzumab in breast cancer in 17 Italian hospi-
M, et al. Resource utilization and cost saving analysis of subcu- tals based on a systematic survey. Clinicoecon Outcomes Res.
taneous versus intravenous trastuzumab in early breast cancer 2016;8:227–33.
patients. Oncotarget. 2017;8(46):81343–9. 67. Tjalma WAA, Van den Mooter T, Mertens T, Bastiaens V, Huiz-
52. Favier M, Le Goc-Sager F, Vincent-Cantini I, Launay V, Giroux ing MT, Papadimitriou K. Subcutaneous trastuzumab (Herceptin)
EA, Lievremont K, et al. Medico-economic benefits of subcuta- versus intravenous trastuzumab for the treatment of patients with
neous formulations of trastuzumab and rituximab in day hospi- HER2-positive breast cancer: a time, motion and cost assessment
talisation (SCuBA Study). Bull Cancer. 2018;105(10):862–72. study in a lean operating day care oncology unit. Eur J Obstet
53. Franken MG, Kanters TA, Coenen JL, de Jong P, Koene HR, Gynecol Reprod Biol. 2018;221:46–51.
Lugtenburg PJ, et al. Potential cost savings owing to the route 68. Vangheluwe E, Giraud J, Pingaud C. Medico-economic
of administration of oncology drugs: a microcosting study impacts of use of subcutaneous formulations of rituximab
of intravenous and subcutaneous administration of trastu- and trastuzumab in outpatient care units. Eur J Oncol Pharm.
zumab and rituximab in the Netherlands. Anticancer Drugs. 2018;1(3S):Abstract 191.
2018;29(8):791–801. 69. Coombes M, Yin L, Liu I, Shek N, Rusu F, Mukherjee S. Subcu-
54. Hedayati E, Fracheboud L, Srikant V, Greber D, Wallberg S, taneous trastuzumab for the treatment of HER2+ breast cancer
Linder SC. Economic benefits of subcutaneous trastuzumab in Canada: a cost-minimization study. Cancer Res. 2020;80(4
administration: a single institutional study from Karolinska Uni- Suppl):Abstract P6-13-02.
versity Hospital in Sweden. PLoS ONE. 2019;14(2): e0211783. 70. Ghosh W, Lim S, Wong A. Cost-minimisation analysis of subcu-
55. Jackisch C, Müller V, Dall P, Neumeister R, Park-Simon TW, taneous versus intravenous trastuzumab for the treatment of early
Ruf-Dördelmann A, et al. Subcutaneous trastuzumab for HER2- breast cancer and metastatic breast cancer in Singapore. Value
positive breast cancer—evidence and practical experience in 7 Health. 2018;21:Abstract PCN55.
German centers. Geburtshilfe Frauenheilkd. 2015;75(6):566–73. 71. Rojas L, Muñiz S, Medina L, Peña J, Acevedo F, Pinto MP, et al.
56. Lee VW, Cheng F. Cost-minimization analysis of trastuzumab Cost-minimization analysis of subcutaneous versus intravenous
intravenous versus trastuzumab subcutaneous regimen for breast trastuzumab administration in Chilean patients with HER2-pos-
cancer management in Hong Kong. Value Health. 2018;21(Suppl itive early breast cancer. PLoS ONE. 2020;15(2): e0227961.
2):Abstract PCN57. 72. A N, Ali A, Al-Tweigeri T, Zekri J, Awad N, Safwat M, et al.
57. Lewis P, Jones H, Skelley K, Simpson R, Beresford M. Switch- Financial impact of introducing SC trastuzumab (Herceptin) ver-
ing to subcutaneous trastuzumab administration: quantifying the sus currently used IV trastuzumab (Herceptin) on the budgets of
benefits. Clin Oncol. 2017;29(6):Abstract E101. different hospitals across Kingdom of Saudi Arabia (KSA). Value
58. López MA, Samanes MS, Tena IP, Alonso EF, Turlan VC, Health. 2017;20(9):Abstract PCN60.
Sanchez MC, et al. Switching from intravenous to subcutaneous 73. Kashiura D, Souza PV, Garrido SD, Nardi E, Alves M. Budget
formulation of TRASTUZUMAB: Costs and safety. Eur J Hosp impact model of subcutaneous trastuzumab compared with intra-
Pharm. 2017;24(Suppl 1):Abstract CP-127. venous trastuzumab on the treatment of HER-2 positive breast
59. Lopez-Vivanco G, Salvador J, Diez R, López D, De Salas- cancer in the brazilian private healthcare system. Value Health.
