FormalPara Key Points for Decision Makers

Most of the publications identified in this systematic review showed time/resource and cost savings associated with subcutaneous versus intravenous administration of anticancer biologics in a hospital setting.

This evidence can provide relevant inputs for economic evaluations of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO®, F. Hoffmann-La Roche Ltd; PH FDC SC)).

1 Introduction

Breast cancer (BC) is the most prevalent form of invasive cancer among women, with over 2.2 million cases and almost 700,000 deaths worldwide in 2020 [1, 2]. Approximately 20% of BC cases are human epidermal growth factor receptor 2 (HER2)-positive, a subtype defined by amplification of the HER2 oncogene and overexpression of the HER2 transmembrane receptor protein on the surface of tumor cells. HER2 interacts with other HER family proteins as part of signal transduction pathways, mediating cell growth, survival, and differentiation [3]. HER2-positive BC is associated with poor prognosis, arising from increased tumor aggressiveness, higher rates of recurrence, and increased mortality [3, 4].

Trastuzumab (Herceptin®, F. Hoffmann-La Roche Ltd, Basel, Switzerland), the first approved HER2-targeted monoclonal antibody, transformed the treatment and prognosis of patients with HER2-positive BC in both the early and the metastatic settings [5,6,7,8,9,10,11,12,13,14,15]. This has led to the development of dual anti-HER2 blockade with pertuzumab plus trastuzumab (PERJETA® and Herceptin®, F. Hoffmann-La Roche Ltd; standard of care in first-line HER2-positive metastatic BC (MBC) and high-risk early BC (EBC)) [13,14,15,16,17,18,19,20,21] and the anti-HER2 antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla®, F. Hoffmann-La Roche Ltd; used in second-line HER2-positive MBC and in EBC for the treatment of residual invasive disease following neoadjuvant therapy and surgery) [13,14,15,16, 22,23,24]. These treatment options have improved the prognosis for patients with HER2-positive BC substantially.

However, intravenous (IV) administration of anticancer biologics can present multiple challenges for many patients, including long infusion and observation times, the need for repeated, invasive IV access (sometimes over long periods of time in cases where there is evidence of a treatment response), and the potential risks associated with indwelling venous access (e.g., catheter-associated pain/discomfort, thrombosis, or risk of systemic infections) [25,26,27,28]. Moreover, the increasing use of IV administered agents in oncology has placed a strain on medical centers and healthcare professionals (HCPs) with respect to the time and resources required to prepare and administer infusions [25, 29].

A subcutaneous (SC) formulation has previously been developed for trastuzumab (Herceptin® SC or Herceptin HylectaTM, F. Hoffmann-La Roche Ltd) [11, 30]. The HannaH study (NCT00950300) compared the pharmacokinetics, efficacy, and safety of SC trastuzumab with IV trastuzumab. SC trastuzumab was shown to be non-inferior to IV, for both co-primary endpoints (serum trough concentration at pre-dose cycle 8 and pathologic complete response rates), demonstrating that the SC formulation is a valid treatment alternative to IV [31,32,33,34]. Further to this, the safety and efficacy profiles for SC trastuzumab in combination with IV pertuzumab and docetaxel as a first-line treatment for patients with HER2-positive MBC in the MetaPHER study (NCT02402712) was found to be consistent with those observed for IV trastuzumab in combination with IV pertuzumab and docetaxel in the CLEOPATRA study (NCT00567190) [21, 35,36,37,38].

The PrefHer study (NCT01401166), in which patients with EBC were randomized to receive four cycles of SC trastuzumab followed by four cycles of IV trastuzumab, or vice versa, demonstrated a strong patient preference and increased HCP satisfaction with SC over IV administration [39, 40]. These results were also confirmed in the metastatic setting in the MetaspHer study (NCT01810393) [41]. The approval of a fixed-dose combination of pertuzumab and trastuzumab for SC injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO®, F. Hoffmann-La Roche Ltd; PH FDC SC)) [42] presents an opportunity for an option that is preferred by patients and can potentially provide time-saving benefits to patients and HCPs versus IV administration, according to patient and HCP questionnaires in the PHranceSCa study (NCT03674112) [43].

