Abstract
Introduction
Subcutaneous (SC) drug administration, such as the Herceptin® in an oncology day hospital reduces the administration time of trastuzumab. In the context of combination therapy administration, this time-saving may be called into question. The challenge posed by the deployment of much less expensive IV biosimilar forms raises questions about the cost-effectiveness of SC administration.
Methods
Using data from a french Diagnostic Related Groups regarding prescriptions of intravenous Herceptin® (HIV), Herceptin® biosimilar IV (BSIV), and Herceptin® subcutaneous (HSC), we conducted two simulations. This simulation involved replacing all HSC with BSIV in combination therapy administration (Simulation 1) and subsequently substituting IV forms with SC forms only when prescribed as monotherapy (Simulation 2). A cost-benefit analysis was conducted based on these two simulations, from the hospital's perspective, for Normandy's population over a 1-year timeframe.
Results
In Simulation 1, there was an average cost-saving of €12 per patient per year, but it resulted in a loss of 10140 min, equivalent to 10 min per patient per year when compared to the current situation. Simulation 2 yielded average cost-savings for the hospital amounting to €51 per patient per year, along with a time-saving of 67 min per patient per year compared to the current situation.
Conclusions
The development of a program aimed at optimizing the prescription of Trastuzumab holds the potential to deliver significant cost-savings to hospitals while enhancing the quality of service provided to the patients. This optimization involves using H SC in monotherapy and BS IV in combination therapy administration.
Keywords: Neoplasms, Health policy, Biosimilar pharmaceuticals, Economics, Pharmaceutical, Costs and cost analysis, Patient preference
Highlights
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Optimized use of trastuzumab IV/SC increases the proportion of biosimilar usage by 150 %.
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Optimized use of trastuzumab IV/SC results in a cost-saving of 51€ per patient per year.
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Optimized use of trastuzumab IV/SC leads to a time saving of 68 min per patient per year.
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Sensitivity analyses demonstrate robust results.
1. Introduction
Advances in the understanding of cancer biology have led to the development of innovative but expensive treatments such as targeted therapies. These expensive drugs are mainly used in day hospitals, which are subject to increased patient flow and budgetary constraints.
In 2000, intravenous (IV) trastuzumab arrived on the European market. Trastuzumab has become an essential component in the management of HER2-positive breast cancer. Before the expiry of the IV trastuzumab patent, the laboratory extended the marketing authorization to a subcutaneous (SC) version of trastuzumab. Very quickly, studies showed a favorable cost-effectiveness ratio for the SC administration of trastuzumab compared to IV administration [1,2]. Moreover, the SC route of administration is preferred by caregivers and patients [[3], [4], [5]] and offers significant time savings for both, allowing day hospitals to respond to increased patient flow. Following the expiry of a patent, the formulation of a drug falls into the public domain, opening up to competition and the marketing of IV biosimilars, allowing a reduction in costs. For IV trastuzumab the expiry of the patent in 2014 resulted in the marketing of at least 6 biosimilars of IV trastuzumab between 2017 and 2019. This massive arrival of IV trastuzumab biosimilars has contributed to a significant drop in the cost of these treatments, altering the results of the aforementioned studies comparing SC and IV formulations of trastuzumab [1,2].
In breast cancer, trastuzumab, IV or SC, can be administered either alone or in combination IV chemotherapy (e.g. paclitaxel, etc.). When trastuzumab is administered subcutaneously in combination IV chemotherapy the time saving is no longer so obvious because the only difference is the time of injection. A recent survey conducted in France evaluated the use of trastuzumab using data from the Program de Médicalisation des Systèmes d'Informations, the French diagnosis related group (fDRG). This survey revealed a lower use of IV biosimilars of trastuzumab compared to a SC formulation of trastuzumab in 2013.
The arrival of biosimilars has probably changed the cost/effectiveness ratio of IV trastuzumab compared to SC trastuzumab, but has made no difference in time savings or patients’ preferences for SC trastuzumab. Therefore, we wondered what would be the optimal use of trastuzumab.
