Cost–effectiveness of palivizumab in infancy

Drug Profile

10.1586/14737167.7.5.445 © 2007 Future Drugs Ltd ISSN 1473-7167 445www.future-drugs.com

Cost–effectiveness of palivizumab in infancyNicholas D Embleton†, Sandeep T Dharmaraj and Sanjeev Deshpande

†Author for correspondenceNewcastle Neonatal Service, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UKTel.: +44 191 282 5156Fax: +44 191 282 [email protected]

KEYWORDS: bronchopulmonary dysplasia, chronic lung disease, cost–effectiveness analysis, monoclonal antibody, palivizumab, pre-term infant, respiratory syncytial virus, synagis

Respiratory syncytial virus is the most common cause of bronchiolitis, a lower respiratory tract infection occurring in infancy. It is responsible for several rehospitalizations, substantial morbidity and occasional deaths in the UK every year. Palivizumab is a recombinant monoclonal antibody that has been shown to reduce hospitalizations in infected infants. It is licensed for high-risk infants, primarily those born pre-term or with chronic pulmonary or cardiac conditions. Palivizumab is expensive, but several economic analyses have determined highly discrepant costs. This article reviews the limitations of the available efficacy and economic data, and highlights problems in interpretation and extrapolation. We also present the results of a cost–effectiveness analysis relevant to populations of high-risk infants in the UK.

Expert Rev. Pharmacoeconomics Outcomes Res. 7(5), 445–458 (2007)

Respiratory syncytial virus (RSV) is the mostcommon cause of bronchiolitis (a lower respi-ratory tract infection) among infants andyoung children worldwide [1], with nearly allindividuals being infected by 2 years of age[2]. In working, healthy adults, RSV infectionhas been shown to be symptomatic in 84%,with lower respiratory tract manifestations in22% [3]. The burden due to RSV on health-care systems is considerable, with hospitaliza-tion rates in the UK of 19.1–28.3 per 1000infants to 1.3 per 1000 children aged1–4 years [4,5]. Recently, a monoclonal anti-body (palivizumab) has been shown to be effec-tive in preventing hospitalization associatedwith RSV.

What is RSV?RSV is a paramyxovirus, and two majorstrains, A and B, typically cause winter out-breaks simultaneously. Two surface proteins, Fand G, are important in the infectivity andpathogenesis by allowing attachment and pen-etration of the virus [1]. Naturally acquiredimmunity to RSV infection is incomplete,variable and not durable. The adaptiveimmune response is complex and involvescell-mediated immunity and antibody [1].High titers of serum antibody correlate with

resistance, as demonstrated in studies of RSVhyperimmune globulin [6] and monoclonalantibody [7].

RSV-related hospitalization in infancy hasincreased in recent years with those dischargedon home oxygen therapy being at particularrisk [8]. Rehospitalization rates are approxi-mately 3–13% in pre-term infants [9–11],although some report higher rates [12]. In theUSA, mortality from RSV in infancy was 3.1per 100,000 person-years [13]. In the UK,national mortality data showed that RSV wasresponsible for 17 deaths per year (8.4 per100,000 population) in infancy [14].

Treatment & prevention of RSVThere is no effective preventative vaccine andtreatment remains supportive with oxygentherapy, nutrition and good nursing care.Pooled hyperimmune RSV intravenousimmunoglobulin reduces admission rates inpre-term infants [6], but is associated with ahigh administration cost and the risk of trans-mission of blood-borne pathogens. It is notlicensed for use in the UK. The nucleosideanalogue ribavarin has been shown to be ofsome clinical benefit in hospitalized patients,but is costly [1]. Palivizumab is a combinedhuman and murine monoclonal antibody

CONTENTS

What is RSV?

Treatment & prevention of RSV

What are the high-risk groups for symptomatic RSV infection & how robustly are they defined?

Clinical efficacy of palivizumab

Clinically relevant outcomes for assessing cost–effectiveness

Cost–effectiveness of palivizumab: published data

Cost–effectiveness model & assumptions for current analysis

Results

Discussion

Expert commentary

Five-year view

Financial & competing interests disclosure

Key issues

References

Affiliations

http://www.future-drugs.com

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Text Box

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Embleton, Dharmaraj & Deshpande

446 Expert Rev. Pharmacoeconomics Outcomes Res. 7(5), (2007)

produced by recombinant DNA technology that inhibits RSVby binding to the F protein. Palivizumab has been shown tobe safe and effective in reducing hospitalizations in pre-terminfants in a randomized controlled trial, IMpact-RSV [7], andin those with hemodynamically significant congenital heartdisease (CHD) [15].

Palivizumab is licensed and recommended for use in the UK(TABLE 1) [16,101]. It is administered monthly during the RSV sea-son by intramuscular injection at a dose of 15 mg/kg. Palivizu-mab is expensive (£360–600 per dose) and several economicanalyses of palivizumab prophylaxis have been published usinglocal data. This article will evaluate the cost–effectiveness ofpalivizumab prophylaxis by reviewing published studies andexamine the cost–effectiveness by developing a model relevantto the UK.

What are the high-risk groups for symptomatic RSV infection & how robustly are they defined?Pre-term delivery, CHD and chronic lung disease (CLD) are theprincipal risk factors for symptomatic RSV infection. Whilstdegree of prematurity and presence of CHD can be preciselydefined, other criteria are more difficult. Eligibility criteria to thecontrolled trial in infants with CHD required there to be hemo-dynamically significant CHD determined by the investigator,but infants were not eligible if they had unstable cardiac status[15]. There may be considerable inter-unit or inter-individualinterpretation of these terms.

