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International Immunopharmacology 11 (2011) 1358–1361
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International Immunopharmacology
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Kiovig for primary immunodeficiency: Reduced infusion and decreased costsper infusion
Mark Connolly a, Steven Simoens b,⁎a Global Market Access Solutions, Switzerlandb Research Centre for Pharmaceutical Care and Pharmaco-economics, Katholieke Universiteit Leuven, Leuven, Belgium
⁎ Corresponding author at: Research Centre for Pharmeconomics, Katholieke Universiteit Leuven, Onderwijs enO. Box 521, 3000 Leuven, Belgium. Tel.: +32 16 323465
E-mail addresses: [email protected] (M. [email protected] (S. Simoens).
1567-5769/$ – see front matter © 2011 Elsevier B.V. Adoi:10.1016/j.intimp.2011.04.021
a b s t r a c t
a r t i c l e i n f oArticle history:Received 18 June 2010Received in revised form 28 April 2011Accepted 29 April 2011Available online 12 May 2011
Keywords:BelgiumCost-minimization analysisKiovigPrimary immunodeficiency
Kiovig is a ready-to-use 10% liquid immunoglobulin preparation that is medically indicated for the treatmentof primary immunodeficiency. This study aims to conduct an economic evaluation which compares theintravenous immunoglobulin (IVIg) preparations Kiovig, Multigam, and Sandoglobulin from the Belgiansocietal perspective. As three prospective studies have observed no difference in outcomes, a cost-minimization analysis is considered appropriate to evaluate differences in treatment costs that can arise fromIVIgs. A decision-analytic model simulated treatment costs attributed to one infusion. Resource use data werederived from a Dutch costing study. Cost items included immunoglobulin costs, pharmacy administration andnursing costs, mini-forfait for hospital infusion, costs of adverse events, and lost productivity with 2009 asbase year. Cost data were identified from published sources and Belgian hospital administrators. Aprobabilistic sensitivity analysis explored the impact of parameter uncertainty on cost results. Costs perinfusion cycle in adult primary immunodeficiency patients were €1,046 (95% confidence interval: €1,006–1,093) with Kiovig; €1,102 (€1,064–1,147) with Multigam; and €1,147 (€1,108–1,193) with Sandoglobulin.The average cost savings per infusion with Kiovig as compared to Multigam and Sandoglobulin amounted to€56 and €101 per infusion. In conclusion, treatment costs with Kiovig were shown to be lower as compared toother IVIgs in Belgium. Reduced costs per infusion were attributed to lower costs associated with treatingadverse events and the opportunity cost of nursing time and time off work for working adults.
aceutical Care and Pharmaco-Navorsing 2, Herestraat 49, P.; fax: +32 16 323468.),
ll rights reserved.
© 2011 Elsevier B.V. All rights reserved.
1. Introduction
Primary immunodeficiency disorders are associated with anincreased susceptibility to recurrent bacterial infections affecting therespiratory tract and gastrointestinal canal [1]. Intravenous immuno-globulin treatment is themainstay of therapy for infections and patientsoften require lifelong immunoglobulin therapy [2]. Immunoglobulintherapy replaces functionally deficient or absent immunoglobulins,reduces the incidence of infections, and prevents organ damage causedby recurrent infections [3].
Kiovig (intravenous human immunoglobulin, Baxter AG, Vienna,Austria), a ready-to-use 10% liquid immunoglobulin preparation, ismedically indicated for the treatment of, amongst other indications,primary immunodeficiency disorders [4]. This plasma-derived productconsists of a highly purified preparation of human immunoglobulin. It issupplied as a ready-to-use liquid formulationwith apHof 4.6 to 5.1. Threededicated virus clearance steps are integrated in the manufacturing
process and the resulting product exhibits an intact immunoglobulinmolecule with complete functional activity. Kiovig is supplied in single-dose vials that nominally contain 1 g, 2.5 g, 5 g, 10 g, and 20 g protein pervial. Three prospective, open-label, multi-center studies have demon-strated that Kiovig has a favorable pharmacokinetic, safety, andeffectiveness profile in the treatment of primary immunodeficiencypatients [5–7]. The European Commission granted a marketing authori-zationvalid throughout theEuropeanUnion forKiovig in January2006 [4].