Cansado M, Navarro B, et al. Cost minimization analysis of treat- 2018;21(Suppl 3):Abstract PCN75.
ment with intravenous or subcutaneous trastuzumab in patients 74. Poquet-Jornet JE, Carrera Hueso J, Crespo C, Cuesta-Grueso
with HER2-positive breast cancer in Spain. Clin Transl Oncol. C, Ramón Barrios MA, Gasent-Blesa JM, et al. Budget impact
2017;19(12):1454–61. analysis with use of subcutaneus trastuzumab. Value Health.
60. Nestorovska A, Naumoska Z, Grozdanova A, Stoleski D, 2018;21(Suppl 3):Abstract PCN80.
Ivanovska A, Risteski M, et al. Subcutaneous vs intravenous 75. Calvache J, Briceno V. Budget impact analysis of the use of tras-
administration of trastuzumab in HER2+ breast cancer patients: tuzumab SC in the treatment of HER2 positive in public health
a Macedonian cost-minimization analysis. Value Health. institutions of Ecuador. Value Health. 2017;20.
2015;18(7):Abstract PCN188. 76. Agirrezabal I, Gaikwad I, Cirillo L, Lothgren M. Predicted
61. Nierenberger A, Gessier F, Forges F, Simoens X. Subcutaneous treatment costs and savings per patient of ­Kanjinti® (trastu-
trastuzumab versus intravenous trastuzumab: an impact study. zumab biosimilar) vs. subcutaneous (SC) and intravenous (IV)
Eur J Hosp Pharm. 2017;24(Suppl 1):Abstract PP-034. ­Herceptin® and other trastuzumab biosimilars in italy. Value
62. North RT, Harvey VJ, Cox LC, Ryan SN. Medical resource Health. 2018;21(Suppl 3):Abstract PCN103.
utilization for administration of trastuzumab in a New Zealand 77. D'Arpino A, Savoia M, Cirillo L, Despiégel N, Haffemayer B,
oncology outpatient setting: a time and motion study. Clinico- Giannopoulou A, et al. Comparative cost analysis of subcutane-
econ Outcomes Res. 2015;7:423–30. ous trastuzumab originator ­(Herceptin®) vs intravenous trastu-
63. O’Brien GL, O’Mahony C, Cooke K, Kinneally A, Sinnott zumab biosimilar (Kanjinti) from a hospital perspective in Italy.
SJ, Walshe V, et al. Cost minimization analysis of intrave- Value Health. 2019;22(Suppl 3):Abstract PCN72.
nous or subcutaneous trastuzumab treatment in patients with 78. Jang Y, Byrne A, Toron F, Yoon S. Budget impact analysis of
HER2-positive breast cancer in Ireland. Clin Breast Cancer. intravenous biosimilars compared with intravenous origina-
2019;19(3):e440–51. tors and subcutaneous products. Value Health. 2018;21(Suppl
64. Olofsson S, Norrlid H, Karlsson E, Wilking U, Ragnarson TG. 3):Abstract PMU26.
Societal cost of subcutaneous and intravenous trastuzumab for
34 C. McCloskey et al.

79. Todorovic V, Durutovic I, Ivanovska A, Zajmovic A. Subcuta- lymphoma (NHL): a case study from Tunisia. HemaSphere.
neous vs intravenous administration of trastuzumab in HER2+ 2019;3:Abstract PB2294.
