Cost utility of palivizumab prophylaxis among pre-term infants in the United States: a national policy perspective

Abstract

Objective:

The cost-effectiveness of palivizumab has previously been reported among certain guideline-eligible, high-risk premature infants in Medicaid. Because guideline authorities base decisions on a national perspective, the economic model of palivizumab was adapted to include all infants, that is, public and privately insured patients (60% of palivizumab use is public, 40% is private).

Methods:

This study examined four groups of premature infants without chronic lung disease of prematurity or congenital heart disease: (1) <32 weeks gestational age (wGA) and ≤6 months chronologic age (CA); (2) 32–34 wGA, ≤3 months CA, with 2009 American Academy of Pediatrics (AAP) risk factors (RFs); (3) 32–35 wGA, ≤6 months CA, with 2006 AAP RFs; and (4) 32–35 wGA, ≤6 months CA, with ≤1 RF. An average estimate was used between public and private payors for (1) background rates of respiratory syncytial virus hospitalization (RSV-H), (2) direct medical costs associated with RSV-H, and (3) cost of palivizumab. Incremental cost-effectiveness ratios (ICERs) are reported in cost per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed.

Results:

Palivizumab saved costs and improved QALYs among infants <32 wGA. Palivizumab was cost-effective in infants 32–34 wGA with 2009 AAP RFs ($44,774 per QALY) and in infants 32–35 wGA with 2006 AAP RFs ($79,477 per QALY). The ICER for infants 32–35 wGA with ≤1 RF was $464,476 per QALY. Influential variables in the sensitivity analysis included background rate of RSV-H and cost and efficacy of palivizumab.

Limitations:

The results are not generalizable to populations outside of the US. The model did not examine all RFs. The wholesale acquisition cost was used as a payment benchmark; actual price paid by end providers varies.

Conclusions:

From a national policy perspective, palivizumab remained cost-effective for publically and commercially insured, guideline-eligible, high-risk premature infants. Palivizumab was not cost-effective in infants of 32–35 wGA with ≤1 RF.

Keywords::

• Respiratory syncytial virus
• Palivizumab
• Prophylaxis
• Cost-effectiveness
• Medicaid
• Private insurance

Introduction

Palivizumab is a monoclonal antibody administered monthly before and throughout the respiratory syncytial virus (RSV) season to prevent severe RSV disease among high-risk infants1. In a previous study2, we reported that palivizumab when dosed according to the US Food and Drug Administration (FDA)-approved labeling, was either cost-saving or cost-effective among current guideline-eligible infants in the Medicaid population. The market utilization for palivizumab is mostly in the public sector (55% Medicaid, 5% other), with the rest (40%) among the privately insured3. Guidelines consider cost-effectiveness in their deliberations, and having a national view that includes all infants (public and private) is most informative.

Our objective was to adapt our prior Medicaid economic model to be more relevant to guideline authorities in the US. We blended background rates of RSV hospitalization4–6, healthcare costs associated with RSV disease7,8, and the cost of palivizumab3 for both public and private sectors to come up with a national policy estimate.

Methodology

The structure of our economic model comparing palivizumab use to no RSV prophylaxis has been described previously2 and is shown in Figure 1. The primary clinical outcome is RSV hospitalization, where the risk of hospitalization depends on the gestational age of the infant, chronologic age, and the presence of risk factors.

Figure 1.  Structure of decision tree model. ICU, intensive care unit; RSV, respiratory syncytial virus.

Similar to our prior economic analysis of palivizumab in a Medicaid population2, we examined four groups of premature infants without chronic lung disease of prematurity (CLDP) or congenital heart disease (CHD): (1) <32 weeks gestational age (wGA) and ≤6 months chronologic age (CA); (2) 32–34 wGA, ≤3 months CA, with 2009 American Academy of Pediatrics (AAP) risk factors; (3) 32–35 wGA, ≤6 months CA, with 2006 AAP risk factors; and (4) 32–35 wGA, ≤6 months CA, with ≤1 risk factor. CA was determined at the start of the RSV season. Although premature infants with CLDP and CHD are included in the labeled indication for palivizumab, we only examined premature infants without these conditions to control for the additional effect of comorbidity on the risk of RSV hospitalization. We examined these four groups because they vary in their risk of RSV hospitalization, owing to differences in gestational age and the presence of risk factors. The groups also differ in CA and weight, which impacts the amount of drug that is administered and the cost-effectiveness results.