The aim of this study is to conduct an economic evaluation whichcompares Kiovig with two alternative intravenous immunoglobulinproducts (i.e. Multigam and Sandoglobulin) from the Belgian societalperspective. The findings may serve to aid local decision-makers inallocating scarce health care resources, and to inform the prescribingbehavior of physicians. Such an exercise fits within an overall trendtowards evidence-based decision-making in health care and moreefficient allocation of scarce healthcare resources [8].
2. Materials and methods
2.1. Analytic technique
Three clinical studies have observed no differences in the outcomemeasures of incidence of infections and antimicrobial use between
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Kiovig and other 5% intravenous immunoglobulin products (such asMultigam and Sandoglobulin) [5–7]. The European Public AssessmentReport of Kiovig revealed no special risk for humans based on theexploration of safety pharmacology and toxicity [4]. Because therewas no difference in outcomes between Kiovig, Multigam andSandoglobulin, the economic evaluation took the form of a cost-minimization analysis, which considered differences in costs that canarise from different immunoglobulin products used in adults withprimary immunodeficiency. It follows that the cheapest product istherefore the most efficient immunoglobulin product.
2.2. Societal perspective
The analysis was conducted from the societal perspective inBelgium. In addition to health care costs, the opportunity cost ofdifferences in infusion times between Kiovig and the comparators wasaccounted for in the model. Reduced infusion times reported for 10%Kiovig compared with 5% intravenous immunoglobulin formulationswere expected to translate into economic advantages for society asfollows: a) reduced time required for nursing staff to administerKiovig, and b) reduced time for working adults to attend infusionclinics.
2.3. Immunoglobulin treatments
Kiovig was compared with the two leading 5% intravenous immuno-globulin products in Belgium, i.e. Multigam (50% market share in 2007)and Sandoglobulin (40% market share) [9].
2.4. Decision-analytic model
To compare treatment costs for the three intravenous immunoglob-ulin preparations in Belgium, a decision-analytic model was constructed.The costs of a single infusionwere calculated in the economicmodelwiththe ability to extrapolate findings to multiple infusion cycles. There is noreported difference in outcomes or costs over time of repeated infusions;therefore it was considered appropriate to consider costs related to asingle intravenous immunoglobulin infusion. Considering the short timeperiod, discounting was not performed. The analysis was conducted inTreeAge Pro 2008, Williamstown, MA, USA.
Clinical data used to populate themodel were derived from a studyconducted in Groningen, the Netherlands [10]. The Dutch studyenrolled 14 adult patients who had received in-hospital replacementtherapy with a 6% intravenous immunoglobulin lyophilized solutionfor at least 6 months and were then switched to 10% Kiovig. Patientshad a median age of 53.5 years (range: 23–80 years). Twelve patientswere diagnosed with common variable immunodeficiency, onepatient with X-linked agammaglobulinemia and one patient withdysgammaglobulinemia. Our analysis assumed that the patientpopulation treated in the Dutch study was similar to patients treatedin Belgium. Dosing was based on the approved product labeling for
Table 1Resource items and unit values used in decision-analytic model.
Resource item Unit value Description
Kiovig €42.04 per gram Hospital purchasing price. The priceMultigam €42.04 per gram Hospital purchasing price. The priceSandoglobulin €42.04 per gram Hospital purchasing price. The priceForfait infusion €61.07 (€30–€131) Represents the average and variatioPharmacist per hour €45.49 Pharmacist time for reconstitution oParacetamol €1.76 Based on a survey of 3 clinics in BelgNursing cost per hour €37.31 Average hourly wage for nurse. BasedHourly wage Belgium €18.91 Average monthly salary in Belgium
Based on 39 hours work week.Unemployment rate 7% The average hourly rate was adjuste
each product of 0.4 g/kg every 3–4 weeks. The median infusion timeamounted to 104.4 min with the 6% lyophilized solution and 51.0 minwith 10% Kiovig. The corresponding median maximum infusion rateswere 4.1 ml/kg/hour and 5.9 ml/kg/hour, respectively. Median gam-maglobulin trough levels amounted to 7.1 g/l for the 6% lyophilizedsolution and 7.9 g/l for 10% Kiovig. The rate and duration of adverseevents were extracted from the Dutch study in a stable population ofadult primary immunodeficiency patients [10].