breast cancer patients: a montenegrin cost-minimization analysis. 94. Chansung K, Chuncharunee S, Khuhapinant A, Bunworasate
Value Health. 2017;20(9):Abstract PCN172. U, Norasetthada L, Prayongratana K. Preference of rituximab
80. Villarreal-Garza C, O-Maldonado CDl, Díaz-Pérez H, Mesa- subcutaneous (R-SC) in Thai patients with diffused large b-cell
Chavez F, García-García M, Cardona-Huerta S, et al. Cost lymphoma (DLBCL) and follicular lymphoma (FL): a Thai con-
and time savings of subcutaneous trastuzumab (SC-T) in a text. Value Health. 2018;21(Suppl 2):Abstract PCN67.
public health system in Mexico. J Clin Oncol. 2019;37(15 95. Delgado Sánchez O, Gutiérrez A, do Pazo F, Ginés J, Martorell
Suppl):Abstract e18387. C, Boyeras B, et al. Comparative cost analysis of intravenous and
81. De La Vega ZI, Celia A, Manuel P, Agustín S, Miguel C. subcutaneous administration of rituximab in lymphoma patients.
Economic impact of the introduction of subcutaneous trastu- Clinicoecon Outcomes Res. 2019;11:695-701.
zumab in the pharmacotherapeutic guide. Eur J Clin Pharm. 96. Di Rocco A, Scerbo G, Ansuinelli M, al e. Efficacy, safety
2017;19(3):213–5. and cost analysis of subcutaneous vs intravenous rituximab in
82. Lazaro Cebas A, Cortijo Cascajares S, Pablos Bravo S, Del Puy patients with diffuse large b-cell lymphoma treated with RCHOP.
Goyache Goni M, Gonzalez Monterrubio G, Perez Cardenas MD, Haematologica. 2017;102:108.
et al. Subcutaneous versus intravenous administration of trastu- 97. Fisher MD, Wallick C, Miller PJ, Walker MS, Lash S, Dawson
zumab: preference of HER2+ breast cancer patients and financial KL, et al. How time spent on rituximab infusion impacts patient
impact of its use. J BUON. 2017;22(2):334-9. satisfaction, stress, employment, and caregiver burden. Blood.
83. Kulikov A, Rybchenko Y. Pharmacoeconomic evaluation of the 2017;130(Suppl 1):Abstract 5666.
use of trastuzumab for subcutaneous administration compared to 98. Irwin S, Rowntree C, Cosh H, Bloodworth C. Positive benefits of
intravenous dosage form in the treatment of breast cancer. Value changing from intravenous rituximab administration to subcuta-
Health. 2015;18(7):Abstract PCN189. neous administration: a single centre experience. British Journal
84. Martin C, Alcedo J, Araúz E. Comparative analysis of costs of Haematology. 2017;176:Abstract E1151.
between subcutaneous formulation of trastuzumab versus 99. Lebas E, Guillotel R, Evrard J, Kugarajah R, Lassiaz C, Diakhate
intravenous formulation from the perspective of the Instituto C. Time and money: the issues of setting up a rituximab biosimi-
Oncológico Nacional of Panamá from January to December lar in hospital. Eur J Oncol Pharm. 2018;1:Abstract 197.
2016. Cancer Res. 2018;78(4 Suppl):Abstract P4-12-3. 100. McBride A, Balu S, Campbell K, MacDonald K, Abraham I.
85. Mitchell H, Morrissey D. Intravenous versus subcutaneous Economic modeling for the US of intravenous vs subcutaneous
trastuzumab: an economic and patient perspective. Br J Nurs. rituximab in non-Hodgkin’s lymphoma treated with R-CHOP.
2019;28(10):S15–20. Value Health. 2018;21(Suppl 3):Abstract PCN93.