This systematic literature review (SLR) was performed to identify evidence relating to differences in time/resource use and the resulting cost differences between SC and IV administration (but not differences in the drug costs themselves). The rationale for performing the SLR was as preliminary work that will ultimately inform economic modeling and associated health technology assessment of PH FDC SC. The most analogous evidence was likely to be data relating to the time/resource use and cost differences for SC versus IV administration of trastuzumab for the treatment of BC, or of rituximab (Rituxan® or MabThera®, F. Hoffmann-La Roche Ltd) for treatment of non-Hodgkin’s lymphoma (NHL)/follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Thus, the SLR initially sought to identify cost analyses as well as time-and-motion analyses for any indication where patients’ treatment requires IV or SC administration in a hospital setting, and was then restricted to oncology biologics.

2 Methods

A systematic search was conducted via the Ovid platform (Wolters Kluwer, Alphen aan den Rijn, Netherlands) on 9 April 2020 using a predefined search strategy within the Embase (1980–present), MEDLINE (1946–present), and EconLit (1961–present) electronic databases. The database search strings identified all relevant studies (full papers or abstracts from any conferences) indexed in Embase, and were modified for performing searches in MEDLINE and EconLit to account for differences in syntax and thesaurus headings. Searches included terms for free text and Medical Subject Heading (MeSH) terms. The search strategies used and details of any additional hand searches that were carried out to identify publications not captured in the electronic database search are provided in the Online Supplemental Material, Resource 1. Details on the study eligibility criteria are presented in Table 1.

Table 1 Eligibility criteria for the systematic literature review
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The SLR followed the standard Cochrane review methodology [44] and included double screenings by two independent reviewers. Relevant data from included publications were extracted by a reviewer and verified by a second independent reviewer; any disputes were resolved through discussion. The types of data to be collected were predefined and included: study country, study design, industry sponsor, inclusion/exclusion criteria, target population, study aims, data source, intervention, study limitations, and conclusions. Cost and time/resource use outcomes were also captured and stratified by disease and route of administration. Quality assessments of the studies in the included publications were conducted by a single analyst and verified by a second analyst or project lead. The quality of economic evidence reported in the included cost analysis publications were assessed using the 36-item checklist of the National Institute for Health and Care Excellence Single Technology Appraisal Specification for manufacturer/sponsor submission of evidence (January 2015), adapted from Drummond and Jefferson [45]. The methodologic limitations of publications reporting on time/resource use and costs were assessed based on a model described by Drummond et al. [46] and adapted to cost of illness by Molinier et al. [47].

3 Results

This search identified 2,740 records, of which 237 underwent full-text screening. Ninety-five publications were excluded during full-text screening, leaving 142 potentially eligible publications, a higher number than anticipated due to broad eligibility criteria. Prioritization was therefore given to publications of patients with a cancer diagnosis, 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 the revised eligibility criteria, resulting in 72 final included publications, relating to 71 unique studies. The PRISMA diagram is presented in Fig. 1.

Fig. 1
figure 1

PRISMA diagram: Study flow of included and excluded publications. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

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3.1 Characteristics of Included Studies