We hypothesized that optimizing the prescription of SC trastuzumab would allow a better management of trastuzumab biosimilars in day hospitals. The objective of this study was to evaluate the use of trastuzumab biosimilars compared to trastuzumab original drugs to treat breast cancer in a hospital setting from a medico-economic point of view, taking into account factors such as time savings and patients’ preferences for SC trastuzumab.
2. Methodology
2.1. Study population
The study was conducted in Normandy, France in 2019. The population included 544 patients treated with trastuzumab for all indications.
2.2. Study design
Two conditions were simulated. In simulation 1, in combination therapy, an IV trastuzumab biosimilar was used to replace IV trastuzumab and SC trastuzumab original drugs. In simulation 2, in addition to the approach applied in simulation 1, SC trastuzumab was used to replace IV trastuzumab. Simulation 1 and simulation 2 are presented in Table 1.
Table 1.
Description of the current situation, simulation 1 and simulation 2.
| Single agent chemotherapy (SAC) |
Compilation chemotherapy (CC) |
|||||
|---|---|---|---|---|---|---|
| Patent trastuzumab | SC trastuzumab | Biosimilar trastuzumab | Patent trastuzumab | SC trastuzumab | Biosimilar trastuzumab | |
| Current situation | 2.1 % | 77.7 % | 20.2 % | 7.0 % | 39.9 % | 53.1 % |
| Simulation 1 | 2.1 % | 77.7 % | 20.2 % | 0.0 % | 0.0 % | 100.0 % |
| Simulation 2 | 0.0 % | 100.0 % | 0.0 % | 0.0 % | 0.0 % | 100.0 % |
2.3. Study period and perspective
The study period was set at 1 year, corresponding to 18 cycles of trastuzumab at three-week intervals. The perspective adopted is the hospital perspective.
2.4. Health data
The health data used for this study were obtained from the e-PMSI (French DRG). Data were collected in 2019.
2.5. Length of chemotherapy session in day hospital
The length of a chemotherapy session in day hospital in monotherapy was defined according to the De Cock study [6]. For IV trastuzumab, the time of infusion was considered to be the same in monotherapy and in combination IV chemotherapy. For SC trastuzumab, the pre-infusion and post-infusion times in combination IV chemotherapy were added to the chair time as described in Fig. 1.
Fig. 1.
Duration of HDJ chemotherapy session for patients treated with trastuzumab in multi-drug therapy
SC: Subcutaneous; IV: intravenous.
We calculated an overall chair occupancy time by multiplying the proportion of patients, the number of cycles, the number of simulated patients (1000) to the corresponding chair time.
2.6. Costs
2.6.1. Direct costs
The direct costs considered and their sources are described in Table 2.
Table 2.
Direct costs.
| Direct costs | Sources |
|---|---|
| Chemotherapy session on a public/private basis | Program de Médicalisation des Systèmes d'Informations, the French diagnosis related group (fDRG) |
| Consumables related to the route of trastuzumab | Lieutenant et al., 2015 [7] |
| Hourly wages for health care professionals | Lieutenant et al., 2015 [7] |
| Trastuzumab cost | Program de Médicalisation des Systèmes d'Informations, the French diagnosis related group (fDRG) |
The cost of stay was based on the different formulations of trastuzumab used (with or without chemotherapy), the cost of consumables related to the route of trastuzumab (IV or SC) and the time that healthcare professionals spent with the patient.
The difference in costs relative to consumables was obtained by subtracting the cost of consumables estimated for the SC route of administration from the cost of consumables estimated for the IV route. The cost of consumables includes the equipment required for preparation and injection (needle syringe, bag of solution, etc.). The aggregate cost of consumables generated by the preparation and administration of trastuzumab in a session were retrieved from the study by Lieutenant et al. [7].
Induced costs, relative to the time that healthcare professionals spent with the patient, were calculated by multiplying the time spent by each healthcare professional (Table 3) by their corresponding hourly rate. The information related to the calculation of induced costs was retrieved from the De Cock et al. study [6].
Table 3.