Furthermore, the definition of CLD is not entirely straight-forward. The original descriptions of pre-term infants withbronchopulmonary dysplasia (BPD) identified a requirementfor oxygen at 28 postnatal days in infants born pre-term whohad received mechanical ventilation [17]. With increasing sur-vival of very pre-term infants, the relative importance of themany etiological factors has changed, and most now define CLDas the requirement for oxygen at 36 corrected weeks gestation.

One of the eligibility criteria for the IMpact study was a clini-cal, diagnosis of BPD requiring ongoing medical treatment [7].Thus, this could have included infants born at 24 weeks gestation(i.e., extremely pre-term) with an ongoing requirement for oxy-gen at 1 year of age, and more mature infants who were still in

oxygen at 28 postnatal days, but were discharged in room air.Many clinicians now accept that, in the context of controlled tri-als, a standardized robust definition of CLD is required, and aseverity-based definition, preferably using physiological criteria(i.e., the amount of inspired oxygen required to maintain a givenoxygen saturation level determined by pulse oximetry), has beendeveloped [18,19] This is important as palivizumab’s efficacyappears to be dependent on the severity of the infant’s respiratorycondition. For the remainder of the article, we will use the termBPD to refer to all infants born pre-term with an ongoing clinicaldiagnosis of lung disease requiring supplemental oxygen.

Other risk factors for susceptibility to RSV infection includethe presence of other underlying conditions that predispose torespiratory complications; for example, neurological disease orimmunodeficiency. Additional aspects, such as crowding, lowersocioeconomic income, daycare attendance, multiple siblings,presence of smoking in the house and older siblings in school,have all been reported as risk factors [20]. Multiple gestation andmild CHD have also been shown to be risk factors [21].

Clinical efficacy of palivizumabControlled trial dataThe clinical efficacy of palivizumab in reducing hospitalizationdue to RSV has been proved in studies conducted in infants bornpre-term [7] and those with lung or heart disease [15]. Althoughthere are data from other controlled trials using alternative prepa-rations [6,22], the data upon which any economic analysis of pal-ivizumab can be based are primarily restricted to these two largecontrolled trials. These trials were both of good quality, but nei-ther included a contemporaneous economic analysis. Withinthese international collaborative studies, sub-group analysis ofoutcomes for infants enrolled in the UK was available, but pre-cise details on infant demography (i.e., whether the subgrouprecruited in the UK were higher or lower risk) were not.

The IMpact-RSV study was a large, multinational, PhaseIII, double-blind randomized controlled trial conducted overthree RSV seasons, which involved the administration of fiveintramuscular injections of palivizumab to high-risk infantsevery 30 days [7]. The primary outcome was hospitalizationwith laboratory proven RSV, but this end point may have

Table 1. Recommendations for palivizumab prophylaxis.

Organization Recommendations Ref.

American Academy of Pediatrics

<2 years and treatment for CLD within 6 months of start of RSV seasonPre-term ≤28 weeks and <12 months old at start of RSV seasonPre-term 29–32 weeks and <6 months old at start of RSV seasonPre-term 32–35 weeks and <6 months old at start of RSV season if 2 or more risk factors (child care attendance, school-age siblings, abnormalities of airway, severe neuromuscular disease and exposure to environmental air pollutants) are present<2 years with hemodynamically significant CHD

[16]

Joint Committee on Vaccination and Immunisation (UK)

<2 years with CLD, on home oxygen or prolonged use of oxygen (at least for 28 days)<6 months with left to right shunt, hemodynamically significant CHD and/or pulmonary hypertension<2 years with severe congenital immunodeficiency

[101]

CHD: Congenital heart disease; CLD: Chronic lung disease; RSV: Respiratory syncytial virus.

Palivizumab

www.future-drugs.com 447

included infants admitted for other reasons who coincidentallyhad an RSV infection. The overall reduction in hospitalizationwas 55%. In the UK subgroup, the reduction was 64%, butthese data related to a total of only seven admissions out of the123 infants enrolled (four of 40 for placebo vs three of 83 forpalivizumab). Gestational age was not a significant predictor ofrehospitalization in this study, although others have shown thata relationship does appear to exist [23].

Subgroup analysis showed that the reduction in rehospitaliza-tion for infants with BPD (39%) was approximately half that ofthose without (78%). The background admission rate for thosewith BPD (12.8%) was much higher than those without(8.1%). This suggests that palivizumab is less effective in higherrisk infants, and emphasizes the importance of using the appro-priate figure for risk reduction when developing economicmodels. This is of particular relevance to the UK where manyclinicians appear to primarily restrict palivizumab usage toinfants with BPD, rather than pre-term infants per se.

Feltes et al. addressed the safety, tolerance and efficacy of paliv-izumab prophylaxis in infants and children with hemo-dynamically significant CHD [15]. This was a large multinational

controlled trial conducted over four seasons. A 45% reduction inhospitalization rates for RSV was demonstrated, with a reduc-tion in total days admitted and number of days with increasedoxygen requirements.

Data from other studiesPalivizumab has been assessed for safety, tolerance and pharmaco-kinetics by two stage I/II, placebo-controlled, dose-escalationtrials [24,25]. Adverse events were balanced between treatmentand placebo groups, with the only side effect related to the drugbeing injection-site erythema. There are no recorded fatalitiesrelated to palivizumab. These trials also showed that palivizu-mab maintained adequate mean trough serum concentrationsof neutralizing antibody. Infants do not appear to develop anysignificant antipalivizumab antibody response [26].