86. Mylonas C, Skroumpelos A, Fountzilas G, Maniadakis N. Cost 101. McBride A, Balu S, Campbell K, MacDonald K, Abraham I.
minimization analysis of Herceptin subcutaneous versus hercep- Economic modeling for the U.S. of intravenous versus subcu-
tin intravenous treatment for patients with HER2+ breast cancer taneous rituximab as single-agent maintenance therapy in fol-
in Greece. J Cancer Policy. 2017;13:11–7. licular lymphoma. J Manag Care Spec Pharm. 2018;24(10A
87. Mylonas C, Kourlaba G, Fountzilas G, Skroumpelos A, Mani- Suppl):Abstract C29.
adakis N. Cost-minimization analysis of trastuzumab intravenous 102. McBride A, Balu S, Campbell K, MacDonald K, Abraham I.
versus trastuzumab subcutaneous for the treatment of patients Subcutaneous versus intravenous rituximab in non-Hodgkin lym-
with HER2+ early breast cancer and metastatic breast cancer in phoma treated with R-CHOP: Economic modeling for the US.
Greece. Value Health. 2014;17(7):A640–1. Blood. 2018;132(Suppl 1):Abstract 4776.
88. De Cock E, Kritikou P, Sandoval M, Tao S, Wiesner C, Carella 103. Nikolov O, Sterjev Z, Dimovski A, Kapedanovska-Nestorovska
AM, et al. Time savings with rituximab subcutaneous injection A, Naumovska Z, Grozdanova A, et al. Cost-minimization analy-
versus rituximab intravenous infusion: a time and motion study sis of rituximab subcutaneous formulation versus intravenous
in eight countries. PLoS ONE. 2016;11(6): e0157957. administration of rituximab for the treatment of non-hodgkin’s
89. Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau lymphoma in the Republic of Macedonia. Haematologica.
JP, Nagler A, et al. Efficacy and safety of subcutaneous and 2017;102:Abstract E1471.
intravenous rituximab plus cyclophosphamide, doxorubicin, 104. Tomarchio V, Surano MA, Tafuri MA, Becilli M, Sarlo C, Berti
vincristine, and prednisone in first-line diffuse large B-cell P, et al. Management, economic and social impact of sub-cuta-
lymphoma: the randomized MabEase study. Haematologica. neous rituximab administration in lymphoproliferative malignan-
2017;102(11):1913–22. cies. Haematologica. 2017;102(Suppl 1):Abstract P736.
90. Mihajlovic J, Bax P, van Breugel E, Blommestein HM, Hoogen- 105. Cicchetti A, Coretti S, Mascia D, Mazzanti N, Refolo P, Rolli FR,
doorn M, Hospes W, et al. Microcosting study of rituximab et al. Assessing social and economic impact of subcutaneous mAbs
subcutaneous injection versus intravenous infusion. Clin Ther. in oncology. Glob Reg Health Technol Assess. 2018;5(1):1–9.
2017;39(6):1221–32. 106. Chansung K, Sirijerachai C, Teawtrakul N. Cost minimization
91. Fargier E, Ranchon F, Huot L, Guerre P, Safar V, Dony A, study between intravenous rituximab (r-iv) vs subcutaneous rituxi-
et al. SMABcare study: subcutaneous monoclonal antibody mab (R-SC) in Thai patients with diffused large b-cell lymphoma
in cancer care: cost-consequence analysis of subcutaneous (DLBCL): a simulation of electronic health record (E-HR) and evi-
rituximab in patients with follicular lymphoma. Ann Hematol. dence synthesis. Value Health. 2018;21(Suppl 2):Abstract PSY9.
2018;97(1):123–31. 107. Annibali O, Tomarchio V, Becilli M. Management, economic and
92. Rule S, Collins GP, Samanta K. Subcutaneous vs intrave- social impact of sub-cutaneous rituximab administration in dif-
nous rituximab in patients with non-Hodgkin lymphoma: a fuse large b cell lymphoma (DLBCL) and follicular lymphoma.
time and motion study in the United Kingdom. J Med Econ. Haematologica. 2017;102:111.