Dedicated time of healthcare professionals in the management of a patient treated with SC trastuzumab or IV trastuzumab.
| "Active" time per patient of healthcare professionals (in min) | IV | SC |
|---|---|---|
| Doctor | 2.5 | 1.8 |
| Pharmacist | 4.0 | 3.2 |
| Pharmaceutical assistant | 6.45 | 3.9 |
| Nurse | 18.9 | 10.0 |
| Total | 31.8 | 18.7 |
The cost of each session was estimated using the rate corresponding to the fDRG 28Z07Z "Chemotherapy for tumor in session" for the year 2019: €383.1 for the public hospital sector, and €302 for the private for-profit sector. In order to take into account the differences between these two sectors, a weighted rate was calculated using the distribution of stays between the public and private sectors according to fDRG data.
2.6.2. Indirect costs
Indirect costs corresponding to the potential gains or losses in productivity induced by a variation in the length of a chemotherapy session were calculated. This variation made it possible to estimate the number of sessions lost or gained over 18 cycles. This number of sessions (or stays) was valued using the Normandy department's case mix.
2.7. Sensitivity analysis
2.7.1. Deterministic analysis
To test the robustness of our results, we performed a deterministic analysis represented as a Tornado diagram for the two simulations. We varied each parameter by ± 20 % as is common in the literature [8]. The parameters were: trastuzumab biosimilar + combination IV chemotherapy/SC trastuzumab in monotherapy, trastuzumab biosimilar + combination IV chemotherapy, hourly cost of healthcare professionals, time of healthcare professionals relative to IV administration and time of healthcare professionals relative to SC administration.
2.7.2. Probabilistic analysis
We completed our sensitivity analysis with a bootstrap method. We carried out 10 000 samples per simulation and varied the same parameters as in the deterministic analysis, as well as the infusion time for SC trastuzumab in combination IV chemotherapy. All parameters were varied according to a normal distribution.
3. Results
The proportions of trastuzumab use in monotherapy and combination IV chemotherapy are presented in Fig. 2. An additional cost of €85 624, i.e. €86/patient/year was incurred, compared to the health insurance reimbursement.
Fig. 2.
Current market share of the different formulations of trastuzumab
Legend: BS: Biosimilar SC: Subcutaneous.
The trastuzumab proportion targets for simulation 1 and simulation 2 are shown in Fig. 3(A) and (B), respectively.
Fig. 3.
Objectifs simulation 1 (A) – Objectifs simulation 2 (B)
Legend: BS: Biosimilar SC: Subcutaneous.
Simulation 1 shows that the use of an IV trastuzumab biosimilar, in combination IV chemotherapy, increased from 54 % to 100 %, leading to a cost saving of €11 889, i.e. €12/patient/year corresponding to a saving of 14 % compared to the current situation. Conversely, simulation 1 also shows an increase in the length of a chemotherapy session compared with the current time of 10 min/patient/year.
Simulation 2 shows that the use of SC trastuzumab, in monotherapy, led to a cost saving of about €51 376, i.e. €51/patient/year, corresponding to a saving of 60 % compared to the current situation. Simulation 2 led to a time saving of 68 min/patient/year compared to the current situation and therefore a saving of 78 min/patient/year compared to simulation 1.
In the sensitivity analysis of simulation 1, variations of ± 20 % in the hourly cost of healthcare professionals and the time spent by healthcare professionals relative to IV administration and SC administration led to variations of 4 % of the earning potential. The details of these variations are presented in Fig. 4.
Fig. 4.
Tornado diagram: Simulation 1 (multi-drug therapy).
In simulation 2, the variation in potential gains followed the same trends as in simulation 1. Variations of ± 20 % in productivity resulted in a ± 27 % variation in gains. Variations of ± 20 % in the other parameters resulted in an impact of less than 1 % the earning potential. The details of these variations are presented in Fig. 5.
Fig. 5.
- Tornado diagram: Simulation 2 (multidrug + single agent).
Compared to the current situation, the bootstrap analysis (Fig. 6) showed an increase in cost savings in 100 % of the resamplings for simulation 1 and 2 and an increase in time savings in 10 % of the cases in simulation 1 and in 90 % of the cases in simulation 2. Simulation 1 was dominant in 10 % of cases and simulation 2 was dominant in 91 % of cases.
Fig. 6.
Bootstrap simulation 1 and 2 (n = 10 000).
