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Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer – An observational study prospectively recording resource utilization in a Swedish healthcare setting
The Breast 29 (2016) 140e146
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The Breast journal homepage: www.elsevier.com/brst
Original article
Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer e An observational study prospectively recording resource utilization in a Swedish healthcare setting Sara Olofsson a, b, *, Hanna Norrlid a, Eva Karlsson c, Ulla Wilking d, Gunnel Ragnarson Tennvall a a
IHE, The Swedish Institute for Health Economics, Box 2127, SE-220 20 Lund, Sweden Department of Clinical Sciences, Lund University, Sweden Department of Oncology, Skåne University Hospital, SE-221 85 Lund, Sweden d Karolinska Institutet, Department of Oncology-Pathology, Karolinska University Hospital Solna, Z1:00, SE-171 76 Stockholm, Sweden b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 April 2016 Received in revised form 4 July 2016 Accepted 7 July 2016
Introduction: Trastuzumab is part of the standard treatment for HER2-positive breast cancer. The aim of this study was to estimate the societal value of trastuzumab administered through subcutaneous (SC) injection compared to intravenous (IV) infusion. Methods: Female patients with HER2-positive breast cancer receiving SC or IV trastuzumab were consecutively enrolled from five Swedish oncology clinics from 2013 to 2015. Data on time and resource utilization was collected prospectively using patient and nurse questionnaires. Societal costs were calculated by multiplying the resource use by its corresponding unit price, including direct medical costs (pharmaceuticals, materials, nurse time, etc.), direct non-medical costs (transportation) and indirect costs (production loss, lost leisure time). Costs were reported separately for patients receiving trastuzumab for the first time and non-first time (“subsequent treatment”). Results: In total, 101 IV and 94 SC patients were included in the study. The societal costs were lower with SC administration. For subsequent treatments the cost difference was V117 (IV V2099; SC V1983), partly explained by a higher time consumption both for nurses (14 min) and patients (23 min) with IV administration. Four IV and 16 SC patients received trastuzumab for the first time and were analysed separately, resulting in a difference in societal costs of V897 per treatment. A majority of patients preferred SC to IV administration. Conclusion: SC administration resulted in both less direct medical costs and indirect costs, and was consequently less costly than IV administration from a societal perspective in a Swedish setting. © 2016 Elsevier Ltd. All rights reserved.
Keywords: HER2-positive breast cancer Trastuzumab Subcutaneous Intravenous Resource use Societal cost
Introduction There are approximately 8000 new cases of breast cancer in Sweden each year [1]. Out of these 15 to 25 percent comprise a subgroup with human epidermal growth factor receptor-2 (HER2)
Abbreviations: CPI, Consumer Price Index; HER2, Human Epidermal growth factor Receptor-2; IV, Intravenous; SC, Subcutaneous; SEK, Swedish Kronor; WTP, Willingness-to-Pay. * Corresponding author. E-mail addresses: [email protected] (S. Olofsson), [email protected] (H. Norrlid), eva.u. [email protected] (E. Karlsson), [email protected] (U. Wilking), [email protected] (G. Ragnarson Tennvall). http://dx.doi.org/10.1016/j.breast.2016.07.008 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
positive breast cancer [2] for which trastuzumab (Herceptin®) e a monoclonal antibody that interferes with the HER2 receptor and inhibits the growth of cancer cells e is part of the standard treatment. Trastuzumab was initially administered intravenously (IV) every three weeks for one year in patients with early breast cancer and until disease progression in patients with metastatic disease. An equally safe and effective subcutaneous (SC) trastuzumab formulation [3], administered via syringe, was approved in Europe in 2013 and has thereafter been implemented in Swedish healthcare. The SC formulation does not require drug preparation (fixed dose of 600 mg) and has a shorter administration time compared to IV therapy. Replacing IV infusion by SC injection might therefore
S. Olofsson et al. / The Breast 29 (2016) 140e146
reduce time and resources allocated to trastuzumab treatment for both the health care system as well as for patients and their family and friends. All of these gains are relevant in a health economic analysis, adopting a societal perspective, which stimulates and supports more cost effective allocation of health care resources. Previous research shows that the non-drug costs (i.e. the costs of administrating the drug) associated with intravenous infusions can be substantial [4,5]. The largest gain of switching to a SC route of administration can therefore not be expected to be found by comparing drug costs. In order to be able to calculate possible reductions in non-drug costs, there needs to be data collected for what resources are required during each route of administration. The objective of this study was to estimate the societal cost associated with IV and SC trastuzumab therapy among patients with HER2-positive breast cancer in a Swedish setting. Patients and methods Sites and study population Individual-based data on resource utilization associated with IV and SC trastuzumab treatment were collected through patient and nurse surveys. The study population consist of females, 18 years or older, diagnosed with early or advanced HER2-positive breast cancer and treated with IV or SC trastuzumab. Patients were consecutively enrolled from five Swedish oncology clinics; IV patients from April to November 2013 and SC patients between November 2013 and January 2015 (i.e. after SC trastuzumab had been introduced at the clinic). Patients included in the IV group were allowed to participate in the SC group after switching to SC treatment. The study was observational and the clinic and health care personal were responsible for deciding which treatment should be provided to the patient. All included patients signed an informed consent and the study received ethical approvals from the Ethical Board in Lund, Sweden (Dnr 2012/801, 2013/287 and 2013/647). Questionnaires and data collection The nurse and patient questionnaires were available in one IV and one SC version. The patient questionnaires included background questions (e.g. age, occupation), question about disease and treatment, transportation, opinion about trastuzumab treatment (asked about which treatment they would prefer after having been presented with the administration route of both SC and IV trastuzumab), and willingness-to-pay (WTP) for switching from IV to SC trastuzumab (WTP results are not reported in this paper). The patient questionnaires were pre-tested for comprehension and compliance on a small convenience sample. The nurse questionnaires included questions about the patient (e.g. arrival and departure time at the hospital and diagnosis) and about the time and resources allocated to trastuzumab treatment. The nurse questionnaires were constructed in collaboration with medical expertise. Data and statistical analysis All data and statistical analysis was performed using STATA 13.1 (StataCorp. 2013. Stata Statistical Software: Release 13. Collage Station, TX: StatCorp LP). Descriptive statistics is presented as mean or proportions. Differences were tested for statistical significance using t-tests. A pvalue <0.05 was considered statistically significant throughout the analysis.