We assumed risk of RSV infection only in the first RSV season, defined in our model as November 1 to March 31, although the start and length of the RSV season can vary across geographic regions in the US. Infants born before the RSV season received up to five monthly doses of palivizumab throughout the RSV season, consistent with the dosing regimen in the registration trials for palivizumab9,10. Infants born during the RSV season received monthly doses until March 31. Our model did not examine the 2009 AAP recommendation of a maximum of three doses for infants of 32–34 wGA because the clinical efficacy associated with this dosing administration is unknown. We assumed that the first dose of prophylaxis for infants born during the RSV season was administered in the hospital at birth. We assumed 100% compliance with palivizumab and 5% drug wastage. We discounted costs and quality-adjusted life years by 3% annually. Costs have been adjusted to 2010 US$, when necessary, using the medical care services component of the consumer price index11.

Among infants with an RSV hospitalization, a proportion will require care in the pediatric intensive care unit (ICU). In a recent study, ∼20% of premature infants hospitalized for RSV required an ICU admission12. Of those infants in the pediatric ICU, the outcomes are either death during the hospital stay or survival. Mortality, therefore, is conditional on a pediatric RSV ICU admission. Gunville et al.13 examined patients who were admitted to the pediatric ICU with respiratory distress, the majority with RSV lower respiratory tract infection, and reported a mortality rate from 4.3–6.1%, depending on the gestational age of the infant.

Our economic model of palivizumab is focused only on RSV hospitalization as the primary outcome of interest. The efficacy of palivizumab in the high-risk groups was taken from the IMpact RSV Clinical Study3,10. Specifically, we used a 75.1% relative risk reduction (RRR) in RSV hospitalization rates for infants ≤32 wGA, ≤6 months CA (1.78% palivizumab; 7.14% placebo). There was an 82.2% RRR (1.78% palivizumab; 10% placebo) for infants of 32–35 wGA, ≤6 months CA, in the clinical trial. We used this particular efficacy for infants of 32–34 wGA with 2009 AAP risk factors, infants of 32–35 wGA with 2006 AAP risk factors, and for infants of 32–35 wGA with ≤1 risk factor.

We incorporated a 63% RRR (11.1% palivizumab [2/13] vs 30% placebo [12/31]) in the incidence of ICU admissions among those who were hospitalized with RSV based on post-hoc analysis of infants of ≤35 wGA without CLDP from the IMpact-RSV Clinical Study10. The 63% RRR in ICU admissions was used across all cohorts in the model.

Adaptations to the economic model

We adapted our previous economic model to include a blended average of public (60%) and private (40%) sector data along the following inputs: the background rate of severe RSV disease, the cost of RSV hospitalization, and palivizumab drug costs (Table 1). For infants of <32 wGA and ≤6 months CA, we used RSV hospitalization data from a recent meta-analysis of 10 studies examining prophylaxis with palivizumab vs no prophylaxis. Checchia et al.14 found a 10.7% RSV hospitalization background rate for pre-term infants of ≤32 wGA. The meta-analysis, however, did not specify rates for the other cohorts in our model. Therefore, we used the estimate of 7.1% for infants of 32–34 wGA with 2009 AAP risk factors and infants of 32–35 wGA with 2006 AAP risk factors, and a 1.7% RSV hospitalization rate was used for infants of 32–35 wGA with ≤1 risk factor based on the moderate- and low-risk groups from the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study15. In addition, the rate of severe RSV disease has been documented to be twice as high among Medicaid vs commercially insured infants4,6. We used the aforementioned information to estimate the rates of RSV hospitalization in the four cohorts in a Medicaid population (see footnote in Table 1). Blending the public and private sector utilization, 60% and 40%, respectively, the average rates of RSV hospitalization for infants in the four groups used in our current model were 15.4% (<32 wGA), 10.9% (32–34 wGA with 2009 AAP risk factors and 32–35 wGA with 2006 AAP risk factors), and 2.7% (32–35 wGA with ≤1 risk factor).