Given that there are only two controlled trials, we havecompared the rates of RSV-rehospitalization (RSV-RH) fromthese two trials with those from epidemiological studies incomparable cohorts not receiving palivizumab and in post-mar-keting surveillance studies, respectively. These data are presentedin TABLE 2 [7,15,27–30].

Table 2. Respiratory syncytial virus rehospitalization rates.

Study Study type and country

Year (RSV seasons) and number

Population RSV-RH (%) Percentage reduction of RSV-RH (p-value)

Ref.

Control Palivizumab

IMpact RCT 1996–1997 (1) All; 10.6 4.8 55 (<0.001) [7]

International n = 1502 <35 weeks; <6 months

8.1 1.8 78 (<0.001)

<2 years and BPD 12.8 7.9 39 (0.038)

Feltes et al. RCT 1998–2002 (4) <24 months and CHD

9.7 5.3 45 (0.003) [15]

International n = 1287

Grimaldi et al. Observational 1999–2004 (5) ≤30 weeks and no BPD

13.5 1.1 92 (<0.0001) [27]

France n = 206

Mitchell et al. Observational 1995–2002 (6) <33 weeks and CLD

7.3 3 60 (0.003) [28]

Canada n = 2879 33–35 weeks and no CLD

3.3 2.7 18 (0.4)

Shireman et al. ObservationalUSA

1999–2000 (1)n = 274

<37 weeks and CLD, <10 months

11.7 5.8 50 (0.067) [29]

Sorrentino et al. ObservationalUSA

1998–1999 (1)n = 1839, no controls

≤35 weeks; <2 years and CLD

2.3 [30]

<28 weeks and CLD (n = 445)

3.4

28–31 weeks, and CLD (n = 611)

2

32–35 weeks and CLD (n = 548)

1.4

Note: RSV confirmed by laboratory testing in all rehospitalizations.BPD: Bronchopulmonary dysplasia; CHD: Congenital heart disease; CLD: Chronic lung disease; RCT: Randomized controlled trial; RSV: Respiratory syncytial virus; RSV-RH: RSV-rehospitalization.



TABLE 3 presents data from European epidemiological studiesthat estimate rates of rehospitalization due to RSV in cohortswhere palivizumab was not administered [5,8–12,20,31–39]. Thesesuggest that background admission rates for all pre-term infantsare 3–13% and approximately 7–15% for those with BPD.Post-marketing surveillance rates in pre-term infants receivingpalivizumab are less than 5% for those without, and between 2and 8% for those with BPD (TABLE 2). Therefore, it appears thatwhilst the rates observed in the controlled trials may be similarto those seen in the UK, uncritical generalization should beavoided. Combinations of risk factors such as BPD, smoking

and the presence of siblings in day-care nursery will increase thehospitalization rates [31], but this level of detail is available infew studies and may not be generalizable to the UK setting.

Clinically relevant outcomes for assessing cost–effectivenessHospitalizationThe available data on clinically relevant outcomes are largelyrestricted to those collected in the large trials and primarilyrelate to preventing rehospitalization. Whilst it is relatively easyto assign a cost using currently available published prices, thelatter vary between hospitals and healthcare settings.

Table 3. Background respiratory syncytial virus admission rates in European studies.

Study Study period (RSV seasons)

Country Population characteristics (n)

RSV testing for all admissions

Percentage RSV admission rates (population)

Ref.

Clark et al. (2000) 1998–2000 (2) UK <36 weeks; <6 months;<2 years and CLD (656)

No 8.1 (all); 6.2 (<36 weeks, <6 months); 15.3 (<2 years and CLD)

[9]

Thomas et al. (2000) 1995–1997 (3) UK <32 weeks (82) No 4 [32]

McCormick et al. (2002)

2001–2002 (1) UK <36 weeks (2011) Yes 6.4 (<36 weeks); 7.3 (≤32 weeks) [33]

Muller-Pebody et al. (2002)

1995–1998 (4) UK Children <5 years (not specified)

No 2.83 (<12 months); 0.13 (1–4 years)

[5]

Deshpande et al. (2003)

1996–1999 (3) UK All infants (14,664) No (77%) 2.4 (all); 8.9 (≤32 weeks); 12.5 (≤28 weeks)

[8]

Zaw et al. (2003) 1995–1999 (5) UK <35 weeks (not specified)

Yes 3.6 [11]

Broughton et al. (2006)

Year not specified (1)

UK <32 weeks (39) Yes 15.4 [34]

Carbonell-Estrany et al. 2000

1998–1999 (1) Spain ≤32 weeks (584) Yes 10.1 [20]

Carbonell-Estrany et al. (2001)

1999–2000 (2) Spain ≤32 weeks (not specified)

Yes 13.4 (season 1); 13.1 (season 2) [10]

Duppenthaler et al. (2001)

1998–2000 (2) Switzerland All infants (10,000) Yes 1.3 (<12 months); 6 (≤35 weeks); 16 (≤35 weeks and CLD)

[35]

Resch et al. (2006) 2001–2003 (2) Austria 29–32 weeks (801) Yes 4.5 [36]

Esposito et al. (2005)

2002–2003 (1) Italy <15 years (1520) Yes 7.6 (all); 22.7 (<2 years) [37]

Roeckl-Wiedman et al. (2003)

1998–1999 (1) Germany <35 weeks (717) No 5.2 [31]

Heikkinen et al. (2005)

1991–2000 (10) Finland <36 weeks and CLD (1824)

Yes 12 (CLD); 7.1 (≤28 weeks); 6.8 (29–32 weeks); 3.7 (33–35 weeks)

[12]

Rackham et al. (2005)

Years not specified (3)

UK CHD (131) Yes 10 [38]

Meberg et al. (2006) 1987–2004 Norway CHD (500) Yes 4.8 [39]

CHD: Congenital heart disease; CLD: Chronic lung disease.