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Cost calculations Direct medical costs refer to the cost of resources used to provide treatment, e.g. drugs, medical supplies, and nurse time. Direct nonmedical costs include the cost of transportation. Indirect costs represent the cost of patient and kin time lost to treatment, including both time off from work (production loss) and lost leisure time. These costs were calculated by multiplying the estimated resource use by its associated unit cost (Table 1). The drug cost of SC trastuzumab refers to the fixed dose of 600 mg while the IV dose is weight dependent. In this study, the average patient is assumed to weigh 72.3 kg (data from the breast cancer database RealQ-Breast; personal communication with the registry holder H Lindman, Department of Oncology, Uppsala University), corresponding to a dose of 578 mg per first time treatment and 434 mg per subsequent treatment. In terms of weight data, existing registry data was used instead of collecting individualbased data to limit the number of survey questions of sensitive nature. Nurse time refers to the time the nurse actively dedicates to the patient. The difference between start and stop time was used to calculate the time used for collecting trastuzumab at the pharmacy (IV only), initiation and start-up, injection (SC only), and termination, respectively. The number of controls was used to calculate
Table 1 Unit costs associated with trastuzumab administration (2015 V). Type of resource
Direct medical costs Pharmaceuticals Herceptin® (trastuzumab) IV, 150 mg SC, 600 mg Paracetamol, 1 tablet, 500 mg Heparin, 100 ml Sodium Chloride, 1000 ml Materials and supplies Fee for preparation of trastuzumab at hospital pharmacy Standard unit of material utilization before, during and after administration, IV/SC IV SC Nurse time, per minute Direct non-medical costs Transportation cost per kilometre Car Taxi/transportation service Public transportation Walking/biking Indirect costs Production loss, per houra Patient Kin Leisure time lost due to treatment, per hourb Patient Kin
Unit cost V
Source
678.37 1920.18 0.03 35.59 6.65
[21] [21] [21] [21] [21]
47.04
Correspondence with included sites
4.40
0.50
Assumption. Prices from [22] Assumption. Prices from [22] [6e8]
0.08 0.76 0.01 0.00
[9] [9] [9] Assumption
28.31 29.05
[6e8] [6e8]
14.08 14.45
[6e8] [6e8]
0.77
a Calculated using the human capital approach. Patient wage is based on the average wage for females aged 55e64 in Sweden while kin wage is based on hourly net wage on the total Swedish labour market in 2014 [7]. Wages are CPI adjusted (CPI, August 2014eAugust 2015) [8]. A payroll tax of 41% is added [6]. The unit cost of production loss assumes 250 yearly workdays a 8 h. b Lost leisure time was calculated as the net wage, based on the wage data used for production loss and assuming 30 percent income tax.
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monitoring time by assuming that the average control took 2 min. The unit cost of nurse time was based on wage statistics of nurses from Statistics Sweden [6e8]. No primary data on resource utilization associated with preparation of IV trastuzumab at the hospital pharmacy was collected. Instead, the unit cost was based on the average fee the sites were charged by the hospital pharmacies. Transportation cost was calculated based on the mode of transportation and the travel distance indicated in the patient questionnaires and was calculated for round trips. Unit costs of transportation was derived from standard units produced by the Swedish Transportation Administration (Trafikverket) [9]. Indirect costs translates into production loss and lost leisure time, calculated using the human capital approach [10]. The unit cost of production loss (gross income including payroll tax) of patients was based on average wage rates of women aged 55 to 64 in Sweden and the production loss of kin applied the average wage of the working population age 18e64 years in Sweden [7,8]. The value of lost leisure time is assumed to correspond to the net wage for both patients and their kin [11]. The reported time off work for both patients and kin was multiplied by the unit costs for production loss. The time allocated to treatment (both at the clinic and on transportation), but not reported as work absenteeism, was assumed to be lost leisure time. The difference between arrival and departure time for the patient at the hospital recorded in the nurse questionnaire was used to calculate the time the patient spent at the hospital. The time of transportation as stated in the patient questionnaire was used to calculate time spent on transportation. Accompanying kins' were assumed to spend as much time at the hospital and on transportation as the patient. All costs were calculated on an individual level and presented as sample means. Costs were originally collected in, and calculated using, Swedish kronor (SEK). They were adjusted to 2015 price level using
consumer price index (CPI) when needed [8]. For the purpose of this article all costs were translated to Euros (V1 ¼ SEK 9.37 [12]). It is reasonable to suspect differences in resource utilization between first time patients and patients who had received trastuzumab treatment before (subsequent patients) due to differences in time allocated to treatment, IV dose (8 mg/kg vs. 6 mg/kg) and recommendations on post administration monitoring. The result was therefore stratified by first and subsequent treatment occasions. Results A total of 101 HER2-positive female breast cancer patients were included in the IV cohort and 94 in the SC cohort (Table 2). The majority of patients in both cohorts were diagnosed with early breast cancer. A larger proportion in the SC group received trastuzumab for the first time (IV 4%, SC 17%, p ¼ 0.0013). About half of the SC patients had previous experience of IV infused trastuzumab, and 19 percent (n ¼ 18) had been enrolled in the IV group of this study. One case of complication/discomfort during treatment was reported among IV patients and 10 in SC patients (p ¼ 0.0025), but only one complication in the SC population required treatment. Time allocated to treatment The average nurse time was shorter for SC compared to IV trastuzumab treatment (Fig. 1). The time difference was 17 min for first time visits (p ¼ 0.0026), and 14 min for subsequent treatment occasions (p < 0.0001). The time spent on monitoring was similar for both therapies while nurses spent less time on initiation and termination with SC patients. An average IV patient allocated more time to treatment than the average SC patient (Fig. 2). The difference in time spent at the hospital was 101 min for first time visits (p ¼ 0.0499), and 23 min
Table 2 Characteristics of patients treated with IV or SC trastuzumab. Characteristics
IV
SC
Number of patients, n Mean age, years (SD) Diagnosis Early breast cancer Metastatic breast cancer No information Mean time since diagnosis, months (SD)a Mean time with trastuzumab treatment, months (SD)b First trastuzumab treatment, n (%) First SC trastuzumab treatment Experience of IV trastuzumab Enrolled in IV cohort Infusion port None -cath Port-a CVK PICC-line No information Concomitant IV infusion Employment status Employed Self-employed Retired Unemployed Sick leave No information/Other Complication/Discomfort
101 56.2 (10.1)
94 58.4 (10.6)
67% 33% 0% 34.6 (50.5) 16.9 (27.4) 4 (4%) e e e
76% 23% 1% 23.0 (42.0) 13.1 (31.3) 16 (17%) 50% 54% 19%
24% 71% 2% 3% e 33%
37% 45% e 16% 2% 41%
37% 4% 24% 2% 29% 5% 1%
39% 4% 31% e 23% 2% 11%
SD ¼ Standard Deviation. a IV n ¼ 92; SC n ¼ 87. b IV n ¼ 82; SC n ¼ 82. Assuming zero months of treatment for first time patients.