Table 1.  Blended inputs from Medicaid and commercial populations for base case.*

Variable	Infant population	Medicaid	Source	Commercial	Source	Blended value (60% Medicaid, 40% commercial)
Background risk of RSV hospitalization	<32 wGA, ≤6 mo CA	18.5%	†	10.7%	†	15.4%
	32–34 wGA, ≤3 mo CA with 2009 AAP RF	13.4%	†	7.1%	†	10.9%
	32–35 wGA, ≤6 mo CA with 2006 AAP RF
	32–35 wGA, ≤6 mo CA with ≤1 RF	3.4%	†	1.7%	†	2.7%
Direct medical costs ∼1 year after RSV infection compared with placebo	<32 wGA, ≤6 mo CA	$39,399	Shi et al.7	$32,458	Stewart et al.8	$36,622
	32–34 wGA, ≤3 mo CA with 2009 AAP RF	$20,160	Shi et al.7	$25,368	Stewart et al.8	$22,243
	32–35 wGA, ≤6 mo CA with 2006 AAP RF
Cost of palivizumab	All groups	100 mg, $1,190.97 50 mg, $631.10	Estimated average public cost for palivizumab; MedImmune, Data on File.	100 mg, $2027.80 50 mg, $1073.88	WAC; Thomson Healthcare, Inc. 201017	100 mg, $1,525.70 50 mg, $808.12

* All other inputs in the model remained the same as the original model in the Medicaid population (see Weiner et al.2).

† We first estimated the background RSV hospitalization rates for infants of <32 wGA, ≤6 months CA (10.7%); 32–34 wGA, ≤3 months CA, 2009 AAP RF (7.1%); 32–35 wGA, ≤6 months CA, 2006 AAP RF (7.1%); and 32–35 wGA, ≤6 months CA, ≤1 RF (1.7%) from Checchia et al.14 (10.7%) and Sampalis et al.20 (7.1% and 1.7%). To obtain rates of RSV hospitalization for these cohorts covered by Medicaid, we converted these probabilities to odds (O = P/[1 − P], where O = odds and P = probability). We then multiplied the baseline odds by the OR of 2.03 (95% CI = 1.99–2.06), the increased odds of RSV hospitalization among infants from the Medicaid California population compared with the non-Medicaid California population. Finally, we converted the transformed OR to probabilities of RSV hospitalization for Medicaid infants of < 32 wGA, ≤ 6 months CA (18.5%); 32–34 wGA, ≤ 3 months CA with 2009 AAP RF (13.43%); 32–35 wGA, ≤ 6 months CA with 2006 AAP RF (13.43%); and 32–35 wGA, ≤ 6 months CA, with ≤ 1 RF (3.4%).

AAP, American Academy of Pediatrics; CA, chronologic age; OR, odds ratio; RF, risk factor; RSV, respiratory syncytial virus; WAC, wholesale acquisition cost; wGA, weeks gestational age.

We included the total healthcare costs within ∼1 year after a severe RSV episode in our economic model. Shi et al.7 examined healthcare costs associated with RSV within 12 months of diagnosis among Medicaid infants from 12 states compared with infants without RSV. We used United Healthcare data (a private health plan in the US) from Stewart et al.8, who estimated the total healthcare costs within the first year of life among infants with RSV compared with infants without RSV. Because the healthcare costs may differ between a Medicaid and commercially-insured population, we took the blended average of the healthcare costs associated with RSV.

The overall payer spend for palivizumab differs between Medicaid and commercially-insured infants. The cost of palivizumab is lower in Medicaid programs owing to significant manufacturer rebates, which should be reflected in economic analyses2,16. The estimated average public payer cost was calculated by taking the average reimbursement methodology of the top 10 palivizumab-using states in 2010 under Medicaid programs (ingredient cost and dispense fee) minus the unit rebate amount from the fourth quarter of 20102. We used the wholesale acquisition cost (WAC) for the private cost of palivizumab17. The average cost of palivizumab, blending the societal public and private cost for palivizumab, was $1525.70 for the 100-mg vial and $808.21 for the 50-mg vial.