Palivizumab


Hospitalization is robustly defined, but may not be a precisemeasure of illness, as indications and requirements for hospitalcare or treatment are likely to reflect how healthcare is organ-ized [40]. Whilst data from the IMpact study do not suggestthat UK admission rates are substantially different from thosein the USA, it is not possible to know whether demographiccharacteristics were the same as in the remainder of the cohort.

Whilst the risk of rehospitalization is clearly reduced, there isno evidence that it reduces the potentially substantial costs asso-ciated with the need for prolonged hospitalization in occasionalinfants. In the IMpact study, three of 500 infants (0.7%) receiv-ing placebo, and seven of 1002 (0.7%) receiving palivizumabhad rehospitalizations of 14 days or greater. Although admis-sion to the pediatric intensive care unit (PICU) was lower inthe palivizumab group, more of those infants required mechan-ical ventilation. In the CHD study, there was a nonsignificantlower rate of PICU admission (2% for palivizumab vs 3.7% forplacebo) and requirement for mechanical ventilation (1.3 vs2.2%) [15]. Although neither study was powered to look at dif-ferences in these outcomes, it appears that the effect of palivizu-mab (if any) is small. Combined with a low background rate ofrequirement for mechanical ventilation, any cost savings forindividual units are likely to be negligible.

Adverse eventsThere are no data to suggest that adverse events are more com-mon with palivizumab than placebo in the controlled trials thatadministered palivizumab to 1641 infants. No concerns havebeen raised in post-marketing surveillance studies. Rare adverseevents are still possible, but there is no indication to ascribe acost for these in current economic models.

MortalityMortality due to RSV is uncommon, but is important to identifyit precisely as the economic benefit of life years gained may be fargreater than that of hospitalization alone. There were no signifi-cant differences in mortality in the IMpact study (five of 500 inplacebo vs four of 1002 in the palivizumab groups), or in deathsduring hospitalization for RSV (0 of 500 vs two of 1002) [7].However, some cost-effectiveness studies have interpreted thisdata as showing that “…absolute mortality was lower for palivi-zumab” [41], and have supported this by using data from Sam-palis, which appear to show a decrease in risk of mortalitybeyond the initial hospitalization [42]. This interpretation is opento question, as the primary analysis related to all-cause mortality.In the study by Sampalis, using data from a large cohort of Cana-dian infants, the mortality rate in those who had been hospital-ized with proven or probable RSV was 8.1%. This is high forotherwise low-risk infants of 32–35 weeks gestation. Althoughthe odds ratio of dying for those with RSV was 1.56 (95% confi-dence interval [CI]: 1.29, 2.15) it is worth noting that almostthree-quarters were sudden or otherwise unexplained deaths.

Joffe pooled data from three trials [6,7,22] to estimate the prob-ability of death among high-risk infants hospitalized with RSVto be 1.2% (95% CI: 0, 2.8) [43]. In a large population-based

survey in the UK, there was only one death ascribed to RSVhospitalization in a 3-year period, and that occurred in an infantwith complex CHD [8]. In the CHD study, there were no signif-icant differences in total mortality (21 of 639 [3.3%] in the pal-ivizumab vs 27 of 648 [4.2%] in the placebo group) [15]. Only aminority of these deaths were associated with RSV infection(two of 639 vs four of 648). If the background mortality fromRSV infection in this high-risk group (HRG) is only 0.6%, andthere was no effect from palivizumab, this would further sup-port the idea that there are unlikely to be economic benefits interms of life years gained from palivizumab.

UK population-based data

We have examined data from our own population using arobust and well-validated database of infant mortality [44]. Wewere only able to identify 14 deaths in children under 1 year ofage in the last 20 years due to confirmed RSV infection givingan approximate incidence of 1:50,000 births. Of these, onlyhalf (seven of 14) were born prior to 37 weeks gestation, threeof the seven died during treatment with extra-corporeal mem-brane oxygenation (ECMO), of whom one was transferred intothe region specifically for ECMO treatment. Of the other fourpre-term infants, one had significant ongoing medical prob-lems with liver complications following surgery for necrotizingenterocolitis. Seven infants were born at 37 weeks gestation ormore, and of these only two had identified CHD, one ofwhom had trisomy 21. Even if data from our population haveunder-ascertained deaths from RSV by a factor of two, itappears that the incidence of infant deaths even in high-riskpopulations is very small, and unlikely to be significantlyaffected by widespread use of palivizumab.

Symptomatic RSV infection is more likely to occur in infantswith pre-existing lung abnormalities [34]. Excess mortality ininfants hospitalized with RSV infection, or following hospitali-zation, may simply reflect pre-existing morbidity rather than aneffect of RSV infection per se. We do not think there is strongevidence that palivizumab decreases mortality, and thereforedid not include benefits for life years gained into our analysis.

Delayed respiratory problemsThere is evidence that infants who have had RSV infection aremore likely to wheeze or develop asthma [45], but it remains farfrom clear whether this is due to RSV infection per se, or whetherboth the symptomatic RSV infection and later wheezing andasthma reflect underlying increased vulnerability due to lungfunction deficits. Impaired respiratory reserve has recently beendemonstrated in infants who subsequently develop RSV [34], andothers have suggested that RSV bronchiolitis may act as amarker for genetic predisposition [45].