2.5. Resource use and costs
The decision-analytic model included the following resource items:a) intravenous immunoglobulin costs, b) pharmacy administrationcosts (Sandoglobulin only), c) the mini-forfait paid for administeringintravenous immunoglobulin in hospital, d) costs of adverse events,e) costs of nursing time, and f) costs of lost productivity adjusted forunemployment. Several resource items were defined based on Belgiantreatment practices and reimbursement for services. Resource itemsand unit prices included in themodel are presented in Table 1. Cost datawere identified from published sources and hospital administrators inBelgium responsible for delivering intravenous immunoglobulin ther-apy for adults suffering from primary immunodeficiency based on 2009prices.
The in-hospital intravenous immunoglobulin costs per gram wereused to calculate treatment costs. Given that Kiovig, Multigam, andSandoglobulin possess similar clinical effects, the amount of intrave-nous immunoglobulin required per infusion was assumed to beequivalent. The following assumptions were used: a) the dose wasbased on an adult weighing 60 kg. The dose per kilogram for allproducts was 0.4 g/kg. For each product, the total dose was 24 g.
Similar to the study reported by Kallenberg in the Netherlands,pharmacist time required to reconstitute Sandoglobulin was includedin the economic model. As reported in the Dutch study [10], 1 hourwas required for the pharmacist to reconstitute Sandoglobulin andattend the infusion. This hour was valued using the hourly rate for aBelgian pharmacist [11]. The reconstitution cost did not apply toMultigam because it is available as a liquid ready-to-use formulationsimilar to Kiovig. In Belgium, a mini-forfait of €61.07 is paid for eachintravenous immunoglobulin infusion delivered in hospital [11]. Thisforfait was applied to all three products.
Based on a treatment cycle of 3.5 weeks and two cycles ofintravenous immunoglobulin therapy as reported in the Dutch study[10], the incidence rate of adverse events amounted to 3.7 (95%confidence interval: 1.5–7.6) for Kiovig and 10.6 (95% confidenceinterval: 6.5–16.4) for Multigam. Adverse events occurred on the dayof infusion or on the next two days following infusion and includedmalaise, arthralgia, chills, cutaneous reaction, fever, back pain,dizziness and nausea. Adverse events were mild and transient forboth products and could be treated with paracetamol. To confirm theuse of paracetamol to treat adverse events, we surveyed two infusionclinics in Belgium. The survey participants indicated that paracetamol
Reference
per gram is the same regardless of the vial size. Baxter pricing dossierper gram is the same regardless of the vial size. [11]per gram is the same regardless of the vial size. [11]n in mini-forfait costs required for one infusion. [11]f Sandoglobulin. [11]ium. Unit price per adverse event. [12]on 2005 cost inflated at 2% per year to 2009. [13]
in 2007 inflated to 2009 prices at 2% per annum: €2,951. [14]
d based on unemployment rate in Belgium. [15]
Table 3Treatment costs per cycle intravenous immunoglobulin in Belgium.
Costs per cycle Incremental cost difference†
Kiovig Mean €1,046 –
95% CI €1,006–1,093Median €1,044
Multigam Mean €1,102 €5695% CI €1,064–1,147Median €1,099
Sandoglobulin Mean €1,147 €10195% CI 1,108–1,193Median €1,145
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was often used in practice for patients experiencing mild adverseevents. The recommended dose was 15 mg/kg given 4-times per dayfor two days. The costs of paracetamol were based on a genericformulation available in Belgium and were used to derive the cost peradverse event [12].
The 10% Kiovig formulation has been reported to reduce infusiontimes by 50% in primary immunodeficiency patients [10]. Savings innursing time were valued using an average hourly wage of €37.31 [13].Lost productivity resulting from infusionswasaccounted for by applyingaverage labor wage rates in Belgium and adjusting for unemployment[14,15].