All other clinical inputs (i.e., rates of ICU admission among those with a RSV hospitalization, mortality rate in the ICU, health utilities for RSV hospitalization, and indirect costs) remained the same in our original economic model of palivizumab in the Medicaid population2.

We report the cost-effectiveness of palivizumab as the incremental cost per quality-adjusted life-year (QALY). Extensive 1-way sensitivity analyses were conducted to ascertain which variables were most influential in the model. The parameter ranges (minimum and maximum values) used were identified from the literature or through post-hoc analysis of palivizumab clinical trial studies wherever possible2. To provide decision-makers with additional flexibility, we conducted 2-way sensitivity analyses varying RSV hospitalization rates vs cost of palivizumab to estimate cost-effectiveness under different assumptions (online appendix).

Results

The incremental cost-effectiveness ratios (ICER) for the various high-risk groups are shown in Table 2. For infants <32 wGA, palivizumab was a dominant strategy (i.e., saved costs and improved health outcomes) compared with no RSV prophylaxis. The ICER for infants of 32–34 wGA with 2009 AAP risk factors was $44,774. For infants of 32–35 wGA with 2006 risk factors, the ICER was $79,477. Palivizumab was not cost-effective for infants of 32–35 wGA with ≤1 risk factor ($464,476).

Table 2.  Net costs and QALYs between palivizumab prophylaxis and no prophylaxis among four groups of infants in a Medicaid and commercially-insured population.

	<32 wGA, ≤6 mo CA*			32–34 wGA, ≤3 mo CA*, with AAP 2009 RFs^a			32–35 wGA, ≤6 mo CA*, with AAP 2006 RFs^b			32–35 wGA, ≤6 mo CA*, with ≤1 RF^c
	Palivizumab	No Prophylaxis	Difference	Palivizumab	No Prophylaxis	Difference	Palivizumab	No Prophylaxis	Difference	Palivizumab	No Prophylaxis	Difference
Prophylaxis costs	$4108	$0	$4108	$4095	$0	$4095	$5613	$0	$5613	$5613	$0	$5613
RSV-related costs	$1445	$5803	−$4357	$462	$2599	−$2137	$462	$2599	−$2137	$115	$650	−$534
Total costs	$5553	$5803	−$249	$4557	$2599	$1958	$6075	$2599	$3476	$5728	$650	$5078
QALY	30.907	30.869	0.038	30.909	30.865	0.0437	30.909	30.865	0.0437	30.911	30.900	0.011
ICER	–	–	Dominant	–	–	$44,774	–	–	$79,477	–	–	$464,476

*CA at the start of the RSV season (November 1).

^aHaving siblings <5 years of age and/or attending day care.

^bHaving two of the following: environmental air pollutants, congenital abnormalities of the airways, severe neuromuscular disease, school-aged siblings, or day care attendance.

^cRisk factors described in Sampalis et al.20

AAP, American Academy of Pediatrics; CA, chronologic age; ICER, incremental cost-effectiveness ratio calculated as incremental costs/incremental QALYs; QALY, quality-adjusted life-year; RF, risk factor; RSV, respiratory syncytial virus; wGA, weeks gestational age.

Sensitivity analyses

One-way sensitivity analyses of parameter estimates were performed to determine the robustness of the baseline results across all study cohorts. A baseline rate of RSV hospitalization of 9.4% instead of 15.4% results in an ICER of $61,956 QALY for infants of 32 wGA (Table 3). For infants of 32–34 wGA with 2009 AAP risk factors, the baseline cost-effectiveness results were most sensitive to changes in the background rate of RSV hospitalization and the efficacy of palivizumab (Table 4). Using the WAC cost in the sensitivity analysis (instead of the blended average) results in an ICER of $73,218 for infants of 32–34 wGA with 2009 AAP risk factors. Across sensitivity analysis of most variables, palivizumab was found to be cost-effective for infants of 32–35 wGA with 2006 AAP risk factors (Table 5) and within the range of the ICER of other recommended vaccines, such as meningococcal vaccine, which has an ICER of $157,000 QALY18. Palivizumab did not reach cost-effectiveness in any sensitivity analysis for infants of 32–35 wGA with ≤1 risk factor (Table 6). Overall, influential variables in the sensitivity analysis included the background rate of RSV hospitalization, the cost of palivizumab, and the efficacy of palivizumab. One-way and 2-way sensitivity analyses generally demonstrated robustness of results for each group across a plausible range of parameter estimates and assuming a willingness to pay comparable with other vaccines (Tables 7A–7D in online appendix).

