Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children - a systematic review and economic evaluation

Article history

The research reported in this issue of the journal was commissioned and funded by the HTA Programme on behalf of the Joint Committee on Vaccination and Immunisation (JCVI) as project number 06/29/01. The protocol was agreed in November 2006. The assessment report began editorial review in July 2007 and was accepted for publication in April 2008. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None

Copyright statement

© Queen’s Printer and Controller of HMSO 2008. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2008 Queen’s Printer and Controller of HMSO

Aim of this health technology assessment

This assessment aims

• to review systematically the scientific evidence on the effectiveness and cost-effectiveness of palivizumab for the prevention of respiratory syncytial virus (RSV) infection in children

• to model the cost-effectiveness of palivizumab for prevention of RSV infection in children

• to look at prognostic factors for RSV infection with at view to the identification of subgroups of children for whom there may be important differences in cost-effectiveness.

Background

Prescribing of palivizumab

We were unable to identify an audit or obtain up-to-date data on prescribing of palivizumab across the UK for secondary or tertiary care. However, worldwide, palivizumab is increasingly used, and sales generated a revenue of about US$1.2 billion in 2005. 14 In England and Wales there is no specific funding for palivizumab.

Anecdotally, secondary care clinicians we spoke to told us they would like to use this drug more because it is effective but they actually do so rarely because the very high opportunity cost would have a detrimental effect on their prescribing budgets. Such anecdotal reports, however, may reflect a biased view of clinical opinion. Therefore, we sought data on prescribing in primary and secondary care. Data for both the West Midlands and for England were provided to us by colleagues at the Department of Medicines Management at Keele University and are presented graphically in Figures 1 and 2. Primary care prescribing shows a predictable seasonal pattern and highly restricted use. The net ingredient cost (NIC) of palivizumab prescribed in primary care in England was £39,000 in 2005 and £44,000 in the first 10 months of 2006. 14 The figure suggests that the West Midlands has high levels of primary care prescribing, but without national data on secondary care prescribing it is impossible to tell whether the region has high overall palivizumab prescribing.

FIGURE 1.

Palivizumab prescribing by item and net ingredient cost (NIC) in the West Midlands.

FIGURE 2.

Palivizumab prescribing by item and net ingredient cost (NIC) in England.

Figure 3 shows secondary care prescribing by item in the West Midlands (excluding FP10 prescriptions written by hospital prescribers but dispensed in the community) provided by the Department of Medicines Management, Keele University. It can be seen that most prescribing originates in secondary care and there was an approximate doubling of palivizumab prescribing in 2007 over 2006.

FIGURE 3.

Palivizumab secondary care prescribing by item in the West Midlands.

Methods for reviewing effectiveness

Results for clinical effectiveness

Search results for clinical effectiveness

The searches for studies of effectiveness identified 601 citations, and 17 papers were retrieved after elimination of duplicate citations and exclusions made on scanning the title and abstract (Figure 4). Of these 17 papers, 14 were excluded on reading the paper. Excluded studies included early-phase palivizumab studies with intravenous, rather than intramuscular, administration and two open-label safety studies (these included adverse event data; Appendix 5, Table 43).

FIGURE 4.

Flow chart showing identification of effectiveness studies.

Two RCTs of palivizumab (IMpact16 and Feltes12) and one systematic review17 that met the inclusion criteria were identified from the clinical effectiveness searches. Additional systematic reviews were identified in the economic searches (see Table 1 for details) and were read to see if they contained additional useful information on effectiveness. None of these systematic reviews, however, included any trials other than those identified in the searches or included formal meta-analyses.

TABLE 1 - Systematic reviews

Identified in the health economics searches.

Study	Comments
Raya et al., 200618	Update. Systematic review as part of cost-effectiveness study. Population: preterm babies. One trial and one cohort study included
Dunfield and Mierzwinski-Urban, 200717	Postdates effectiveness searches. Includes IMpact and Feltes
Viswanathan et al., 200319	Cited in Dunfield and Mierzwinski-Urban, 200717
Embleton et al., 200520	Cited in Dunfield and Mierzwinski-Urban, 2007,17 Population: preterm children. Included IMpact, Subramanian, 1998,21 and Saez-Llorens, 199822
Simpson and Burls, 20019a	Health technology assessment

Summary of effectiveness results

There is limited good-quality evidence from two trials that palivizumab reduces the need for hospitalisation due to RSV by around 50% in the trial populations and is relatively safe.