Table 2 summarizes the characteristics of all included studies. In total, 40 publications were identified that described the time/resource use and/or costs associated with SC versus IV trastuzumab administration for the treatment of HER2-positive BC. Of these, 22 publications [25, 48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68] (13 full papers [25, 51,52,53,54,55, 59, 62,63,64,65,66,67] and nine abstracts [48,49,50, 56,57,58, 61, 68]) reported time/resource use for administration of SC versus IV trastuzumab (Fig. 2). This included two publications related to PrefHer, a multinational study conducted in eight countries (Canada, France, Switzerland, Denmark, Italy, Russia, Spain, and Turkey), 18 publications that reported studies that were conducted in at least 12 individual European countries (the country was not stated in one of the publications) [48,49,50,51,52,53,54, 57,58,59,60,61, 63,64,65,66,67,68], one publication that reported a study in Hong Kong [56], and one that reported a study in New Zealand [62]. A total of 24 publications reported on the costs of SC versus IV trastuzumab administration. Of these, 19 reported data for at least 13 individual European countries (the country was not stated in one of the publications) [48,49,50,51, 53, 54, 57, 59,60,61, 63,64,65, 67]. The other five were in Canada, Chile, Singapore, Hong Kong, and New Zealand [56, 62, 69,70,71]. Budget impacts of introducing SC trastuzumab were reported by five publications (Arabia, Ecuador, Canada, Brazil, Spain) [69, 72,73,74,75]. Six other publications described costs related to SC trastuzumab: three compared SC trastuzumab with an IV trastuzumab biosimilar [76,77,78], two described cost minimization analyses for SC versus IV administration [79, 80], and one reported on cost savings for the administration of the SC route over 18 months compared with a combination of SC and IV [81].

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

Numbers of publications reporting time/resource use and costs for each agent/indication

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A total of 28 publications were identified that described time/resource use and/or costs associated with rituximab SC 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 were an additional seven publications that reported only on costs, to give 18 publications with cost-related analyses. The remaining three publications described the likely budget impact of introducing the rituximab SC formulation for the treatment of NHL or DLBCL, and provided limited evidence relating to the comparative costs of rituximab SC and administrations.

3.2 Quality Assessment Results

A quality assessment of all full publications was conducted. Overall, the studies were considered to be of adequate quality. However, due to the wide range of study designs and the paucity of studies reporting individual outcomes, it was not feasible to categorize the studies according to risk. Although the study designs of the economic evaluations were generally well described, reporting of data collection methods and of analysis and interpretation of the results was inconsistent between studies. For example, time horizons of costs and benefits, discount rates, and sensitivity analyses were only discussed in a small proportion of the publications.

3.3 Time/Resource Use With IV Versus SC Administration of Trastuzumab

Of the 22 publications reporting data regarding time required, or the difference in time required, for administration of SC versus IV trastuzumab for the treatment of BC, 16 reported data either from time-and-motion studies or studies where the time for each specific procedure was directly measured. Some reported single-center studies, while others reported studies involving up to 16 centers. Two publications reported studies that estimated time based on information provided by drug preparation/administration software [51, 68]; one publication reported a study that estimated time from a survey of HCPs [66], and three publications did not report the manner in which time was estimated [52, 56, 58].

HCP time includes drug preparation and administration times, and may be reported according to specific roles (e.g., pharmacists, nurses, nursing assistants), or as an average of the HCP times. Variation in the description of the elements involved in preparation and administration of trastuzumab may limit comparison between publications. For example, one time-and-motion study publication [63] described the measured time for each step involved in preparation and administration, including involvement of the pharmacist, staff nurse, and clinical nurse specialist, and then provided the average HCP time required for administration based on this. Another publication [53] only reported active HCP times for preparation and administration, obtained from detailed case reports and stopwatch time measurements for all nurse activities for a subgroup of observed cases.

3.3.1 Preparation Time

Preparation time for trastuzumab was reported in seven publications, including two where only the difference in preparation time between SC and IV was reported. Within these, preparation time was directly measured [25, 49, 53, 62] or estimated from software records [51, 68] or HCP questionnaires [66]. HCP estimates were consistent with publications from studies in which time was measured directly. Preparation of IV trastuzumab for administration was reported to require 14–21 min, compared with 0–11 min for SC trastuzumab. The time difference between SC and IV was 3–14 min per preparation [25, 49, 51, 53, 62, 66, 68]. An additional publication reported preparation time for the loading dose to be 8 versus 2 min, for IV and SC trastuzumab, respectively. Nursing time was reported as 16 versus 7 min, and was deemed likely to relate to preparation rather than administration of the dose, giving a total time of 24 versus 9 min [61].