CI, confidence interval.†, based on difference in means.
2.6. Base case analysis
The base case analysis calculated the costs for one infusion cycle ofKiovig as compared to Multigam and to Sandoglobulin.
2.7. Sensitivity analysis
A probabilistic sensitivity analysis based on a 5,000-iterationMonte Carlo simulation was conducted to explore the impact ofparameter uncertainty on cost results. Such an analysis requires that aprobability distribution is assigned to each input parameter (seeTable 2). During each iteration, the simulation drew input parametersat random from their statistical distributions and calculated costresults for Kiovig, Multigam and Sandoglobulin.
3. Results
The results presented in Table 3 describe the mean and mediantreatment costs per cycle for adult primary immunodeficiency patientstreated with Kiovig, Multigam, and Sandoglobulin from the societalperspective. Themean andmedian costs per cycle for all products weresimilar suggesting that the results from the Monte Carlo simulationwere not skewed. The average costs per cycle obtained from theMonteCarlo simulation were €1,046 (95% confidence interval €1,006–€1,093)for Kiovig; €1,102 (95% confidence interval: €1,064–€1,147) for Multi-gam; and €1,147 (95% confidence interval: 1,109–€1,193) for Sando-globulin. Cost savings were demonstrated with Kiovig of €56 and €101as compared with Multigam and Sandoglobulin, respectively.
The disaggregated costs per cycle are shown in Table 4. For thethree products, intravenous immunoglobulin and forfait costs werethe same. The small difference in adverse events with Kiovigtranslated into a small savings of €12.14 per cycle as compared withMultigam and Sandoglobulin. The need for pharmacy reconstitutionincreased costs with Sandoglobulin by €45 per infusion. From thesocietal perspective, the opportunity cost of reduced infusion timewith Kiovig was applied as a reduction of €43.34 to the costs per cycleas compared with other intravenous immunoglobulins in Belgium.
Table 2Variables and values used in probabilistic sensitivity analysis.
Variable Description
Reduced infusion time (minutes) The intra-patient difference in infusion time afterswitching to intravenous immunoglobulin 10%
Pharmacist reconstitution costs Time reconstitute and attend infusionMini-forfait cost Forfait for infusion
Kiovig adverse event rate Adverse event rateMultigam/Sandoglobulin adverseevent rate
Adverse event rate
4. Discussion
Since the 1950s, immunoglobulin products have been adminis-tered to patients suffering from primary immunodeficiency [16].Administration routes have evolved over time from the initialintramuscular preparations to intravenous preparations since the1960s and 1970s and subcutaneous preparations since the 1980s. Theintravenous route allows larger immunoglobulin doses to beadministered, enables a fast onset of action, and has been demon-strated to be safe, effective, and well-tolerated [3]. However, adverseevents may occur, administration in patients with poor venous accessis difficult, and the cost of intravenous infusion is high [17].
With the introduction of the Kiovig intravenous immunoglobulin10% liquid formulation, infusion times for patients suffering fromprimary immunodeficiency are likely to be reduced by 50% [10].Reduced infusion times offer benefits for hospitals and patients.Whenthese costs are extrapolated to consider the need for 12–15 infusionsper year for primary immunodeficiency adults, the costs savings arelikely to be substantial. Our analysis from the societal perspectiveconsidered the opportunity cost of nursing time and of lostproductivity for working adults with primary immunodeficiency.The results indicated that Kiovig decreased average costs per infusionas compared with Multigam by €56, and by €101 as compared withSandoglobulin.
Our economic evaluation considered costs only because multipleprospective studies have observed no difference in outcomes betweenKiovig, Multigam and Sandoglobulin [5–7]. Based on the outcomesreported in the Dutch study [10], the only differences between Kiovig,Multigam and Sandoglobulin were in terms of the infusion time andadverse event rates. The cost implications of such differences weretaken into account in our decision-analytic model. Also, given thatthere is no evidence of long-term outcome differences between thesethree products, the estimated costs for a single infusion can beextrapolated to the number of infusions required per year.