Table 3.  One-way sensitivity analysis for infants of <32 wGA, ≤6 months CA.

	Baseline results: Input		Dominant ICER
	Minimum	Maximum	Input minimum	Input maximum
RRR of RSV hospitalization (75.1%)	27.2%	91.5%	$85,613	Dominant
Background risk of RSV hospitalization (15.4%)	9.4%	34.2%	$61,956	Dominant
Discount rate for outcomes (3%)	0%	5%	Dominant	Dominant
Cost of palivizumab per mg^a ($15.71)	$12.57^b	$18.85^b $20.88^c	Dominant	$13,081 $25,737
Increased direct medical costs 12 months after RSV infection compared with placebo ($36,623)	$29,298	$43,947	$15,635	Dominant
Probability of infant fatality in ICU (4.3%)	3.0%	8.11%	Dominant	Dominant
Background risk of ICU admission (19.5%)	17.8%	48.4%	Dominant	Dominant
RRR of ICU admission (63%)	0%	94.8%	Dominant	Dominant

^aDue to weight-based dosing of palivizumab, the model calculations are based on a cost per mg value that is derived from the average cost per mg for 100-mg and 50-mg vials of palivizumab, respectively.

^bDerived from ±20% of the average base case cost per mg for 100-mg and 50-mg vials of palivizumab.

^cWAC scenario.

ICER, incremental cost-effectiveness ratio; ICU, intensive care unit; RRR, relative risk reduction; RSV, respiratory syncytial virus; LRI, lower respiratory tract illness; wGA, weeks gestational age; CA, chronologic age.

Table 4.  One-way sensitivity analysis for infants of 32–34 wGA, ≤3 months CA, with 2009 AAP risk factors.

	Baseline results: Input		$44,774 ICER
	Minimum	Maximum	Input minimum	Input maximum
Background risk for RSV hospitalization (10.9%)	8%	34.2%	$78,481	Dominant
Cost of palivizumab per mg^a ($15.71)	$12.57^b	$18.85^b $20.88^c	$27,485	$62,063 $73,218
RRR of RSV hospitalization (82.2%)	45.4%	94.2%	$79,560	$35,769
Discount rate for outcomes (3%)	0%	5%	$18,257	$65,856
Increased direct medical costs 12 months after RSV infection compared with placebo ($22,243)	$17,795	$26,692	$53,874	$35,674
Background risk of ICU admission (21.9%)	17.8%	48.4%	$54,351	$20,874
Probability of ICU death (6.1%)	3%	8.11%	$85,749	$33,920
RRR ICU admission (63%)	0%	94.8%	$50,500	$42,345

^aDue to weight-based dosing of palivizumab, the model calculations are based on a cost per mg value that is derived from the average cost per mg for 100-mg and 50-mg vials of palivizumab, respectively.

^bDerived from ±20% of the average base case cost per mg for 100-mg and 50-mg vials of palivizumab.

^cWAC scenario.

ICER, incremental cost-effectiveness ratio; ICU, intensive care unit; LRI, lower respiratory tract infection; RRR, relative risk reduction; RSV, respiratory syncytial virus; wGA, weeks gestational age; CA, chronologic age.

Table 5.  One-way sensitivity analysis for infants of 32–35 wGA, ≤6 months CA, with 2006 AAP risk factors.