There are limited data that appear to show a reduction inasthma scores in those treated with polyclonal anti-RSV anti-body [46]. Simoes et al. examined the potential long-term effectof palivizumab by matching a cohort of pre-term infants whoreceived it with those of similar gestation who did not [47].They demonstrated that the incidence of physician-diagnosed



recurrent wheezing was significantly less in palivizumab-treated pre-term infants (8%) compared with those who werenot treated (16%). However, the authors [47] and others [48]

have pointed out substantial limitations to this study. Deci-sions regarding who should have received prophylaxis, or not,and the precise eligibility criteria were not robustly defined.Although those receiving prophylaxis were of lower birth-weight and slightly more pre-term, the control group hadmore additional risk factors for RSV. There are few other stud-ies examining this issue, and none are prospectively and ran-domly assigned. The study by Simoes et al. is important but“…unavoidable questions about selection of infants with thisstudy design mean that the conclusions are uncertain” [48].Given this major uncertainty, we elected not to include anycost–benefit in terms of reduction in longer term health out-comes following palivizumab.

Cost–effectiveness of palivizumab: published dataPalivizumab is expensive and has been introduced into wide-spread clinical use in the UK without strong evidence of longerterm health benefit, or the backing of influential bodies such asthe National Institute for Health and Clinical Excellence(NICE). Cost-effectiveness analyses have been performed[41,43,49,50], expressing the costs in monetary units and measur-ing health effects in non-monetary units such as life yearsgained, quality-adjusted life years gained and/or incrementalcost–effectiveness ratios per rehospitalization avoided.

Studies using a cost–benefit analysis where both costs andhealth effects are described in the same units (usually mone-tary) could be performed, but it remains a matter of debate asto whether a truly accurate financial cost can be ascribed to allthe consequences of being rehospitalized. Cost–benefit analysisalone will not determine the introduction of newer expensivetherapies such as palivizumab into routine practice, as thehealth benefit to the infant and family of not being admittedare difficult to quantify. Although a cost utility analysis focusedaround RSV might examine how best to achieve healthy yearscompared with other strategies, such as hand-washing advice,for example, we are not aware of any such published studies inrelation to palivizumab [51].

The economic analyses of palivizumab that have been pub-lished show a wide variability in their results. This might partlybe explained by differences in study methods and assumptions,geography and type of population, or simply reflect poor qual-ity. [52] A systematic review of economic analyses found a signif-icant association between funding source and study results [52].None of the studies without industry sponsorship reportedcost–benefit or acceptable cost–effectiveness. It is clear thatthere is a substantial potential for introducing bias into eco-nomic studies given the discretionary nature of model buildingand data selection [53].

The key studies are listed in TABLE 4 [8,9,11,12,23,29,31–33,35,38,39,

41,43,49,50,54–60]. Although this does not include every relevantstudy, we feel it provides a reasonable overview of current data.To enable a meaningful comparison between studies in different

countries, where necessary, we converted the costs to poundssterling using published exchange rates [102]. Mid-year (30thJune) currency exchange rates were used for the year duringwhich the study was performed or published. We did not adjustfor inflation. The costs of preventing rehospitalization variedwidely depending on risk group and population. In studiesfrom the UK and Ireland, the cost of preventing one rehospital-ization varied from £60,000 to £118,181 in infants born at orless than 35 weeks [11,33].

In other European studies, there was again a wide variation incosts ranging from £26,650 to £135,450 [12,35]. In infants withBPD, costs ranged from £7560 to £47,250 per rehospitalizationprevented [12,43], and in those with CHD, costs varied from£17,700 to £107,250 depending on the type of populationchosen [38,39]. Even in studies that accounted for the societalperspective, there was no cost saving.

Cost–effectiveness model & assumptions for current analysisEfficacy & rehospitalization ratesWe developed a model using the criteria and assumptions asdiscussed previously. We used the hospitalization rates observedin the IMpact study, and the rates for infants with BPD. Weperformed a sensitivity analysis using different backgroundRSV-RH rates from 4 to 12% for those without, and 6 to 21%for those with BPD (TABLE 5). We calculated efficacy using theranges observed:

and repeated the analyses with efficacies ranging up to 0.85.The effect of reduced hospitalizations was restricted to a singleRSV season.

Utility costsWe did not include costs for RSV-related mortality or long-term complications of RSV infection (e.g., wheezing,asthma). Therefore, we did not consider discounting of costsor longer term utility costs as others have done [41,61]. Theassociated resource costs, except that for palivizumab, havenot been robustly defined. These are likely to be only a frac-tion of the drug itself as many of the high-risk infants mayalready be attending a clinic or being visited by a health pro-fessional and the additional time taken for administration isprobably short.

Costs for palivizumabWe repeated the analysis for infants discharged with oxygen.We performed a sensitivity analysis using differing costs for pal-ivizumab assuming that infants only received four doses (totaldifference = £600 per infant) or that weight gain was slowerthan we observed. Slower weight gain might result in infantsreceiving one more 50-mg vial and one less 100-mg vial (totaldifference = £240 per infant). We assumed that vial sharing wasnot allowed and that there was no drug wastage (i.e. all drugsprepared were administered).

Efficacy RSH-RH non-immunized RSH-RH palivizumab–RSV-RH non-immunized

------------------------------------------------------------------------------------------------------------------------=

Palivizumab


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e 4.

Pal

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umab

cos

ting

stu

dies

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s*Re

f.