3.3.2 Administration Time

Administration time for trastuzumab was reported in five publications, of which four directly measured time [49, 53, 54, 62]; one publication reported estimated time from drug delivery software [51], which was found to be consistent with the other four publications. Administration times of 90 and 30 min were reported for IV trastuzumab loading and subsequent doses, respectively, in two of the publications [51, 54]. A further two publications reported times of 38 and 97 min for IV trastuzumab administration [53, 62]. In contrast, the reported times for SC trastuzumab administration ranged from 5 to 10 min, with no difference between loading and subsequent doses. The differences in administration time between IV and SC were 80–85 (loading dose) and 20–25 min (subsequent doses) [51, 54], and 32–107 min in the three publications in which loading/subsequent doses were not specified [49, 53, 62]. Additionally, two publications reported time savings of 47 min [60] and 61 min [48] with SC trastuzumab, for combined preparation and administration times.

3.3.3 Active Healthcare Professional (HCP) Time

  • Active HCP time, and time savings with SC versus IV trastuzumab, were reported in nine publications and are shown in Fig. 3. Based on direct measurements, active HCP time was 13–92 min (IV) versus 7–30 min (SC); a difference of 6–62 min [50, 53, 59, 62,63,64,65, 67]. Two publications reported a longer administration time for the loading dose of IV trastuzumab (92 and 44 min); here, the time differences between the loading dose of IV and SC were 62 and 18 min [64, 65]. One publication reported only on the time difference (15 min) between IV and SC [57]. One other publication reported only the difference in HCP time (7 min), which was estimated based on drug preparation software [68]. One report of active HCP time included a range of 7–12 min (IV) versus 4–7 min (SC) [55]; however, it is unclear what was included within the time, and why the HCP times in this report were shorter than those of other publications. Active time differences were also reported for different HCPs and were all in favor of SC versus IV administration: differences in nursing times were 6.1 min [62] and 10.6 min [59]; pharmacist and nursing assistant time differences were 3.0 min and 0.3 min, respectively [59]; and one publication reported time savings of 0.18 full-time equivalents (FTE) and 0.14 FTE with SC for nurses and pharmacists, respectively [56].

Fig. 3
figure 3

HCP time as reported across included studies. HCP healthcare professional, IV intravenous, mins min, SC subcutaneous. Δ, difference in HCP time between IV and SC administration presented in min and as a percentage of total time

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3.3.4 Patient Chair/Infusion Time

Chair time, where defined, was described consistently as the period between entry and exit from the infusion chair; however, how the time was determined varied between publications, with some reporting studies that measured the time directly [25, 59, 62, 67] and others reporting studies that estimated time from chemotherapy prescription software and HCP interviews [57, 68]. Differences in chair time for trastuzumab administration were reported in 10 publications [25, 50, 52, 55, 57,58,59, 62, 67, 68], of which seven reported actual chair times and differences obtained through direct measurement; one publication estimated the chair time based on drug delivery software [68] and was consistent with the other seven publications. Chair time was 47–180 min (IV) versus 8–120 min (SC); the difference in time was 33–126 min (Fig. 4). One publication reported a sixfold decrease in chair time with SC administration [58], with another describing a 56% reduction [52]. The PrefHer time-and-motion study reported chair time differences from nine countries (Fig. 5), ranging from a difference of 47.1 min (Denmark) to 85.5 min (Spain) for administration with the single-use injection device and 40.3 min (Italy) to 80.6 min (Spain) for administration with a hand-held syringe [25]. Total time spent at the hospital was also reported, ranging from 3–7 h (IV) to 1–5 h (SC), with a difference of 1.5–2 h [59, 64, 67]. One publication reported the difference for subsequent doses (following the loading dose) to be lower (23-min difference: 90 min IV vs. 67 min SC) [64].

Fig. 4
figure 4

Patient chair time reported across included studies. IV intravenous, mins min, SC subcutaneous. Δ, difference in chair time between IV and SC administration presented in min and as a percentage of total time

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Fig. 5
figure 5

Source: De Cock et al 2016 [25]

Differences in chair time for IV and SC administration for countries included in the PrefHer time-and-motion study. HHS hand-held syringe, IV intravenous, SC subcutaneous, SID single-use injection device.