	Baseline results: Input		$79,477 ICER
	Minimum	Maximum	Input minimum	Input maximum
Background risk for RSV hospitalization (10.9%)	8%	34.2%	$125,677	Dominant
Cost of palivizumab per mg^a ($15.71)	$12.57^b	$18.85^b $20.88^c	$55,482	$103,471 $118,952
Probability of case fatality in ICU (6.1%)	3.0%	8.11%	$152,210	$60,211
Discount rate for outcomes (3%)	0%	5%	$32,407	$116,899
RRR of RSV hospitalization (82.2%)	45.4%	94.2%	$120,982	$68,732
Background risk of ICU admission (21.9%)	17.8%	48.4%	$96,476	$37,052
Increased direct medical costs 12 months after RSV infection compared with placebo ($22,243)	$17,795	$26,692	$88,576	$70,377
RRR of ICU admission (63%)	0%	94.8%	$89,640	$75,166

^aDue to weight-based dosing of palivizumab, the model calculations are based on a cost per mg value that is derived from the average cost per mg for 100-mg and 50-mg vials of palivizumab, respectively.

^bDerived from ±20% of the average base case cost per mg for 100-mg and 50-mg vials of palivizumab.

^cWAC scenario.

ICER, incremental cost-effectiveness ratio; ICU, intensive care unit; LRI, lower respiratory tract infection; RRR, relative risk reduction; RSV, respiratory syncytial virus; wGA, weeks gestational age; CA, chronologic age.

Table 6.  One-way sensitivity analysis for infants of 32–35 wGA, ≤6 months CA, ≤1 risk factor.

	Baseline results: Input		$464,476 ICER
	Minimum	Maximum	Input minimum	Input maximum
Background risk of RSV hospitalization (2.7%)	1.7%	6.6%	$772,476	$162,699
Case fatality in the ICU (6.1%)	3%	8.11%	$889,543	$351,884
Discount rate for outcomes (3%)	0%	5%	$189,394	$683,178
Cost of palivizumab per mg^a ($15.71)	$12.57^b	$18.85^b $20.88^c	$368,498	$560,454 $622,378
Background risk of ICU admission (21.9%)	17.8%	48.4%	$563,827	$216,540
RRR of RSV hospitalization (82%)	45.4%	94.2%	$580,530	$434,435
Increased direct medical costs 12 months after RSV infection compared with placebo ($22,243)	$17,795	$26,692	$473,576	$455,377
RRR of ICU admission (63%)	0%	94.8%	$523,874	$439,283

^aDue to weight-based dosing of palivizumab, the model calculations are based on a cost per mg value that is derived from the average cost per mg for 100-mg and 50-mg vials of palivizumab, respectively.

^bDerived from ±20% of the average base case cost per mg for 100-mg and 50-mg vials of palivizumab.

^cWAC scenario.

ICER, incremental cost-effectiveness ratio; ICU, intensive care unit; LRI, lower respiratory tract infection; RRR, relative risk reduction; RSV, respiratory syncytial virus; wGA, weeks gestational age; CA, chronologic age.

Table 7A.  Two-way sensitivity analysis examining RSV hospitalization rates by palivizumab costs for infants <32 wGA, ≤6 months CA.

Scenario #	Background risk of RSV hospitalization: 15.4% (base case)	Cost of palivizumab per mg: $15.71 (base case)	ICER: Dominant (base case)
1	9.4% (min)	$12.57 (min)	$29,862
2	9.4% (min)	$20.08 (max)	$106,608
3	9.4% (min)	$20.88 (WAC scenario)	$114,758
4	34.2% (max)	$12.57 (min)	Dominant
5	34.2% (max)	$20.08 (max)	Dominant
6	34.2% (max)	$20.88 (WAC scenario)	Dominant

CA, chronologic age; ICER, incremental cost-effectiveness ratio; RSV, respiratory syncytial virus; wGA, weeks gestational age; WAC, wholesale acquisition cost.

Discussion

Our economic model was adapted to reflect the current market of palivizumab in the US: public and private sectors represent 60% and 40% of palivizumab utilization, respectively. From a societal perspective, palivizumab, administered consistently with the FDA-approved label, is cost-effective among guideline-eligible, high-risk premature infants without CLDP or CHD in the US. Palivizumab did not demonstrate cost-effectiveness in infants of 32–35 wGA with ≤1 risk factor.