S. Olofsson et al. / The Breast 29 (2016) 140e146
143
for subsequent treatments (p ¼ 0.0033). About 35 percent of IV patients and 26 percent of SC patients was accompanied by a kin.
Work absenteeism and transportation More patients in the IV group had taken time off from work (IV 14%; SC 5%, p ¼ 0.0223). The average time off from work for subsequent patients were 33 min in the IV group and 12 min in the SC group. The corresponding time for the accompanying kin was 22 min in the IV group and 21 min in the SC group. The average trastuzumab patient spent 79 min per round trip to the hospital (both IV and SC).
Societal treatment costs
Fig. 1. Time (minutes) per treatment occasion spent by health care personnel on different administration tasks.
Fig. 2. Time (minutes) per treatment occasion that the patient spends at the hospital.
The resource utilization, per visit, of pharmaceuticals, health care resources and transportation to and from the hospital are presented in Table 3. The time allocated to trastuzumab treatment, both by patients and their kin, are presented in Table 4. These resources are the basis of the cost calculations in Table 5. The societal cost per first time treatment occasion is estimated to V2974 for IV infused trastuzumab (whereof V2616 are drug costs) and V2079 for SC injected treatment (whereof V1920 are drug costs), generating a cost decrease of V895 for SC trastuzumab per visit. The societal cost per subsequent treatment occasion is estimated to V2099 for IV infused trastuzumab (whereof V1962 are drug costs) and V1983 for SC injected trastuzumab (whereof V1920 are drug costs), resulting in a cost decrease of V117 per subsequent visit. Apart from the drug cost of trastuzumab, indirect costs (production loss and lost leisure time) is the major driver of the societal costs of trastuzumab treatment for both therapies (Fig. 3). When including drug waste associated with preparation of IV trastuzumab by rounding up the drug consumption to full drug packages, there was an additional cost reduction of V73 per subsequent SC treatment and V98 per first SC treatment (data not shown).
Table 3 Resource utilization of pharmaceuticals, health care resources and transportation to and from the hospital, per patient group and visit occasion. Type of resource
First time patients IV (n ¼ 4) Mean
Subsequent patients SC (n ¼ 16)
SD
Mean
Direct medical costs Pharmaceuticals Herceptin® (trastuzumab) IV, 150 mg 578 mga e e SC, 600 mg e e 600 mg Paracetamol, 1 tablet, 500 mg 500 mg e e Heparin, 100 ml 5 ml e e Sodium Chloride, 1000 ml 20 ml e e Materials and supplies Fee for preparation of trastuzumab at hospital pharmacy 1 e e Standard unit of material utilization before, during and after administration, IV/SC IV 1 e e SC e e 1 Nurse time, per minute 43.25 22.20 26.13 Direct non-medical costs Transportation e average kilometre travelled per transportation type and treatment occasion Car 35.64 (29.50) 35.64 Taxi/transportation service 1.01 (7.60) 1.01 Public transportation 5.59 (18.08) 5.59 Walking/biking 0.12 (0.79) 0.12 a
IV (n ¼ 97)
SC (n ¼ 78)
SD
Mean
SD
Mean
SD
e e e e e
434 mga e 500 mg 5 ml 20 ml
e e e e e
e 600 mg e e e
e e e e e
e
1
e
e
e
e e 10.18
1 e 30.03
e e 21.82
e 1 16.44
e 12.96
(29.50) (7.60) (18.08) (0.79)
35.64 1.01 5.59 0.12
(29.50) (7.60) (18.08) (0.79)
35.64 1.01 5.59 0.12
(29.50) (7.60) (18.08) (0.79)
Assuming an average patient weight of 72.3 kg and a dose for the first treatment occassion of 8 mg/kg and a dose for the subsequent treatment occassion of 6 mg/kg.