4. Discussion
Today, in Normandy, the proportion of trastuzumab biosimilars is 39 %. Based on simulation 1, using an IV trastuzumab biosimilar, incombination IV chemotherapy, the proportion of biosimilars would reach 65 %, representing a 1.7-fold increase compared to the current situation. Based on simulation 2, using SC trastuzumab in monotherapy, the proportion of biosimilars would reach 57 %, representing a 1.5-fold increase compared to the current situation, and a reduction in market share of 12 % compared to simulation 1. Simulation 2 led to a time saving of approximately 52 min/patient/year, including 36 min (68 %) of nurses' time, 10 min (20 %) of pharmacists' time, and 6 min (12 %) of physicians’ time.
From a hospital perspective, an optimized use of IV biosimilars/SC trastuzumab appeared to be cost effective. Replacing SC trastuzumab and IV trastuzumab original drugs with biosimilars was effective from a cost point of view but increased the time spent by healthcare professionals relative to SC administration. Combining trastuzumab monotherapy with a subcutaneous route of administration would allow a 1.5-fold increase in the proportion of biosimilars.
The deterministic sensitivity analysis shows a high stability of our simulations, supporting the robustness of our results. However, it is worth noting that the productivity earning potential was the factor that caused the most variation in simulation 2, with a variation in results (27 %) greater than the variation in the productivity parameter (20 %). This productivity earning potential was mainly due to the time saving relative to the SC administration of trastuzumab in monotherapy, which is unlikely to vary over time. For example, the time of administration would have to last more than 70 min to be more expensive than the current situation and more than 60 min to be less effective than simulation 1. This finding was confirmed by the bootstrap analysis, the resampling didn't impact the results whatever the simulation.
As for SC trastuzumab in monotherapy, the determining factor remains the time of administration of SC trastuzumab in combination IV chemotherapy and therefore of productivity. Based on the study by De Cock et al. [6], we estimated that the maximum difference between the two (IV/IV and SC/IV) could be 21 min. This earning time potential time for SC trastuzumab in combination IV chemotherapy is not sufficient to change the interpretation of the results of this study.
The probabilistic sensitivity analysis showed the stability of simulation 1 in terms of cost saving but not of time saving, whereas the bootstrap analysis of simulation 2 showed a greater overall stability. This analysis shows a good robustness of the results of simulation 2 confirming that it is the most stable and reliable model.
The SC route offers the advantage of a short time of administration, reducing the time spent by healthcare professionals and the length of stay of patients in day hospital. In the literature, the use of the SC route led to an estimated cost saving of €126 to 269 per cycle compared to the IV form [[9], [10], [11]]. In our study, simulation 2 showed that SC administration would result in a cost saving of only €4 per cycle. This difference is explained by the fact that our study focused on the gross savings and did not take into account the savings due to the incentive of each country. Thus, it is quite interesting to observe that regardless of public health policy, the optimization of trastuzumab use (100 % biosimilar in combination IV chemotherapy and 100 % SC in monotherapy) will necessarily be the most advantageous option. Indeed, a 100 % biosimilar option in monotherapy and combination IV chemotherapy will probably be the most advantageous from a cost perspective with an incentive policy but it will always entail a considerable loss of time. In our study, this loss of time amounted to 10 min, which is equivalent to 21 working days per year and therefore practically 1 additional month just for trastuzumab. On the contrary, the use of 100 % SC would cause a 90 % increase in the cost of trastuzumab without improving the time saving of simulation 2. From an economic point of view, SC has shown a benefit in monotherapy but not in combination IV chemotherapy.
Beyond the economic aspect, it is essential to consider the role of SC trastuzumab because this route of administration is preferred by patients, even though it is more painful [[3], [4], [5]] and therefore reinforces the importance of using it as a single agent, but not in multidrug therapy.
The study by Tjalma et al. [9] estimated that switching from IV to SC forms of trastuzumab resulted in a time saving of 71 %. In our second simulation, when switching from IV to SC forms as monotherapy, our time saving was 60 %, which is consistent with the literature. The relatively small difference between the two results probably lies in the fact that our study was a partial simulation, based on current prescription of biosimilars. In addition, we have highlighted a gain in logistical and technical time that can be reinvested in the accompaniment, listening and care of patients with breast cancer.