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3.4 Costs Associated with IV Versus SC Administration of Trastuzumab

Costs for IV versus SC administration of trastuzumab were gathered from 24 publications with sufficient level of detail to show how the costs were defined. Costs were reported per administration, per treatment course, per patient per year, or for a particular cohort. Of these 24 publications, 18 reported costs based on data from time-and-motion studies or studies in which the time for specific procedures was directly measured; one based estimates on information provided by drug preparation/administration software [51], one estimated time from a survey of HCPs [70], and four did not report how time was estimated [56, 69, 82, 83]. Twelve of the publications were full publications, with the other 12 being congress abstracts with limited detail (Fig. 2).

Thirteen publications covering ten countries reported total direct medical costs for IV versus SC administration [51, 53, 54, 59, 60, 63, 64, 69, 82,83,84,85,86], which included non-drug costs for preparation, administration, HCP time and consumables, and savings related to reduced drug wastage or administered dose. All but four publications [51, 69, 82, 83] indicated that time assessments were made directly. Cost savings for SC compared with IV administration were reported in all but one publication, which reported data from a study conducted in Italy that used time estimates from drug delivery software rather than direct time assessments [51]. In this publication, total costs were numerically greater for SC administration; however, the difference was not statistically significant and was likely related to differences in drug acquisition costs as preparation and day hospital costs were shown to be significantly lower for SC administration [51].

In seven of the publications, direct costs for SC administration were approximately 1.3–6% lower than those for IV administration. One publication from a Russian study reported a 12.6% decrease [83] and one from the UK reported a 2.8-fold decrease [85] in direct costs with SC versus IV administration. Twelve publications provided information on costs directly related to active HCP time, preparation and/or administration time, patients’ time, or chair time [50, 53, 54, 56, 59, 62,63,64,65, 67, 84, 85]. All reported reduced time-related costs with SC versus IV administration.

In the five publications reporting total costs including indirect costs, indirect costs were lower for patients who received SC versus IV trastuzumab [51, 59, 63, 64, 71]. SC administration costs were also lower for consumables [49, 53, 54, 57, 59, 61,62,63,64, 67], drug wastage [67], use of central venous access devices [86], overheads [87], nursing and pharmacy supplies [84], and avoiding catheter implantation surgeries [54] compared with administration costs for IV in all publications that reported such information. One publication reported non-drug costs for the first and for subsequent cycles of therapy; reported costs were higher for the first cycle of therapy for both SC and IV administration [65]. One publication reported the costs for management of adverse events, which were slightly higher for SC versus IV delivery (US$1574 vs. US$1715 for 18 cycles) [71].

In addition to the 24 publications reporting cost-related data, five further publications were identified that reported on the budget impact of introducing SC trastuzumab; all reported cost savings across varying time periods [69, 72,73,74,75].

3.5 Time/Resource Use with IV Versus SC Administration of Rituximab

Nineteen publications (seven full publications [52, 66, 88,89,90,91,92] and 12 abstracts [93,94,95,96,97,98,99,100,101,102,103,104]) reported data on time required, or differences in time required, for IV versus SC rituximab for the treatment of lymphoma (NHL/FL or DLBCL in most publications) (Fig. 2). Of these, 12 reported data from time-and-motion studies or studies in which the time for specific procedures was directly measured, two estimated time from a survey of HCPs [66, 93], and five did not report how time was estimated [52, 89, 101].

3.5.1 Preparation Time

Preparation time or pharmacist time per infusion of rituximab was reported in five publications and ranged from 4–40 min (IV) to 2–20 min (SC) [66, 88, 90, 91, 104]. One of these publications reported a study that collected relevant data using a survey [66]; however, data were consistent with those estimated from direct measurement. In all publications, preparation/pharmacist time was shorter for SC administration, with time savings of 5.6–21 min (in one publication there was a marginal difference of 0.3 min (4.0 vs. 3.7 min) [90]).