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S. Olofsson et al. / The Breast 29 (2016) 140e146
Table 4 Patient and kin time allocated to trastuzumab treatment, per patient group and visit occasion. Time slot
First time patients
Subsequent patients
IV (n ¼ 4)
Patient time, in minutes At clinic Travelling to and from hospital Total time, patienta Patients production loss, in hours Lost leisure time of patients, in hoursb Proportion of patients assisted/accompanied by a kin Total time, in minutes, kinc Production loss, kin Lost leisure time, kind
SC (n ¼ 16)
IV (n ¼ 97)
SC (n ¼ 78)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
413.75 78.97 492.72 0 8.21 100% 492.72 3.25 4.96
40.08 55.54
313.21 78.97 392.19 0 6.54 44% 171.58 0.56 2.30
110.92 55.54
90.04 78.97 169.02 0.55 2.27 32% 54.57 0.37 0.54
55.62 55.54
66.66 78.97 145.63 0.20 2.23 22% 32.58 0.35 0.19
52.40 55.54
e
2.22
e
1.55
1.63
1.55
0.99
1.33
a
The sum of the mean time spent at the hospital and the mean time spent travelling to and from the hospital. The mean leisure time lost by patients was calculated as the total patient minutes allocated to trastuzumab treatment (translated into hours) minus the average patient's production loss. c Kins that accompany patients were assumed to allocate the same amount of time to both being at the hospital and travelling, as the patient. The total kin time, for the average patient, was thus calculated by multiplying the total patient time with the proportion of patients that were accompanied by a kin. d Lost leisure time of kins were set to the difference between total kin time and the reported production loss of kins. b
Table 5 Societal costs of IV and SC trastuzumab treatment (2015 V). Cost category
Direct medical cost Trastuzumab Materials and supplies, including premedication Nurse time Direct non medical costs Transportationa Indirect costs Production lossb Lost leisure timeb Total a b
First time patients
Subsequent patients
IV (n ¼ 4)
SC (n ¼ 16)
Difference
IV (n ¼ 97)
SC (n ¼ 78)
Difference
2616 53 22
1920 1 13
1962 53 15
1920 1 8
42 52 7
4
4
4
4
0
94 187 2976
16 125 2079
696 52 9 0 0 0 78 62 897
26 40 2099
16 34 1983
10 6 117
Cost of transportation to and from the hospital. For both patients and their accompanying kin.
Patient opinion SC injection was the preferred therapy in both treatment groups (Fig. 4), although more so among SC patients (p < 0.0001). The hospital was the preferred treatment location for both IV infused and SC injected trastuzumab among IV as well as SC patients (Table 6). A minority of patients in both groups (IV: 7%; SC: 5%) indicated (i.e. agreed with a pre-defined statement) that it took too long to receive treatment, about one fifth (IV: 19%; SC: 23%) indicated that it was burdensome to go to the hospital, about four percent of IV patients and 16 percent of SC patients indicated a feeling of unease/discomfort during trastuzumab administration (p ¼ 0.0023) and a majority in both groups (IV: 79%; SC: 73%)
Fig. 3. Cost per treatment occasion, excluding the cost of trastuzumab.
Fig. 4. Patient preferences for SC injected or IV infused trastuzumab, when asked what they would prefer if given the choice (after presentation of both administration routes).
S. Olofsson et al. / The Breast 29 (2016) 140e146 Table 6 Patients' preferences for treatment location, by treatment group. Preferences
IV (n ¼ 101)
SC (n ¼ 94)
If the Herceptin (trastuzumab) is administered via an IV infusion, where would you prefer to get the infusion? At the hospital 64% 68% In primary care 25% 17% At home, by nurse 9% 6% No information 2% 9% If the Herceptin (trastuzumab) is administered via a SC injection, where would you prefer to get the injection? At the hospital 34% 49% In primary care 33% 26% At home, by nurse 5% 5% At home, by myself or kin 25% 19% No information 4% 1%
145
overall costs when compared to IV trastuzumab [20], which is confirmed in the present study. An additional benefit of SC trastuzumab is that it is delivered ready for use which allows a more flexible treatment adaptable to the patient's needs, e.g. work schedule. Conclusions This study found that SC administration result in a cost reduction and imply that it could induce increased capacity within existing health care budgets. In addition, a majority of Swedish HER2-positive breast cancer patients preferred SC over IV administration. Conflict of interest statement
indicated that they found it important to be able to interact with healthcare personal during treatment. Discussion This study analyses the societal value of the previous standard IV compared to SC trastuzumab treatment by estimating and comparing the societal cost associated with both treatment alternatives. The results show that SC compared to IV trastuzumab saves both nurse and patient time and results in a cost savings for both first and subsequent treatment occasions. More cases of complications/discomfort during treatment was found among SC patients, in line with previous research [3,13,14], where a difference in the overall adverse event rates, driven by more minor events (grade 1), was detected. A majority of patients preferred SC injected trastuzumab if given the option, and the preference was stronger among SC patients. This is in line with a previously established reluctance towards unknown treatments [15]. Several studies have examined patient preferences of methods and routes of drug delivery showing that 89 to 92 percent of patients prefer SC to IV trastuzumab [14,16]. Similar results have been found when given the choice between infusions and injections within other diagnostic fields [17,18]. Cost estimates of production loss associated with trastuzumab treatment should be interpreted with caution since few patients indicated work absenteeism. Also note that analyses of first time patients are based on a limited number of observations. In addition, the lack of primary data on resource utilization associated with preparation of IV trastuzumab at a pharmacy as well as of individual patients' weight might be a limitation of the present study. This study include an estimation of leisure time lost which is valued according to the average net wage. This is a rather common procedure which have some theoretical support [11]. However, since leisure time lack an explicit market price there is a lack of consensus regarding its valuation. The true amount of drug waste was not measured in this analysis, but was assumed to correspond to a dose increase of four percent. An Australian study examining the use of IV trastuzumab in clinical practice found that drug waste was up to 24% [19]. Drug wastage may however be limited through designated days where the oncology clinic gathers multiple trastuzumab patients for parallel treatment sessions. Replacing IV trastuzumab by SC trastuzumab may reduce the need to insert permanent venous catheters, and this study show that the share of patients with a permanent venous catheter was lower among SC patients. Potential savings due to a reduced use of permanent venous catheters was not included in the analysis. A previous UK study found that SC trastuzumab substantially reduced patient time, active nurse time, material consumption and
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Original article
Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer e An observational study prospectively recording resource utilization in a Swedish healthcare setting Sara Olofsson a, b, *, Hanna Norrlid a, Eva Karlsson c, Ulla Wilking d, Gunnel Ragnarson Tennvall a a
IHE, The Swedish Institute for Health Economics, Box 2127, SE-220 20 Lund, Sweden Department of Clinical Sciences, Lund University, Sweden Department of Oncology, Skåne University Hospital, SE-221 85 Lund, Sweden d Karolinska Institutet, Department of Oncology-Pathology, Karolinska University Hospital Solna, Z1:00, SE-171 76 Stockholm, Sweden b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 April 2016 Received in revised form 4 July 2016 Accepted 7 July 2016
Introduction: Trastuzumab is part of the standard treatment for HER2-positive breast cancer. The aim of this study was to estimate the societal value of trastuzumab administered through subcutaneous (SC) injection compared to intravenous (IV) infusion. Methods: Female patients with HER2-positive breast cancer receiving SC or IV trastuzumab were consecutively enrolled from five Swedish oncology clinics from 2013 to 2015. Data on time and resource utilization was collected prospectively using patient and nurse questionnaires. Societal costs were calculated by multiplying the resource use by its corresponding unit price, including direct medical costs (pharmaceuticals, materials, nurse time, etc.), direct non-medical costs (transportation) and indirect costs (production loss, lost leisure time). Costs were reported separately for patients receiving trastuzumab for the first time and non-first time (“subsequent treatment”). Results: In total, 101 IV and 94 SC patients were included in the study. The societal costs were lower with SC administration. For subsequent treatments the cost difference was V117 (IV V2099; SC V1983), partly explained by a higher time consumption both for nurses (14 min) and patients (23 min) with IV administration. Four IV and 16 SC patients received trastuzumab for the first time and were analysed separately, resulting in a difference in societal costs of V897 per treatment. A majority of patients preferred SC to IV administration. Conclusion: SC administration resulted in both less direct medical costs and indirect costs, and was consequently less costly than IV administration from a societal perspective in a Swedish setting. © 2016 Elsevier Ltd. All rights reserved.
Keywords: HER2-positive breast cancer Trastuzumab Subcutaneous Intravenous Resource use Societal cost
Introduction There are approximately 8000 new cases of breast cancer in Sweden each year [1]. Out of these 15 to 25 percent comprise a subgroup with human epidermal growth factor receptor-2 (HER2)
Abbreviations: CPI, Consumer Price Index; HER2, Human Epidermal growth factor Receptor-2; IV, Intravenous; SC, Subcutaneous; SEK, Swedish Kronor; WTP, Willingness-to-Pay. * Corresponding author. E-mail addresses: [email protected] (S. Olofsson), [email protected] (H. Norrlid), eva.u. [email protected] (E. Karlsson), [email protected] (U. Wilking), [email protected] (G. Ragnarson Tennvall). http://dx.doi.org/10.1016/j.breast.2016.07.008 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
positive breast cancer [2] for which trastuzumab (Herceptin®) e a monoclonal antibody that interferes with the HER2 receptor and inhibits the growth of cancer cells e is part of the standard treatment. Trastuzumab was initially administered intravenously (IV) every three weeks for one year in patients with early breast cancer and until disease progression in patients with metastatic disease. An equally safe and effective subcutaneous (SC) trastuzumab formulation [3], administered via syringe, was approved in Europe in 2013 and has thereafter been implemented in Swedish healthcare. The SC formulation does not require drug preparation (fixed dose of 600 mg) and has a shorter administration time compared to IV therapy. Replacing IV infusion by SC injection might therefore
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reduce time and resources allocated to trastuzumab treatment for both the health care system as well as for patients and their family and friends. All of these gains are relevant in a health economic analysis, adopting a societal perspective, which stimulates and supports more cost effective allocation of health care resources. Previous research shows that the non-drug costs (i.e. the costs of administrating the drug) associated with intravenous infusions can be substantial [4,5]. The largest gain of switching to a SC route of administration can therefore not be expected to be found by comparing drug costs. In order to be able to calculate possible reductions in non-drug costs, there needs to be data collected for what resources are required during each route of administration. The objective of this study was to estimate the societal cost associated with IV and SC trastuzumab therapy among patients with HER2-positive breast cancer in a Swedish setting. Patients and methods Sites and study population Individual-based data on resource utilization associated with IV and SC trastuzumab treatment were collected through patient and nurse surveys. The study population consist of females, 18 years or older, diagnosed with early or advanced HER2-positive breast cancer and treated with IV or SC trastuzumab. Patients were consecutively enrolled from five Swedish oncology clinics; IV patients from April to November 2013 and SC patients between November 2013 and January 2015 (i.e. after SC trastuzumab had been introduced at the clinic). Patients included in the IV group were allowed to participate in the SC group after switching to SC treatment. The study was observational and the clinic and health care personal were responsible for deciding which treatment should be provided to the patient. All included patients signed an informed consent and the study received ethical approvals from the Ethical Board in Lund, Sweden (Dnr 2012/801, 2013/287 and 2013/647). Questionnaires and data collection The nurse and patient questionnaires were available in one IV and one SC version. The patient questionnaires included background questions (e.g. age, occupation), question about disease and treatment, transportation, opinion about trastuzumab treatment (asked about which treatment they would prefer after having been presented with the administration route of both SC and IV trastuzumab), and willingness-to-pay (WTP) for switching from IV to SC trastuzumab (WTP results are not reported in this paper). The patient questionnaires were pre-tested for comprehension and compliance on a small convenience sample. The nurse questionnaires included questions about the patient (e.g. arrival and departure time at the hospital and diagnosis) and about the time and resources allocated to trastuzumab treatment. The nurse questionnaires were constructed in collaboration with medical expertise. Data and statistical analysis All data and statistical analysis was performed using STATA 13.1 (StataCorp. 2013. Stata Statistical Software: Release 13. Collage Station, TX: StatCorp LP). Descriptive statistics is presented as mean or proportions. Differences were tested for statistical significance using t-tests. A pvalue <0.05 was considered statistically significant throughout the analysis.