Joff

e et

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(199

9)

USA

Not

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1)De

cisi

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Sens

itivi

ty a

naly

ses

Soci

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per

spec

tive

7.4

(hig

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CHP:

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60),

high

est r

isk

grou

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P: $

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00 (£

756,

000)

, low

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[43]

Clar

k et

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(200

0)

UK

1998

–200

0H

RG (6

56)

<36

wee

ks, <

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19);

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and

CLD

(137

)

Cost

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ectiv

enes

sN

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port

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er a

2-y

ear p

erio

d:

NCP

: £1,

160,

799

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CR: £

95,1

34 (H

RG)

NCP

: £88

3,83

1 (<

36w

eeks

, <6

mon

ths)

NCR

: £48

,650

(<36

wee

ks, <

6m

onth

s)N

CP: £

461,

177

(<2

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146,

484

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[9]

Thom

as e

tal.

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UK

1995

–199

7<3

2w

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(82)

Cost

–eff

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enes

sN

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port

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CP: £

368,

532

NCR

: £44

,188

[32]

Lofla

nd e

tal.

(200

0)

USA

Not

sp

ecifi

edH

RGDe

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on a

naly

sis

mod

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nsiti

vity

ana

lysi

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al c

osts

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repo

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CHP:

$27

02-7

9,70

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Tabl

e 4.

Pal

iviz

umab

cos

ting

stu

dies

(or

dere

d ac

cord

ing

to y

ear

of p

ublic

atio

n) (

cont

.).

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yCo

untr

ySt

udy

perio

dPo

pula

tion

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Type

of

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omic

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alys

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NT

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f.

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vers

ion

to G

BR£

was

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e us

ing

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dy/p

ublic

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n) e

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nge

rate

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D: C

onge

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l hea

rt d

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se; C

HF:

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iss

Fran

cs; C

HP:

Cos

t per

hos

pita

lizat

ion

prev

ente

d; C

LD: C

hron

ic lu

ng d

isea

se; C

LYG

: Cos

t per

life

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r gai

ned;

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: Hig

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k gr

oup;

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onth

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D;

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enta

l cos

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aine

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ear.

Palivizumab


Length of stayThere are no data to suggest a reduction in length of stay for hos-pitalized infants who received palivizumab. The IMpact studyshowed a reduction in PICU admissions, but no effect on theneed for ventilation. There was no significant difference in thosewith CHD [15]. We did not use data from the subset of UK infantsin the IMpact study, as this related to just seven hospitalizations,and therefore used the average length of stay calculated by Nuijtenet al. of 6.45 days (4.58 days on a pediatric ward, and 1.88 days ona PICU) [41]. This figure was only used when costs were calculatedon a daily basis instead of a finished consultant episode.

Hospital costsWe used data on costs for finished consultant episodes from theNHS reference costs 2005–2006 document [103]. We identifiedan admission of RSV bronchiolitis to come under the HRG labelof acute bronchiolitis (HRG code-P27) and the associated cost tobe £1213. However, this code was associated with just a 2-dayadmission. We therefore elected to use the HRG label of bron-chopneumonia without complications as the average length ofstay was 6 days (HRG code-D42), with a national average unitcost of £1397. We also determined costs that would be appliedfor a single day of hospital care using data from our local hospitaland those that would be charged for a private patient admission.These were £271 per day for the pediatric ward and £1827 perday for admission to the PICU. In addition, the cost associatedwith a single day admission to PICU of £2067 (Service code-CC9) was obtained from the NHS reference costs dataset [103].This generated the ranges used in the sensitivity analysis.

Loss of incomeWe used an average household income of £13,300 per year toestimate the loss of earnings associated with a 7-day admission tobe £260 [104]. This is slightly higher than average national

income. We did not adjust this figure in the sensitivity analysis.The costs of work loss during rehospitalizations have been previ-ously reported to be as high as $1039–1292 for one parent for anaverage stay of 10.7–13.3 days, respectively [58].

ResultsResults are presented in TABLE 6. The incremental cost of a strategygiving palivizumab to all pre-term infants less than 32 weeks ges-tation is £2550 per infant, with an incremental cost per rehospi-talization averted of approximately £40,400. Infants with BPDhad higher weights at discharge than those without. Conse-quently, their costs for palivizumab prophylaxis are somewhathigher at £2915 per infant. Palivizumab is less efficacious in thosewith BPD, and even in the scenario where hospital costs werehigher (£4939 per admission) the incremental cost was £2663 perinfant and approximately £54,800 per rehospitalization averted.

In pre-term infants without BPD, increasing the drug efficacyto 0.85 and varying the baseline rehospitalization rate between4 and 21% generated costs of approximately £76,400–13,200per rehospitalization averted. Varying the baseline rehospitaliza-tion rates in infants with BPD between 6 and 21%, but main-taining efficacy at the level observed in the IMpact study (0.38)and keeping hospital costs high (£4939 per admission) generatedincremental cost estimates of approximately £122,700–31,300per rehospitalization averted. The lowest incremental costs wereobserved in the hypothetical scenario of high efficacy (0.85),high baseline admissions (21%), low drug costs (£2055 perinfant) and high rehospitalization costs (£4939 per admission),and were £6314 per rehospitalization averted.

DiscussionWe have reviewed currently available data on efficacy andcost–effectiveness for prophylaxis with palivizumab in pre-terminfants with or without ongoing lung disease (BPD). This

Table 5. Estimates and ranges for variables used in the cost–effectiveness model.