2014;17(7):459–68. 108. Gomes G, Ho R, Rufino C, Alves M. Budget impact analysis of
93. Lakhal RB, Kacem K, Raoudha M, Jabeur D, Denguir MS, rituximab IV versus SC from public Brazilian hospital. Value
Bouattour H, et al. Cost-minimization and budget impact analy- Health. 2017;20(5):Abstract PCN63.
sis of mabthera subcutaneous formulation in non-Hodgkin’s
Time and Resource Use Costs of SC vs. IV Administration of Oncology Biologics 35

109. Kashiura D, Souza PV, Sa AB, Santos BR, Nardi E, Alves M. 121. Lai AG, Pasea L, Banerjee A, Hall G, Denaxas S, Chang WH,
Budget impact model of subcutaneous rituximab compared with et al. Estimated impact of the COVID-19 pandemic on cancer
intravenous rituximab on the treatment of CD-20 positive non- services and excess 1-year mortality in people with cancer
Hodgkin lymphoma in the Brazilian private healthcare system. and multimorbidity: near real-time data on cancer care, cancer
Value Health. 2018;21:Abstract PCN67. deaths and a population-based cohort study. BMJ Open. 2020;10:
110. Rauf M, Dada R, Awad N, Safwat M, Narang A, Goyal R. To e043828.
determine the financial imapct of introducing SC rituximab 122. Tagliamento M, Agostinetto E, Bruzzone M, Ceppi M, Saini
(MABTHERA) vs. currently used IV rituximab (MABTHERA) KS, de Azambuja E, et al. Mortality in adult patients with solid
on the budgets of different hospitals across the Kingdom of Saudi or hematological malignancies and SARS-CoV-2 infection with
Arabia (KSA). Value Health. 2017;20(9):Abstract PCN69. a specific focus on lung and breast cancers: a systematic review
111. Stewart DA, Boudreault JS, Maturi B, Boras D, Foley R. Evalu- and meta-analysis. Crit Rev Oncol Hematol. 2021;163: 103365.
ation of subcutaneous rituximab administration on Canadian 123. Anderson KC, Landgren O, Arend RC, Chou J, Jacobs IA.
systemic therapy suites. Curr Oncol. 2018;25(5):300–6. Humanistic and economic impact of subcutaneous versus intra-
112. Cristino J, Finek J, Jandova P, Kolek M, Pásztor B, Giannopoulou venous administration of oncology biologics. Future Oncol.
C, et al. Cost-effectiveness of denosumab versus zoledronic acid 2019;15(28):3267–81.
for preventing skeletal-related events in the Czech Republic. J 124. Tetteh E, Morris S. Systematic review of drug administration
Med Econ. 2017;20(8):799–812. costs and implications for biopharmaceutical manufacturing.
113. Li S, Wu X, Chen P, Pei Y, Zheng K, Wang W, et al. Interferon- Appl Health Econ Health Policy. 2013;11(5):445–56.
alpha versus interleukin-2 in Chinese patients with malignant 125. Bittner B, Richter W, Schmidt J. Subcutaneous administration of
melanoma: a randomized, controlled, trial. Anticancer Drugs. biotherapeutics: an overview of current challenges and opportu-
2019;30(4):402–9. nities. BioDrugs. 2018;32(5):425–40.
114. Raje N, Roodman GD, Willenbacher W, Shimizu K, García-Sanz 126. Inotai A, Agh T, Karpenko AW, Zemplenyi A, Kalo Z. Behind
R, Terpos E, et al. A cost-effectiveness analysis of denosumab the subcutaneous trastuzumab hype: evaluation of benefits and
for the prevention of skeletal-related events in patients with mul- their transferability to Central Eastern European countries.
tiple myeloma in the United States of America. J Med Econ. Expert Rev Pharmacoecon Outcomes Res. 2019;19(2):105–13.