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Cost calculations Direct medical costs refer to the cost of resources used to provide treatment, e.g. drugs, medical supplies, and nurse time. Direct nonmedical costs include the cost of transportation. Indirect costs represent the cost of patient and kin time lost to treatment, including both time off from work (production loss) and lost leisure time. These costs were calculated by multiplying the estimated resource use by its associated unit cost (Table 1). The drug cost of SC trastuzumab refers to the fixed dose of 600 mg while the IV dose is weight dependent. In this study, the average patient is assumed to weigh 72.3 kg (data from the breast cancer database RealQ-Breast; personal communication with the registry holder H Lindman, Department of Oncology, Uppsala University), corresponding to a dose of 578 mg per first time treatment and 434 mg per subsequent treatment. In terms of weight data, existing registry data was used instead of collecting individualbased data to limit the number of survey questions of sensitive nature. Nurse time refers to the time the nurse actively dedicates to the patient. The difference between start and stop time was used to calculate the time used for collecting trastuzumab at the pharmacy (IV only), initiation and start-up, injection (SC only), and termination, respectively. The number of controls was used to calculate
Table 1 Unit costs associated with trastuzumab administration (2015 V). Type of resource
Direct medical costs Pharmaceuticals Herceptin® (trastuzumab) IV, 150 mg SC, 600 mg Paracetamol, 1 tablet, 500 mg Heparin, 100 ml Sodium Chloride, 1000 ml Materials and supplies Fee for preparation of trastuzumab at hospital pharmacy Standard unit of material utilization before, during and after administration, IV/SC IV SC Nurse time, per minute Direct non-medical costs Transportation cost per kilometre Car Taxi/transportation service Public transportation Walking/biking Indirect costs Production loss, per houra Patient Kin Leisure time lost due to treatment, per hourb Patient Kin
Unit cost V
Source
678.37 1920.18 0.03 35.59 6.65
[21] [21] [21] [21] [21]
47.04
Correspondence with included sites
4.40
0.50
Assumption. Prices from [22] Assumption. Prices from [22] [6e8]
0.08 0.76 0.01 0.00
[9] [9] [9] Assumption
28.31 29.05
[6e8] [6e8]
14.08 14.45
[6e8] [6e8]
0.77
a Calculated using the human capital approach. Patient wage is based on the average wage for females aged 55e64 in Sweden while kin wage is based on hourly net wage on the total Swedish labour market in 2014 [7]. Wages are CPI adjusted (CPI, August 2014eAugust 2015) [8]. A payroll tax of 41% is added [6]. The unit cost of production loss assumes 250 yearly workdays a 8 h. b Lost leisure time was calculated as the net wage, based on the wage data used for production loss and assuming 30 percent income tax.
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monitoring time by assuming that the average control took 2 min. The unit cost of nurse time was based on wage statistics of nurses from Statistics Sweden [6e8]. No primary data on resource utilization associated with preparation of IV trastuzumab at the hospital pharmacy was collected. Instead, the unit cost was based on the average fee the sites were charged by the hospital pharmacies. Transportation cost was calculated based on the mode of transportation and the travel distance indicated in the patient questionnaires and was calculated for round trips. Unit costs of transportation was derived from standard units produced by the Swedish Transportation Administration (Trafikverket) [9]. Indirect costs translates into production loss and lost leisure time, calculated using the human capital approach [10]. The unit cost of production loss (gross income including payroll tax) of patients was based on average wage rates of women aged 55 to 64 in Sweden and the production loss of kin applied the average wage of the working population age 18e64 years in Sweden [7,8]. The value of lost leisure time is assumed to correspond to the net wage for both patients and their kin [11]. The reported time off work for both patients and kin was multiplied by the unit costs for production loss. The time allocated to treatment (both at the clinic and on transportation), but not reported as work absenteeism, was assumed to be lost leisure time. The difference between arrival and departure time for the patient at the hospital recorded in the nurse questionnaire was used to calculate the time the patient spent at the hospital. The time of transportation as stated in the patient questionnaire was used to calculate time spent on transportation. Accompanying kins' were assumed to spend as much time at the hospital and on transportation as the patient. All costs were calculated on an individual level and presented as sample means. Costs were originally collected in, and calculated using, Swedish kronor (SEK). They were adjusted to 2015 price level using
consumer price index (CPI) when needed [8]. For the purpose of this article all costs were translated to Euros (V1 ¼ SEK 9.37 [12]). It is reasonable to suspect differences in resource utilization between first time patients and patients who had received trastuzumab treatment before (subsequent patients) due to differences in time allocated to treatment, IV dose (8 mg/kg vs. 6 mg/kg) and recommendations on post administration monitoring. The result was therefore stratified by first and subsequent treatment occasions. Results A total of 101 HER2-positive female breast cancer patients were included in the IV cohort and 94 in the SC cohort (Table 2). The majority of patients in both cohorts were diagnosed with early breast cancer. A larger proportion in the SC group received trastuzumab for the first time (IV 4%, SC 17%, p ¼ 0.0013). About half of the SC patients had previous experience of IV infused trastuzumab, and 19 percent (n ¼ 18) had been enrolled in the IV group of this study. One case of complication/discomfort during treatment was reported among IV patients and 10 in SC patients (p ¼ 0.0025), but only one complication in the SC population required treatment. Time allocated to treatment The average nurse time was shorter for SC compared to IV trastuzumab treatment (Fig. 1). The time difference was 17 min for first time visits (p ¼ 0.0026), and 14 min for subsequent treatment occasions (p < 0.0001). The time spent on monitoring was similar for both therapies while nurses spent less time on initiation and termination with SC patients. An average IV patient allocated more time to treatment than the average SC patient (Fig. 2). The difference in time spent at the hospital was 101 min for first time visits (p ¼ 0.0499), and 23 min
Table 2 Characteristics of patients treated with IV or SC trastuzumab. Characteristics
IV
SC
Number of patients, n Mean age, years (SD) Diagnosis Early breast cancer Metastatic breast cancer No information Mean time since diagnosis, months (SD)a Mean time with trastuzumab treatment, months (SD)b First trastuzumab treatment, n (%) First SC trastuzumab treatment Experience of IV trastuzumab Enrolled in IV cohort Infusion port None -cath Port-a CVK PICC-line No information Concomitant IV infusion Employment status Employed Self-employed Retired Unemployed Sick leave No information/Other Complication/Discomfort
101 56.2 (10.1)
94 58.4 (10.6)
67% 33% 0% 34.6 (50.5) 16.9 (27.4) 4 (4%) e e e
76% 23% 1% 23.0 (42.0) 13.1 (31.3) 16 (17%) 50% 54% 19%
24% 71% 2% 3% e 33%
37% 45% e 16% 2% 41%
37% 4% 24% 2% 29% 5% 1%
39% 4% 31% e 23% 2% 11%
SD ¼ Standard Deviation. a IV n ¼ 92; SC n ¼ 87. b IV n ¼ 82; SC n ¼ 82. Assuming zero months of treatment for first time patients.