Our economic model compared the cost-effectiveness of palivizumab between 2009 and 2006 AAP guidelines for infants of 32–34 wGA and 32–35 wGA, respectively. The cost-effectiveness of palivizumab was marginally favorable in infants of 32–34 wGA with 2009 AAP risk factors compared with infants of 32–35 wGA with 2006 AAP risk factors. The main reason is that 2009 AAP guidelines focus on a narrow group of premature infants who were ≤3 months CA at the start of the RSV season (i.e., these younger infants had a lower weight, resulting in lower drug costs compared with infants of 32–35 wGA with 2006 AAP risk factors, who were older and heavier at ≤6 months CA at the start of the RSV season). Because both groups had ≥2 risk factors, and having ≥2 risk factors has been shown to increase the risk of RSV hospitalization19,20, we assumed that the background rates of RSV hospitalization were similar in the two groups.

Our results on the cost-effectiveness of palivizumab in a broader population of guideline-eligible, high-risk premature infants and children in the US differ from the results of prior economic analyses of palivizumab21–23. Differences in our results are primarily due to the high-risk groups examined; the background rates of RSV hospitalization used in the model; inclusion or exclusion of health utilities resulting in QALY; estimated costs of RSV hospitalization and the other direct medical costs following acute RSV infection; inclusion of indirect costs (i.e., caregiver burden); and, most importantly, estimated costs of palivizumab and efficacy associated with palivizumab. Our economic model is the first to include the cost of palivizumab that reflects the current utilization of the drug between the publically and privately insured. Finally, we used gestational age-specific efficacy in non-CLDP premature infants (75.1–82.2% RRR).

In a recent systematic literature review of the cost-effectiveness of palivizumab, Smart et al.24 found that the cost-effectiveness of palivizumab became more favorable as the risk profile of the infant increased. Several studies have examined various risk factor combinations to identify infants at high risk for severe RSV disease among the largest group of premature infants (i.e., infants of 32–35 wGA represent ∼75% of all premature infants)25–27. Although young CA is a risk factor for RSV hospitalization, it is one of a set of risk factors, and the risk of RSV hospitalization is likely to increase when young CA is considered along with other risk factors. Similarly, premature infants older than 3 months are also at risk for RSV hospitalization, and, following the same logic, the risk of RSV hospitalization for this CA group can potentially increase with the presence of other risk factors.

Although healthcare has generally shifted from the inpatient to the outpatient setting in the US over the past few decades, the rate of RSV hospitalization has remained stable for young infants28–30. An earlier analysis of the National Hospital Discharge (NHD) data set conducted by Shay et al.31 from 1988–1996 (before FDA approval of palivizumab in 1998) found that hospitalizations associated with bronchiolitis increased substantially. However, a follow-up and recent study conducted by the Centers for Disease Control and Prevention using the NHD data found that the rate of RSV-coded hospitalization was similar between 1997–1999 and 2004--2006 (p = 0.56)30. Fryzek et al.28 also examined the NHD database from 1999–2006 and reported a non-significant decrease in RSV hospitalization across all age groups. In a surveillance study conducted by Hall et al.32, there did not appear to be any trend in confirmed RSV hospitalizations among infants of 0–5 months of age. It is important to note that these studies did not examine the exact cohorts in our model, and, therefore, the rates of RSV hospitalization from these studies may not be directly applicable. There is also the issue of under-diagnosis of RSV using claims data33. The aforementioned studies also differ in study design, groups examined, and definitions of RSV. Nevertheless, it may be reasonable to assume that the background rate of RSV hospitalization (rate of RSV hospitalization without prophylaxis) may have remained stable over time given that the evidence suggests that there is no apparent overall decrease in RSV hospitalization over time.