3.5.2 Active HCP Time

Differences in HCP time per infusion of rituximab were reported in five publications and directly measured [88, 90,91,92, 104]. HCP times were 17–35 min (IV) compared with 12–24 min (SC) in three publications, whereas two publications reported longer times of 144 and 223 min (IV) versus 111 and 49 min (SC). All five publications found that SC administration was associated with a time saving. A further publication reported annual savings of nurse time to be 22 days for a single center in Tunisia [93] and one reported a time saving of 3 h in the day-care unit per infusion [95].

3.5.3 Patient Chair/Infusion Time

Chair time/infusion time for rituximab was reported in ten publications [88, 89, 92, 94, 96, 98, 100,101,102,103] and one further publication reported the time for IV administration [97]. For four of these publications, the method of time assessment was not reported; the remaining publications used direct time measurements. Chair time/infusion time was considerably shorter for SC versus IV administration in all publications, ranging from 150–262 min (IV; one publication reported a time of 6 h and 12 min (372 min)) to 6–11 min (46 and 135 min in two publications) for SC administration. Time saved with SC administration ranged from 1 h 45 min to 3 h 26 min (a saving of 6 h in one publication with a particularly long time for IV administration). A 74% reduction in chair time with SC administration was reported in another publication [52], and annual time savings per center of 101 h [99] and 193.5 days (administration time estimated using a survey) [93] were also reported. Time spent in the treatment room was directly measured and ranged from 264–321 min (IV) to 70–105 min (SC). Time savings with SC administration were ~200 min [66, 88, 92, 97]. One publication reported a time saving of 17.5 h per eight-cycle course of treatment [104].

3.6 Costs Associated with IV Versus SC Administration of Rituximab

Costs for management of patients with NHL/FL or DLBCL receiving IV versus SC administration of rituximab were gathered from 18 publications. Of these, 11 reported costs based on direct assessment of HCP time, one estimated time from a survey of HCPs [93], and six did not report how time was estimated [100,101,102, 105,106,107]. Only three of the publications were full papers; the rest were congress abstracts (Fig. 2). Three simulation analysis study publications conducted in the USA report cost savings for SC versus IV administration incrementally according to patient body surface area [100,101,102], which is used to calculate the IV dose (the SC dose is fixed). One publication reporting costs for rituximab maintenance therapy for FL over 2 years [101] and one publication reporting costs of rituximab as part of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy (R-CHOP) for patients with NHL [102] reported higher cost savings for patients with higher body surface area (BSA). The other publication, which also reported costs of rituximab as part of R-CHOP therapy for NHL, reported the highest cost savings for patients in the highest and lowest BSA categories, respectively [100]. However, the reason for this discrepancy is unclear. Reductions in direct medical costs for SC versus IV administration were reported in all nine of the publications reporting European studies, all but one [107] of which estimated time savings based on direct measurements, and in four additional publications of studies from Tunisia (time savings estimated by HCP survey) [93], Thailand [94, 106], and Brazil [108]. In the European publications, non-drug-related cost savings included savings related to HCP time [53, 91, 92, 103], consumables [53, 91], and day-care unit costs [53, 95]. One of the publications from Thailand, which reported societal costs, reported a reduction in productivity loss with SC versus IV administration [94]. A further three congress abstracts describing the budget impact of introducing SC rituximab in Brazil, Saudi Arabia, and Canada were identified, all of which reported cost savings at 1, 2, 3, or 5 years [109,110,111].

3.7 Other Publications

In addition to the publications regarding trastuzumab and rituximab, eight other publications were identified that report relative time or cost information for IV versus SC administration (Table 2) [112,113,114,115,116,117,118,119]:

  • Three of four cost analysis publications were considered less relevant as they reported time and cost of supportive therapies (SC-administered denosumab vs. IV-administered zoledronic acid) rather than treatment with a targeted oncology drug [112, 114, 115]. The remaining cost analysis publication reported higher administration costs for the regimens containing SC bortezomib, daratumumab, and dexamethasone than for those containing daratumumab, lenalidomide, and dexamethasone (all IV) in patients with relapsed/refractory multiple myeloma from two Phase III clinical trials [116].