2018;21(5):525–36. 127. Roche Registration Ltd. H ­ erceptin® (trastuzumab). Summary of
115. Stopeck A, Rader M, Henry D, Danese M, Halperin M, Cong Z, et al. Product Characteristics. 2021. https://​www.​ema.​europa.​eu/​en/​
Cost-effectiveness of denosumab vs zoledronic acid for prevention of docum​ents/​produ​ct-​infor ​mation/​herce​ptin-​epar-​produ​ct-​infor​
skeletal-related events in patients with solid tumors and bone metas- mation_​en.​pdf. Accessed Sept 2021.
tases in the United States. J Med Econ. 2012;15(4):712–23. 128. Genentech Inc. ­Herceptin® (trastuzumab). Prescribing Informa-
116. Zhang TT, Wang S, Wan N, Zhang L, Zhang Z, Jiang J. Cost- tion. 2021. https://w
​ ww.g​ ene.c​ om/d​ ownlo​ ad/p​ df/h​ ercep​ tin_p​ resc​
effectiveness of daratumumab-based triplet therapies in patients ribing.​pdf. Accessed Sept 2021.
with relapsed or refractory multiple myeloma. Clin Ther. 129. Roche Registration GmbH. ­PHESGO® (pertuzumab and tras-
2018;40(7):1122–39. tuzumab). Summary of Product Characteristics. 2022. https://​
117. Body JJ, Gatta F, De Cock E, Tao S, Kritikou P, Wimberger P, www.​ema.​europa.​eu/​docum​ents/​produ​ct-​infor ​mation/​phesgo-​
et al. An observational time and motion study of denosumab epar-​produ​ct-​infor​mation_​en.​pdf. Accessed 1 June 2022.
subcutaneous injection and zoledronic acid intravenous infusion 130. Kolberg HK, Jackisch C, Hurvitz SA, Winstone J, Barham H,
in patients with metastatic bone disease: Results from three Euro- Hanes V, et al. Is weight-based IV dosing of trastuzumab prefer-
pean countries. Support Care Cancer. 2017;25(9):2823–32. able to SC fixed-dose in some patients? A systematic scoping
118. Despiau F, Zagala Y, Delord JP, Montastruc M, Lacaze JL, review. Breast. 2021;57.
Ferrand R, et al. Observational study of outpatient unit dura- 131. Wright JM, Jones GB. Developing the subcutaneous drug deliv-
tion of stay depending on the route of administration (intra- ery route. Med Res Archiv. 2017;5(12).
venous vs subcutaneous) for a targeted therapy. Bull Cancer. 132. Anderson KC, Landgren O, Arend RC, Chou J, Jacobs IA.
2017;104(10):869–74. Humanistic and economic impact of subcutaneous versus
119. Mateos MV, Nahi H, Legiec W. Efficacy and safety of the ran- intravenous administration of oncology biologics. Fut Oncol.
domized, open-label, non-inferiority, phase 3 study of subcu- 2019;15(28):3267–81.
taneous (SC) versus intravenous (IV) daratumumab (DARA) 133. Altini M, Gentili N, Balzi W, Musuraca G, Maltoni R, Masini
administration in patients (pts) with relapsed or refractory mul- C, et al. The challenge of sustainability in healthcare systems:
tiple myeloma (RRMM): COLUMBA. J Clin Oncol. 2019;37(15 economic and organizational impact of subcutaneous formula-
Suppl):Abstract 8005. tions for rituximab and trastuzumab in onco-hematology. Expert
120. Wynne C, Harvey V, Schwabe C, Waaka D, McIntyre C, Bittner Rev Pharmacoeconomics Outcomes Res. 2020:1–7.
B. Comparison of subcutaneous and intravenous administration 134. Wardley A, Canon JL, Elsten L, Pena Murillo C, Badovinac Crn-
of trastuzumab: a phase I/Ib trial in healthy male volunteers and jevic T, Fredriksson J, et al. Flexible care in breast cancer. ESMO
patients with HER2-positive breast cancer. J Clin Pharmacol. Open. 2021;6(1): 100007.
2013;53(2):192–201.
36 C. McCloskey et al.

Authors and Affiliations

Conor McCloskey1 · María Toboso Ortega2 · Sunita Nair3 · Maria João Garcia4 · Federico Manevy4

4
* Maria João Garcia Pharmaceuticals Division, Global Access‑Evidence
maria_joao.garcia@roche.com Chapter, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124,
4070 Basel, Switzerland
1
Clarivate, Bicester, UK
2
Clarivate, London, UK
3
Clarivate, Mumbai, India