S. Olofsson et al. / The Breast 29 (2016) 140e146
143
for subsequent treatments (p ¼ 0.0033). About 35 percent of IV patients and 26 percent of SC patients was accompanied by a kin.
Work absenteeism and transportation More patients in the IV group had taken time off from work (IV 14%; SC 5%, p ¼ 0.0223). The average time off from work for subsequent patients were 33 min in the IV group and 12 min in the SC group. The corresponding time for the accompanying kin was 22 min in the IV group and 21 min in the SC group. The average trastuzumab patient spent 79 min per round trip to the hospital (both IV and SC).
Societal treatment costs
Fig. 1. Time (minutes) per treatment occasion spent by health care personnel on different administration tasks.
Fig. 2. Time (minutes) per treatment occasion that the patient spends at the hospital.
The resource utilization, per visit, of pharmaceuticals, health care resources and transportation to and from the hospital are presented in Table 3. The time allocated to trastuzumab treatment, both by patients and their kin, are presented in Table 4. These resources are the basis of the cost calculations in Table 5. The societal cost per first time treatment occasion is estimated to V2974 for IV infused trastuzumab (whereof V2616 are drug costs) and V2079 for SC injected treatment (whereof V1920 are drug costs), generating a cost decrease of V895 for SC trastuzumab per visit. The societal cost per subsequent treatment occasion is estimated to V2099 for IV infused trastuzumab (whereof V1962 are drug costs) and V1983 for SC injected trastuzumab (whereof V1920 are drug costs), resulting in a cost decrease of V117 per subsequent visit. Apart from the drug cost of trastuzumab, indirect costs (production loss and lost leisure time) is the major driver of the societal costs of trastuzumab treatment for both therapies (Fig. 3). When including drug waste associated with preparation of IV trastuzumab by rounding up the drug consumption to full drug packages, there was an additional cost reduction of V73 per subsequent SC treatment and V98 per first SC treatment (data not shown).
Table 3 Resource utilization of pharmaceuticals, health care resources and transportation to and from the hospital, per patient group and visit occasion. Type of resource
First time patients IV (n ¼ 4) Mean
Subsequent patients SC (n ¼ 16)
SD
Mean
Direct medical costs Pharmaceuticals Herceptin® (trastuzumab) IV, 150 mg 578 mga e e SC, 600 mg e e 600 mg Paracetamol, 1 tablet, 500 mg 500 mg e e Heparin, 100 ml 5 ml e e Sodium Chloride, 1000 ml 20 ml e e Materials and supplies Fee for preparation of trastuzumab at hospital pharmacy 1 e e Standard unit of material utilization before, during and after administration, IV/SC IV 1 e e SC e e 1 Nurse time, per minute 43.25 22.20 26.13 Direct non-medical costs Transportation e average kilometre travelled per transportation type and treatment occasion Car 35.64 (29.50) 35.64 Taxi/transportation service 1.01 (7.60) 1.01 Public transportation 5.59 (18.08) 5.59 Walking/biking 0.12 (0.79) 0.12 a
IV (n ¼ 97)
SC (n ¼ 78)
SD
Mean
SD
Mean
SD
e e e e e
434 mga e 500 mg 5 ml 20 ml
e e e e e
e 600 mg e e e
e e e e e
e
1
e
e
e
e e 10.18
1 e 30.03
e e 21.82
e 1 16.44
e 12.96
(29.50) (7.60) (18.08) (0.79)
35.64 1.01 5.59 0.12
(29.50) (7.60) (18.08) (0.79)
35.64 1.01 5.59 0.12
(29.50) (7.60) (18.08) (0.79)
Assuming an average patient weight of 72.3 kg and a dose for the first treatment occassion of 8 mg/kg and a dose for the subsequent treatment occassion of 6 mg/kg.