  • One publication from a randomized controlled trial at a single Chinese hospital reported significantly (p < 0.0001) lower direct costs per patient for high-dose SC interferon-alpha compared with continuous IV interleukin-2 administration in patients with malignant myeloma [113].

  • Three publications reported directly measured time assessments for various oncology therapies; all of these publications demonstrated reduced administration time for therapies administered by the SC route versus the IV route [117,118,119].

4 Discussion

4.1 Interpretation of Results

Global increases in yearly cancer rates have resulted in increased numbers of IV infusions of chemotherapies and anticancer biologics. This represents a growing burden for medical centers and HCPs, and has led to a shortage of chair time for patients with cancer. The substantially shorter administration times of therapies administered subcutaneously has the potential to offer several advantages over IV administration, including shorter treatment times, a reduction in healthcare resource use, increased convenience for patients, and greater patient preference [25, 39, 40, 120].

In this SLR, we identified 72 publications reporting on the time/resource use and/or costs associated with IV versus SC administration of oncology biologics in a hospital setting or on the budget impact of introducing an SC formulation. The majority of reported publications were of studies conducted in single countries or even single centers; all studies were published between 2012 and 2020.

Overall, the results were largely consistent in demonstrating the time savings associated with preparation and administration of SC therapies, across both oncology biologics and other supportive therapies. Moreover, reductions were seen in the HCP time and resource use (including non-drug consumables and drug wastage) required for SC versus IV therapy administration. Patient hospital time was also shorter with SC versus IV administration, and additional cost savings may be achieved at the society level due to a reduction in the loss of productivity and leisure time associated with patients attending the hospital for treatment. However, these improvements in patient productivity are likely to be greater in patients receiving maintenance therapy than those receiving SC-administered oncology biologics in combination with chemotherapy, due to the increased patient chair time required for chemotherapy administration. Cost savings due to reduced production and leisure time loss for SC versus IV trastuzumab across five Swedish oncology clinics were €78 and €62, respectively, for first-time patients and €10 and €6, respectively, for subsequent patients [64]. Similarly, a study conducted in six hospitals in the Netherlands reported lower societal costs (travel expenses and costs related to informal care and loss of productivity) for SC versus IV administration for both trastuzumab (cost saving of €22) and rituximab (cost saving of €28) [53].

There was some variation in times reported for IV and SC preparation and administration of trastuzumab, which may reflect differences in time estimate methodologies, definitions of time periods, and clinical practice/hospital setup between the different participating centers. Notably, the multinational PrefHer time-and-motion study reported time differences between countries [25], despite presumably using similar definitions for each time period across the different centers involved in the study. Similar variations were also seen with studies of rituximab [88]; however, a consistent trend in favor of SC administration was observed across all publications. During the COVID-19 pandemic, urgent cancer referrals and chemotherapy attendances declined by up to 84.3% and 63.4%, respectively, which might have resulted in increased mortality rates in patients with cancer and multimorbidity [121]. The time savings of SC administration have the potential to help increase throughput of patients now that cancer services have resumed. In addition to this, decreased hospital time for patients with cancer may help to reduce the risk of COVID-19 infection and the associated high probability of mortality in these patients [122].

As expected, there were also variations in costs for IV and SC administration between publications that could be compared based on use of the same currency. However, six European publications reported similar percentage savings in direct costs and most publications showed a trend for cost saving with SC versus IV administration of trastuzumab. Two of the rituximab publications that showed cost differences for the SC and IV formulations incrementally based on BSA reported that the largest cost savings occurred for patients with higher BSA.

The findings of this SLR are consistent with other published SLRs that have reported on the time, resource, and cost savings associated with SC administration versus IV, for both oncology and non-oncology biologics [123,124,125]. However, cost reductions associated with time savings for HCPs may be difficult to measure and achieve in clinical practice [126]. Therefore, methods of improving the transferability of time-related cost savings to the clinic should be investigated.