This study also complements the work of Touati et al. [12] and Lassale et al. [13]. Indeed, their studies concluded that home administration of bortezomib resulted in savings of 16 % and 20 % for health insurance, associated with a considerable increase in patient satisfaction, and maintenance of the safety and efficacy of the care. For trastuzumab, these results appear to be consistent with the BELIS study [14]. However, none of these studies were conducted from a hospital perspective. Our study is therefore in line with their economic logic, showing that optimizing the prescription of trastuzumab would allow the optimization of hospital costs, even if all patients on monotherapy were managed at home rather than in a day hospital. Our study is thus the first to produce an estimate of time savings in a day hospital, thanks to the administration of subcutaneous chemotherapy in home hospitalization. However, many authors agree that this time saving is now necessary to face the constant increase in demand for home hospitalization, in order to maintain an optimal quality of care [9,12,15] in a context of shortage of caregivers.
Our study has strengths and limitations. We did not present the impact of a biosimilar incentive program per se and thus the costs of implementing such a campaign were not included. However, this study has allowed us to put the results of such a program into perspective and to estimate the potential gains in productivity for healthcare centers. Moreover, the scenario varying the rate of trastuzumab replacement showed a constant cost benefit. The lack of a concrete cost accounting element for a day hospital and the fact that the basic e-PMSI (French DRG) data are dependent on an appropriate coding procedure were also limitations of our study.
At a national and European level, numerous studies and surveys have shown a reluctance on the part of specialist physicians to change their prescriptions from original drugs to biosimilars [16,17]. In France, measures have been taken to facilitate and encourage the transition between original drugs and biosimilars. Some initiatives have focused on demand, while others have focused on education, organization (agreement between volume and price), and even financial incentives [18] for prescribing departments and institutional pharmacies. Sharing efficiency data on trastuzumab biosimilars may contribute to their increased prescription.
Assistance with the study
None.
Financial support and sponsorship
None.
Conflicts of interest
None.
Presentation
None.
Acknowledgments
The authors are grateful to Nikki Sabourin-Gibbs, CHU Rouen, for her help in editing the manuscript.
The authors also acknowledge the help of Mr. Mathias Bignard in the sensitivity analyses.
Finally, the authors thank Doreya Monzat for database access.
Research project realized with the partnership of SFPO (Société Française de Pharmacie Oncologique)
References
- 1.Valachis A., Sundqvist M., Carlsson L., et al. Use of subcutaneous and intravenous trastuzumab: real-world experience from three hospitals in Sweden. Future Oncol. août. 2019;15(23):2733–2741. doi: 10.2217/fon-2019-0160. [DOI] [PubMed] [Google Scholar]
- 2.Olsen J., Jensen K.F., Olesen D.S., Knoop A. Costs of subcutaneous and intravenous administration of trastuzumab for patients with HER2-positive breast cancer. Journal of Comparative Effectiveness Research. J Comp Eff Res. 2018 May;7(5):411–419. doi: 10.2217/cer-2017-0048. [DOI] [PubMed] [Google Scholar]
- 3.Cebas A.L., Cascajares S.C., Bravo S.P., et al. Subcutaneous versus intravenous administration of trastuzumab: preference of HER2+ breast cancer patients and financial impact of its use. J BUON. 2017 Mar-Apr;22(2):334–339. [PubMed] [Google Scholar]
- 4.Pivot X., Spano J.P., Espie M., et al. Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: results of the randomised MetaspHer study. Eur J Cancer. sept. 2017;82:230–236. doi: 10.1016/j.ejca.2017.05.009. [DOI] [PubMed] [Google Scholar]