Our findings on the cost-effectiveness from a national policy perspective are important for healthcare professionals, patients, and policy-makers for several reasons. Palivizumab is the first monoclonal antibody in the area of infectious disease and pediatrics. Palivizumab use is targeted to high-risk infants and children to prevent severe RSV disease. According to the 2009 AAP guidelines, ‘Economic analyses fail to demonstrate overall savings in healthcare dollars because of the high cost if all at risk infants receive prophylaxis’34. Our economic analysis of palivizumab would suggest good pharmacoeconomic value among guideline-eligible, high-risk infants and with ICER within the range of currently-recommended vaccines by AAP and the Advisory Committee for Immunization Practices2. Second, according to Centers for Medicare & Medicaid services, the total population of Medicaid beneficiaries in managed care was 54,612,393 covered individuals. The percentage of managed care enrollment was 71.45%, representing a 25.75% increase from 2001 (56.82%)35. Medicaid managed care is imminent for many states in the US, and our economic analysis of palivizumab provides an integrated view for healthcare administrators who will provide care for both public and commercially-insured populations. Last, our findings are based on full FDA-approved dosing of palivizumab throughout the RSV season. The FDA-approved labeling states, ‘The efficacy of [palivizumab] at… dosing less frequently than monthly throughout the RSV season, has not been established’.

Recent evidence has shown that compliance with palivizumab is poor in Medicaid populations36, among racial/ethnic groups36,37, and capitated health plans37. Non-compliance with palivizumab is also associated with an increased risk of RSV hospitalization in Medicaid infants36,38. Improving compliance with appropriate dosing before and throughout the RSV season for guideline-eligible infants is warranted.

There are several limitations to this economic analysis. More evidence on RSV-specific mortality with and without palivizumab prophylaxis is needed. Non-compliance with palivizumab is a common problem in Medicaid populations, and future economic analyses can determine the cost-effectiveness of non-compliance vs compliance with palivizumab. Our model did not focus on the cost-effectiveness of palivizumab in CLDP or CHD infants. The WAC was used as a payment benchmark in sensitivity analyses in this model; actual price paid by end providers may vary based on a variety of factors. We did, however, widely vary palivizumab cost estimates in sensitivity analysis and the results remained robust. Finally, our results are not generalizable to infants outside of the US.

Our analysis makes several important assumptions, which bias the model in favor of no prophylaxis. First, we did not attribute a reduction in hospital length of stay resulting from palivizumab prophylaxis39. Second, the model did not include RSV disease presenting in outpatient settings. The incidence of outpatient RSV LRI visits and associated costs can be substantial on the healthcare system40–42. Third, we did not assume a mortality risk reduction due to palivizumab14 and modeled a background case fatality rate among RSV ICU patients only. Fourth, we did not value parents’ quality-of-life decrements when their child was hospitalized with RSV43. Some have advocated that pediatric cost-effectiveness analyses should value the effect on both the parents and child because these outcomes are real for both parties44. Fifth, per the Panel on Cost-Effectiveness in Health and Medicine45, we did not value the lifetime earnings lost (indirect costs) of infants because we include infant quality-of-life. Sixth, we did not assume a reduction in recurrent wheezing46. Should any of these aforementioned assumptions be included in the analysis, the cost-effectiveness profile of RSV prophylaxis with palivizumab would likely improve.

Conclusion

In our model, palivizumab remained cost-effective for guideline-eligible high-risk infants across both public and private sectors. Guideline-eligible infants included infants of <32 wGA, 32–34 wGA with 2009 AAP risk factors, and 32–35 wGA with 2006 AAP risk factors. Palivizumab did not demonstrate cost-effectiveness in infants of 32–35 wGA with ≤1 risk factors.

Transparency

Declaration of funding

This study was funded by MedImmune LLC.

Declaration of financial/other interests

PM has disclosed that he is an employee of MedImmune LLC and own shares in the company. AM has disclosed that he is now an employee of Genentech and own shares in the company, but was an employee of MedImmune at the time this study was carried out and completed. MP and LW have disclosed that they have served as consultants for MedImmune for this economic analysis. MP is on MedImmune’s speakers bureau for palivizumab.

Acknowledgments

This manuscript was formatted by Tiffany Buterbaugh of Complete Healthcare Communications, Inc. (Chadds Ford, PA), which was funded by MedImmune.