The purpose of this SLR was to ultimately inform economic modeling and associated health technology assessment of PH FDC SC. Recommendations for durations of post-administration surveillance for SC and IV trastuzumab are identical, with 6 h of observation recommended after the first dose and 2 h of observation for all subsequent doses [42, 127,128,129]. Within the context of this SLR, observation times for SC and IV cancel out (as they are the same). The efficacy and safety profiles of SC and IV trastuzumab were also assumed to be comparable in this study. However, real-world evidence suggests that target levels of trastuzumab may not be reached with the first SC administration in patients with a high body weight and, although cardiotoxicity risk does not appear to be increased in patients with low body weight, Phase III trials have reported higher rates of adverse events with SC vs. IV administration [130].

It is important to note that the focus of this SLR was on administration in the hospital setting only. However, similar to the benefits provided by other SC-administered oncology biologics [131,132,133], PH FDC SC is expected to offer advantages with regard to reduced time/resource utilization, improved patient quality of life, and the potential to be used in the future in a flexible care setting [43]. There is considerable evidence demonstrating that PH FDC SC is well suited to at-home administration by a HCP [134]. Providing at-home treatment requires planning, training, careful patient selection and technology to link patients, caregivers, and specialists in oncology clinics, as well as innovative methods for treatment delivery (e.g., mobile care units) [134]. A US expanded access study (NCT04395508) investigating at-home administration of PH FDC SC by a home health nursing provider is ongoing. This study focuses on patients with HER2-positive breast cancer previously treated with IV pertuzumab plus trastuzumab and chemotherapy and currently receiving or due to receive maintenance therapy with pertuzumab plus trastuzumab alone.

4.2 Strengths and Limitations

One strength of this SLR is that it identified studies with 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 studies conducted in the real-world setting suggests that the reported time and cost savings may be translated to SC versus IV oncology biologics administered during standard clinical practice. The publications included in this SLR also reported several different methodologies for time assessments; however, results from the two studies that reported time estimates from drug delivery software or based on HCP surveys were largely consistent with those from studies that used direct measurements from time-and-motion-type methodologies.

Although the majority of the trastuzumab and rituximab studies identified were performed in European countries, full-text publications were identified for studies conducted in Canada, Chile, China, New Zealand, and the USA, and abstracts identified for studies conducted in Ecuador, Hong Kong, Japan, Mexico, Panama, Singapore, Thailand, Tunisia, and Saudi Arabia. Despite the potentially limited generalizability of the conclusions due to country-specific differences in approaches to healthcare, the consistency of the evidence supporting SC-related time and cost savings compared with IV administration presented in this SLR suggest that the findings are likely to be applicable across different healthcare systems and countries.

Due to the large number of potentially relevant publications comparing SC with IV administration, the decision was made to focus the literature search on anticancer drugs. Although this pragmatic approach could lead to relevant data/insights being missed, the oncology publications included in this SLR can offer a chance of providing valuable insights into the impact of the route of administration on treatment costs.

The focus of this SLR was to identify potential time differences associated with SC versus IV administration, as well as differences in non-time-related cost elements such as non-drug consumables. As a result, the drug costs of the treatments being administered were not considered. However, it is important to acknowledge the need for decision makers to take a holistic approach to healthcare resource utilization, which accounts for both drug and non-drug costs, in order to ensure optimal management of resources.

In the future, more studies should address the economic benefits for different institutions of patients switching from IV to SC oncology biologics [54], rather than simply comparing different patient populations treated via either IV or SC administration. Furthermore, as the current economic assessments have mainly been performed in developed countries and there are concerns about the transferability of SC versus IV benefits to less developed countries [126], more studies should be conducted in regions such as Eastern Europe or Latin America to assess the applicability of our findings there.

5 Conclusion

This SLR indicates that there is a substantial body of evidence demonstrating oncology biologics administered by the SC route in a hospital setting to be associated with important time and resource use savings versus IV administration. The identified evidence provides valuable inputs for economic evaluations of PH FDC SC, or for other SC oncology treatments.