To date, limited information regarding the economics of treatingprimary immunodeficiency with Kiovig is available. One economicevaluation was found in the literature which compared a liquid 10%
Values Probability distribution Reference
48.8 (33.0–60.6) Fractile [10]
1.0 hour (0.8–1.2) Uniform [10]Likeliest €61.07; minimum €30;maximum €131
Triangle [11]
3.7 Poisson [10]10.6 Poisson [10]
Table 4Disaggregated treatment costs per cycle with intravenous immunoglobulin for primary immunodeficiency adults in Belgium.
Intravenous immuno-globulin Mini-forfait Pharmacy Adverse event costs Savings due to reduced infusion time†
Kiovig €1,009 €74.02 €0 €6.52 (€43.34)Multigam €1,009 €74.02 €0 €18.66 €0Sandoglobulin €1,009 €74.02 €45.49 €18.66 €0
† Productivity savings are deducted from aggregated treatment costs.
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intravenous immunoglobulin (Kiovig) with a lyophilized 6% intrave-nous immunoglobulin (Immunoglobuline IV; Sanquin, Amsterdam, theNetherlands) in a hospital setting [10]. Fourteen patients who hadreceived Immunoglobuline IV for at least 6 months were switched tofive successive infusions with Kiovig. The median infusion timedecreased from 104.4 min with Immunoglobuline IV to 51.0 min withKiovig. Median immunoglobulin G trough levels were 7.1 g/l withImmunoglobuline IV and 7.9 g/l withKiovig. Fewer adverse eventswereobserved with Kiovig. The switch from Immunoglobuline IV to Kiovigsaved$78.39 per patient per infusion or $1,332per patient per year. Thiseconomic evaluation did not consider the impact of the shorter infusiontime with Kiovig on costs of productivity loss.
It is worth noting that the demand for immunoglobulin products hasincreased over time, leading to periodic shortages. The importance ofmaintaining supply chains is an important characteristic of intravenousimmunoglobulin therapy that is not ordinarily captured in economicstudies like the one described here. This highlights the importance ofmaintaining supply chains for Kiovig and other immunoglobulinproducts, in which efficient and safe manufacturing processes wouldrepresent added value to primary immunodeficiency patients. Conse-quently, there is a need to follow up demand for and supply ofimmunoglobulins over time, to improve immunoglobulin manufactur-ing processes, to continue research into other therapeutic agents, and todesign plans to prioritize immunoglobulins to specific indications inperiods of acute shortages. Furthermore, appropriate evidence-baseduse of immunoglobulin should be supported by relevant medicalliterature to ensure safety and improve resource allocation byprescribers.
This study reported on one of the few models in primaryimmunodeficiency that assessed the costs associated with intravenousimmunoglobulin treatment. Its results can aid local decision makers toallocate scarce health care resources. Although a cost-minimizationanalysis was used to assess costs, decisionmakersmay alsowish to takeinto account the many other differences between intravenous immu-noglobulin products that cannot be valued in traditional economicevaluations such as differences in viral inactivation steps, concentration(5%, 6% or 10%), vial size, IgG and IgA content, excipient content,maximum infusion speed and storage requirements [3]. Finally, giventhat Kiovig has the potential for home-based administration, futureeconomic evaluations need to be carried out that explore the value ofKiovig in the home care setting.
In conclusion, the cost-minimization analysis reported here hasexamined treatment of primary immunodeficiency with Kiovig,Multigam or Sandoglobulin. The average cost per infusion cycle wasfound to be lower for patients treated with Kiovig as compared withother intravenous immunoglobulins in Belgium. Cost savings with
Kiovig were attributed to a reduction in adverse events and infusiontime, but there was no difference in immunoglobulin costs for thethree products. Costs per cycle were lower with Multigam ascompared to Sandoglobulin.
Conflict of interest statement
The authors have no conflicts of interest that are directly relevantto the content of this manuscript.
Acknowledgments
Financial support for this studywas received fromBaxterHealthcare.The authors are indebted to Bart Fynaerts for his contribution to datainput.
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