Variable Estimate Range used in sensitivity analysis

Non-cost

Probability of rehospitalization in no-prophylaxis group: <32 weeks gestation; BPD 0.081; 0.128 0.04–0.12; 0.06–0.21

Efficacy of palivizumab: <32 weeks gestation; BPD 0.78; 0.39 0.75–0.85; 0.39–0.85

Probability of rehospitalization in prophylaxis group: <32 weeks gestation; BPD 0.018; 0.079 0.009–0.026*; 0.037–0.130*

Length of RSV rehospitalization (days) 6.45

Costs

Palivizumab: 50-mg vial; 100-mg vial; average cost per infant <32 weeks gestation; average cost per infant with BPD

£360; £600; £2655; £2916 £2055–2655; £2316–2916

RSV hospitalization £1397 £1397–4939

Weekly household income £260

*Probabilities of re-admission in palivizumab prophylaxis group calculated from theoretical ranges of efficacy.BPD: Bronchopulmonary dysplasia; RSV: Respiratory syncytial virus.



Tabl

e 6.

Incr

emen

tal c

osts

(£)

and

res

ults

of

sens

itiv

ity

anal

yses

.

Scen

ario

des

crip

tion

Effi

cacy

Base

line

RSV-

RH r

ate

(%)

Paliv

izum

ab c

ost

per

infa

nt

RSV-

RH c

ost

per

adm

issi

onN

umbe

r of

RSV-

RH

aver

ted

per

100

Incr

emen

tal c

ost

per

infa

ntIn

crem

enta

l cos

t pe

r RS

V-RH

ave

rted

Pre-

term

infa

nts

with

out B

PD0.

788.

126

5513

976.

325

5040

,400

Pre-

term

infa

nts

with

out B

PD0.

784–

1226

5513

973.

1–9.

426

03–2

500

83,4

00–2

6,70

0

Incr

ease

d dr

ug e

ffic

acy

0.85

4–21

2655

1397

3.4–

17.9

2599

–235

976

,400

–13,

200

Infa

nts

with

BPD

0.38

12.8

2915

4939

4.9

2663

54,8

00

Infa

nts

with

BPD

0.38

6–21

2915

4939

2.3–

8.0

2797

–250

112

2,70

0–31

,300

Incr

ease

d ef

ficac

y an

d lo

wer

dru

g co

sts

0.85

4–21

2055

4939

3.4–

17.9

1878

–112

755

,200

–630

0

Not

e: In

crem

enta

l cos

ts h

ave

been

roun

ded

to th

e ne

ares

t £10

0.

BPD:

Bro

ncho

pulm

onar

y dy

spla

sia;

RH

: Reh

ospi

taliz

atio

n du

e to

resp

irato

ry s

yncy

tial v

irus;

RSV

: Res

pira

tory

syn

cytia

l viru

s; R

SV-R

H: R

SV-r

ehos

pita

lizat

ion.

shows that palivizumab is both safe and effective, but high-lights the widely differing levels of cost–effectiveness. We havediscussed the difficulties in utilizing variables and cost datafrom the currently available controlled trial and observationalstudies. Furthermore, we have examined the difficulties inextrapolating data on subgroups for these economic analyses,uncertainties in the validity or robustness of risk group defini-tions, and the problems that clinicians or policy-makers facewhen trying to develop workable recommendations for the useof palivizumab.

We developed a model using data that reflect the current UKhealthcare setting, and attempted to generate costs for a hypo-thetical cohort of infants born pre-term and those with BPD.We did not aim to develop a model for those with CHD,although similar limitations would have applied. Incrementalcosts per rehospitalization averted were generally very high andranged from £6300 to £122,700 in the scenarios examined.Even in a hypothetical scenario of high efficacy, high baselinerehospitalization rates, high hospital and low drug costs, therewas still no cost saving observed.

Our model used data from a large cohort of infants to ascer-tain accurate weights, and therefore the costs of palivizumab.The other estimates used are currently valid for the UK,although we accept that costs of hospitalization can vary.Nevertheless, these costs remain significantly lower than that ofpalivizumab prophylaxis. We did not perform a sensitivity anal-ysis adjusting costs of a vial of palivizumab, as price reductionsremain purely hypothetical. It is clear, however, that a reductionin unit cost of palivizumab would have the greatest impact oncost–effectiveness. We assumed no drug was wasted, althoughin practice this may not always be achievable. Neither the man-ufacturer, nor current Department of Health recommendationssupport the use of sharing vials between patients, despite thepotential cost savings associated with this [63].

We calculated costs and length of stay from the averages pub-lished in the controlled trial. This may underestimate the costsassociated with a very prolonged admission. However, suchprolonged hospitalizations occur in less than 1% of RSV-RHamong high-risk infants [7], and the median (interquartilerange) length of RSV-RH in pre-term infants is 2 (1–4) days [8],but we chose to use the longer duration of 6.5 days calculatedby Nuijten et al. [41]. We also used the higher hospitalizationcosts of bronchopneumonia under the NHS tariff, therebyfavoring palivizumab in cost–benefit analysis. We did notinclude costs associated with general practitioner or primarycare visits, the costs of ambulance transfer to hospital, and/orassessment in an accident and emergency department, whichmay improve the cost–effectiveness of palivizumab. Hospitalcosts reflect prices currently charged in the UK NHS, but maynot adequately address total hospital and staff costs.

A potential limitation of our study is our restriction of ben-efit to the first season of RSV. We do not feel that there areany data to support the suggestion that mortality rates aredecreased, especially given the very low incidence in ourbackground population. Whilst studies have shown increased

Palivizumab


frequency of respiratory morbidity and healthcare utilizationin pre-term infants subsequent to RSV-RH [64], there remainsno current evidence of quality of life improvement followingpalivizumab use. Even if this was included, and a reducedprevalence of asthma was assumed, the value of the improve-ment is likely to be small [50]. Although tools such as theHealth Utility Index may be insensitive to quality-of-lifeissues for those with asthma [65], alternative data are not avail-able, and it seems clear that the decrease in health status withasthma must be quite profound for it to significantly affectcost–effectiveness [50,66].