144
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Table 4 Patient and kin time allocated to trastuzumab treatment, per patient group and visit occasion. Time slot
First time patients
Subsequent patients
IV (n ¼ 4)
Patient time, in minutes At clinic Travelling to and from hospital Total time, patienta Patients production loss, in hours Lost leisure time of patients, in hoursb Proportion of patients assisted/accompanied by a kin Total time, in minutes, kinc Production loss, kin Lost leisure time, kind
SC (n ¼ 16)
IV (n ¼ 97)
SC (n ¼ 78)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
413.75 78.97 492.72 0 8.21 100% 492.72 3.25 4.96
40.08 55.54
313.21 78.97 392.19 0 6.54 44% 171.58 0.56 2.30
110.92 55.54
90.04 78.97 169.02 0.55 2.27 32% 54.57 0.37 0.54
55.62 55.54
66.66 78.97 145.63 0.20 2.23 22% 32.58 0.35 0.19
52.40 55.54
e
2.22
e
1.55
1.63
1.55
0.99
1.33
a
The sum of the mean time spent at the hospital and the mean time spent travelling to and from the hospital. The mean leisure time lost by patients was calculated as the total patient minutes allocated to trastuzumab treatment (translated into hours) minus the average patient's production loss. c Kins that accompany patients were assumed to allocate the same amount of time to both being at the hospital and travelling, as the patient. The total kin time, for the average patient, was thus calculated by multiplying the total patient time with the proportion of patients that were accompanied by a kin. d Lost leisure time of kins were set to the difference between total kin time and the reported production loss of kins. b
Table 5 Societal costs of IV and SC trastuzumab treatment (2015 V). Cost category
Direct medical cost Trastuzumab Materials and supplies, including premedication Nurse time Direct non medical costs Transportationa Indirect costs Production lossb Lost leisure timeb Total a b
First time patients
Subsequent patients
IV (n ¼ 4)
SC (n ¼ 16)
Difference
IV (n ¼ 97)
SC (n ¼ 78)
Difference
2616 53 22
1920 1 13
1962 53 15
1920 1 8
42 52 7
4
4
4
4
0
94 187 2976
16 125 2079
696 52 9 0 0 0 78 62 897
26 40 2099
16 34 1983
10 6 117
Cost of transportation to and from the hospital. For both patients and their accompanying kin.
Patient opinion SC injection was the preferred therapy in both treatment groups (Fig. 4), although more so among SC patients (p < 0.0001). The hospital was the preferred treatment location for both IV infused and SC injected trastuzumab among IV as well as SC patients (Table 6). A minority of patients in both groups (IV: 7%; SC: 5%) indicated (i.e. agreed with a pre-defined statement) that it took too long to receive treatment, about one fifth (IV: 19%; SC: 23%) indicated that it was burdensome to go to the hospital, about four percent of IV patients and 16 percent of SC patients indicated a feeling of unease/discomfort during trastuzumab administration (p ¼ 0.0023) and a majority in both groups (IV: 79%; SC: 73%)
Fig. 3. Cost per treatment occasion, excluding the cost of trastuzumab.
Fig. 4. Patient preferences for SC injected or IV infused trastuzumab, when asked what they would prefer if given the choice (after presentation of both administration routes).
S. Olofsson et al. / The Breast 29 (2016) 140e146 Table 6 Patients' preferences for treatment location, by treatment group. Preferences
IV (n ¼ 101)
SC (n ¼ 94)
If the Herceptin (trastuzumab) is administered via an IV infusion, where would you prefer to get the infusion? At the hospital 64% 68% In primary care 25% 17% At home, by nurse 9% 6% No information 2% 9% If the Herceptin (trastuzumab) is administered via a SC injection, where would you prefer to get the injection? At the hospital 34% 49% In primary care 33% 26% At home, by nurse 5% 5% At home, by myself or kin 25% 19% No information 4% 1%
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overall costs when compared to IV trastuzumab [20], which is confirmed in the present study. An additional benefit of SC trastuzumab is that it is delivered ready for use which allows a more flexible treatment adaptable to the patient's needs, e.g. work schedule. Conclusions This study found that SC administration result in a cost reduction and imply that it could induce increased capacity within existing health care budgets. In addition, a majority of Swedish HER2-positive breast cancer patients preferred SC over IV administration. Conflict of interest statement
indicated that they found it important to be able to interact with healthcare personal during treatment. Discussion This study analyses the societal value of the previous standard IV compared to SC trastuzumab treatment by estimating and comparing the societal cost associated with both treatment alternatives. The results show that SC compared to IV trastuzumab saves both nurse and patient time and results in a cost savings for both first and subsequent treatment occasions. More cases of complications/discomfort during treatment was found among SC patients, in line with previous research [3,13,14], where a difference in the overall adverse event rates, driven by more minor events (grade 1), was detected. A majority of patients preferred SC injected trastuzumab if given the option, and the preference was stronger among SC patients. This is in line with a previously established reluctance towards unknown treatments [15]. Several studies have examined patient preferences of methods and routes of drug delivery showing that 89 to 92 percent of patients prefer SC to IV trastuzumab [14,16]. Similar results have been found when given the choice between infusions and injections within other diagnostic fields [17,18]. Cost estimates of production loss associated with trastuzumab treatment should be interpreted with caution since few patients indicated work absenteeism. Also note that analyses of first time patients are based on a limited number of observations. In addition, the lack of primary data on resource utilization associated with preparation of IV trastuzumab at a pharmacy as well as of individual patients' weight might be a limitation of the present study. This study include an estimation of leisure time lost which is valued according to the average net wage. This is a rather common procedure which have some theoretical support [11]. However, since leisure time lack an explicit market price there is a lack of consensus regarding its valuation. The true amount of drug waste was not measured in this analysis, but was assumed to correspond to a dose increase of four percent. An Australian study examining the use of IV trastuzumab in clinical practice found that drug waste was up to 24% [19]. Drug wastage may however be limited through designated days where the oncology clinic gathers multiple trastuzumab patients for parallel treatment sessions. Replacing IV trastuzumab by SC trastuzumab may reduce the need to insert permanent venous catheters, and this study show that the share of patients with a permanent venous catheter was lower among SC patients. Potential savings due to a reduced use of permanent venous catheters was not included in the analysis. A previous UK study found that SC trastuzumab substantially reduced patient time, active nurse time, material consumption and
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