- 5.Pivot X., Gligorov J., Müller V., et al. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. Lancet Oncol. sept. 2013;14(10):962–970. doi: 10.1016/S1470-2045(13)70383-8. [DOI] [PubMed] [Google Scholar]
- 6.De Cock E., Pivot X., Hauser N., et al. A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2‐positive early breast cancer. Cancer Med. 2016;5(3):389–397. doi: 10.1002/cam4.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Lieutenant V., Toulza É., Pommier M., Lortal-Canguilhem B. Is Herceptin® (trastuzumab) by subcutaneous a mini revolution? Pharmaco-economic study. Bull Cancer. mars. 2015;102(3):270–276. doi: 10.1016/j.bulcan.2015.01.007. [DOI] [PubMed] [Google Scholar]
- 8.Jang M., Simoens S., Kwon T. Budget impact analysis of the introduction of rituximab and trastuzumab intravenous biosimilars to EU-5 markets. BioDrugs. janv. 2021;35(1):89–101. doi: 10.1007/s40259-020-00461-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tjalma W.A.A., Van den Mooter T., Mertens T., Bastiaens V., Huizing M.T., Papadimitriou K. Subcutaneous trastuzumab (Herceptin) versus intravenous trastuzumab for the treatment of patients with HER2-positive breast cancer: a time, motion and cost assessment study in a lean operating day care oncology unit. Eur J Obstet Gynecol Reprod Biol. févr. 2018;221:46–51. doi: 10.1016/j.ejogrb.2017.12.006. [DOI] [PubMed] [Google Scholar]
- 10.Burcombe R., Chan S., Simcock R., Samanta K., Percival F., Barrett-Lee P. Subcutaneous trastuzumab (Herceptin®): a UK time and motion study in comparison with intravenous formulation for the treatment of patients with HER2-positive early breast cancer. Adv Breast Cancer Res. 9 sept 2013;2(4):133–140. [Google Scholar]
- 11.Lee S.-M., Jung J.-H., Suh D., et al. Budget impact of switching to biosimilar trastuzumab (CT-P6) for the treatment of breast cancer and gastric cancer in 28 European countries. BioDrugs. 1 août. 2019;33(4):423–436. doi: 10.1007/s40259-019-00359-0. [DOI] [PubMed] [Google Scholar]
- 12.Touati M, Lamarsalle L, Moreau S, et al. Cost savings of home bortezomib injection in patients with multiple myeloma treated by a combination care in Outpatient Hospital and Hospital care at Home. Support Care Cancer. 12;24(12):5007-5014. [DOI] [PMC free article] [PubMed]
- 13.Lassalle A., Thomaré P., Fronteau C., et al. Home administration of bortezomib in multiple myeloma is cost-effective and is preferred by patients compared with hospital administration: results of a prospective single-center study. Ann Oncol. févr. 2016;27(2):314–318. doi: 10.1093/annonc/mdv563. [DOI] [PubMed] [Google Scholar]
- 14.Denys H., Martinez-Mena C.L., Martens M.T., et al. Safety and tolerability of subcutaneous trastuzumab at home administration, results of the phase IIIb open-label BELIS study in HER2-positive early breast cancer. Breast Cancer Res Treat. mai. 2020;181(1):97–105. doi: 10.1007/s10549-020-05604-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Franken M., Kanters T., Coenen J., de Jong P., Jager A., Groot C.U. Hospital-based or home-based administration of oncology drugs? A micro-costing study comparing healthcare and societal costs of hospital-based and home-based subcutaneous administration of trastuzumab. Breast. août. 2020;52:71–77. doi: 10.1016/j.breast.2020.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Hemmington A., Dalbeth N., Jarrett P., et al. Medical specialists' attitudes to prescribing biosimilars. Pharmacoepidemiol Drug Saf. mai. 2017;26(5):570–577. doi: 10.1002/pds.4186. [DOI] [PubMed] [Google Scholar]
- 17.O'Callaghan J., Bermingham M., Leonard M., et al. Assessing awareness and attitudes of healthcare professionals on the use of biosimilar medicines: a survey of physicians and pharmacists in Ireland. Regul Toxicol Pharmacol. août. 2017;88:252–261. doi: 10.1016/j.yrtph.2017.06.013. [DOI] [PubMed] [Google Scholar]
- 18.Godman B., Shrank W., Andersen M., et al. Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications. Expert Rev Pharmacoecon Outcomes Res. déc. 2010;10(6):707–722. doi: 10.1586/erp.10.72. [DOI] [PubMed] [Google Scholar]