Expert commentaryThe true societal burden of RSV is difficult to quantify, andfew economic analyses have taken into account the costs to thecaregiver or the societal perspective [43]. A prospective studyhas attempted to quantify the magnitude of patient, parentaland family distress associated with RSV infection [67]. Parentsof infants hospitalized with RSV reported significantly higherlevels of anxiety, stress and poorer overall health comparedwith their control counterparts that continued during thepost-discharge period. Although the manufacturers haveargued for the incorporation of parental preferences into a cost-ing study [65], this is not standard practice in cost–effectivenessanalyses [66].

In conclusion, we feel there is insufficient evidence to sup-port the cost–effectiveness of palivizumab in pre-term infants.Even in the most extreme scenario likely to benefit palivizumabusage (i.e., high efficacy and high background admission rates),we were unable to demonstrate cost–effectiveness. In those withBPD, it is even less cost–effective – primarily because ofincreased drug costs and decreased efficacy. Does this mean itsuse should not be recommended? There is a substantial psycho-logical burden associated with hospitalization, and limiting thecost–benefit to the family of averting admission to that ofincome may grossly underestimate societal benefits.

It seems possible that there may be longer term health bene-fits in terms of a reduced prevalence of asthma, but current dataare not strongly persuasive. Manufacturers should be stronglyencouraged to support long-term data collection from control-led trials rather than rely on noncontrolled data, and to fundtrials sufficiently large to show a reduction in mortality if suchdata are to be used to recommend the use of palivizumab.

Because it is possible that there may be long-term benefit,many will feel it appropriate to continue recommending its usein those with the highest risk. Neonatal intensive care forextremely pre-term infants (i.e., those who most commonlydevelop BPD) is expensive, may last several weeks and is likelyto be well in excess of £100,000 per infant. In this context, theincremental cost of palivizumab of £2500 per infant might beviewed as little more than the costs of 2–3 days of intensivecare. Restricted use of palivizumab prophylaxis for infants atthe highest risk of adverse sequeale of RSV infection, such asthose with severe CLD (discharged on home oxygen therapy, orthose with severe BPD as defined by the NICHD criteria [19])

and hemodynamically significant CHD, may offer a clinician apragmatic compromise between the desire to protect the mostvulnerable infant and the limited cost–effectiveness of the drug.

Five-year viewPalivizumab will continue to be used and further economic ana-lyses will be produced; however, without long-term health oreconomic data from a controlled trial, the true economic benefitof palivizumab will be difficult to define. The debate surround-ing the widespread use of palivizumab highlights the need forconducting well-defined long-term clinical and pharmacoeco-nomic evaluations alongside short-term clinical efficacy trials.Further studies may more closely define risk groups and benefit,but we suspect that the decision to administer palivizumabprophylaxis will remain largely pragmatic.

The manufacturers have recently sponsored a large head-to-head trial of palivizumab versus a newer preparation, Motavizu-mab®, which was designed to be more efficacious. MedImmuneconducted a multicenter study in approximately 300 centers inover 24 countries recruiting approximately 6600 infants (Gaith-ersburg, MD, USA, November 6, 2006, Healthcare MarketingSales and Network News Newsfeed). The results showed nonin-feriority in the primary end point with a 26% relative reductionin RSV-RH among high-risk infants. Motavizumab alsoshowed superiority over palivizumab for a secondary end pointby achieving a 52% relative reduction in the incidence of ‘med-ically attended outpatient lower respiratory infections’ causedby RSV. Economic analyses must wait until the full results arepublished in a peer reviewed publication, but it seems possiblethat a 26% reduction in hospitalizations will not be sufficienton its own to dramatically affect the interpretation ofcost–effectiveness. Documentation of any longer term healthoutcomes would be important, but there is no evidence that thesponsors plan to undertake such a long-term study on thosewho received either drug.

Currently, the decision to administer palivizumab prophy-laxis is largely left to the clinician’s discretion. Althoughnational advice from the Joint Committee on Vaccination andImmunisation is available, there is no firm recommendationfrom any professional craft body such as the Royal College forPaediatrics and Child Health. Given the expense of palivizu-mab, and the continued lack of cost-efficacy, it would seemprudent that NICE examined current policy and issued clearguidance to clinicians.

Financial & competing interests disclosureSandeep Dharmaraj was part funded by Abbott Laboratories for afollow-up study of RSV infections in preterm infants, but has noongoing affiliations or financial involvement with them or anyother relevant company. The authors have no other relevant affilia-tions or financial involvement with any organization or entity witha financial interest in or financial conflict with the subject matter ormaterials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of thismanuscript.



ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Key issues

• Mortality from respiratory syncytial virus (RSV) infection is low, even among high-risk infants. Hospitalization costs, which include admission to pediatric intensive care, dominate the costs incurred as a result of RSV infection.

• RSV infection in infancy is linked to an increase in wheezy illness in the subsequent 2–3 years.

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Affiliations

• Nicholas D Embleton, BSc, MBBS, MD, FRCPCH

Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UKTel.: +44 191 282 5156Fax: +44 191 282 [email protected]

• Sandeep T Dharmaraj, MBBS, MD, DCH,

MRCPCH

Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK

• Sanjeev Deshpande, MBBS, MD, FRCPCH

Royal Shrewsbury Hospital, Mytton Oak Road, Shrewsbury, SY3 8XQ, UK

Documents

Cost–effectiveness of palivizumab in infancy