Subgroup analysis suggested that palivizumab may be more effective in premature babies than in children with CLD. It could be speculated that this may be related to a greater need for hospitalisation with milder infection in the CLD group.

The reduction in RSV hospitalisation was also slightly greater in children with non-cyanotic rather than cyanotic congenital heart disease (see Table 5), but this trial was underpowered to detect a difference between these subgroups and there is no evidence of a true underlying difference in effect size.

Although we outlined in the protocol that other high-risk groups, for example children with cystic fibrosis or immune deficiency, would be assessed, we have not found the relevant data for cystic fibrosis or immune deficiency subgroups.

Systematic review of economic evaluations

Results of review of economic evaluations

The searches produced 240 citations, of which 207 citations were excluded on the basis of the title and abstracts as they did not fulfil one or more of the inclusion criteria in terms of the population, the intervention or design of the studies. The full text was obtained for 33 citations for further assessment. Twelve studies were excluded. The details of the studies and reasons for exclusion are given in Appendix 5, Table 44. Twenty-one studies reached the final stage of our review and were considered for data extraction (Figure 5). Three of the included studies are systematic reviews of economic evaluations (Table 8) and the remaining 18 are primary economic evaluation studies (Table 9).

FIGURE 5.

Flow chart of identification of existing economic evaluations.

TABLE 8 - Summary results of systematic reviews of economic evaluations

CHD, congenital heart disease; CLD, chronic lung disease.

Study	Country	Population	Intervention	Comparator	Main findings
Dunfield and Mierzwinski-Urban, 200717	Canada	Premature children with or without CLD or children with CHD	Palivizumab	No prophylaxis	The results of the included studies were variable; this may be due to different cost data sources
					Palivizumab was not cost-effective when used in all children for whom it is recommended
					Owing to the high cost of palivizumab, only children at very high risk of RSV should be administered palivizumab
Embleton et al., 200520	UK	Premature infants with or without CLD	Palivizumab	No prophylaxis	None of the identified studies was a comprehensive economic analysis
					All studies noted that true societal costs could not be addressed.
					None of the UK cost studies showed economic benefit for palivizumab prophylaxis
					The costs of prophylaxis were far in excess of any likely savings achieved by decreasing hospital admission rates
					In the absence of a comprehensive economic assessment, continued use of palivizumab for high-risk children, such as those with CLD, may appear justified
Kamal et al., 200232	USA	Premature infants with or without CLD	Palivizumab	No prophylaxis	The potential cost of palivizumab prophylaxis far exceeded the actual cost of hospitalisation
					The reported divergent results may be explained by differences in the study methods, assumptions and the poor quality of some economic evaluations
					Policy-makers, or providers or payers, need to critically appraise and judiciously interpret the cost-effectiveness of palivizumab

TABLE 9 - Characteristics of included primary economic evaluations

CEA, cost-effectiveness analysis; CBA, cost–benefit analysis; CLD, chronic lung disease; CUA, cost–utility analysis; GA, gestational age; NICU, neonatal intensive care unit; RSV, respiratory syncytial virus.

Breast feeding for less than 2 months, age < 10 weeks at start of season, sibling of school age, live with four or more adults, family history of allergy.

Author	Country	Study design	Population	Female (%)	Intervention	Comparator	Perspective	Model	Time horizon
Farina et al., 200231	Argentina	CEA	Born at ≤ 35 weeks GA (≤ 6 months) or at ≤ 28 weeks GA (≤ 12 months) or CLD ≤ 2 years	29	Palivizumab	No prophylaxis	Societal (stated, but not strictly)	Not specified	2 years
Numa, 200038	Australia	CBA, CEA	Born at ≤ 35 weeks GA (≤ 6 months) or CLD ≤ 2 years	43	Palivizumab	No prophylaxis	Provider	Not specified	Not specified
Reeve et al., 200635	Australia	CEA	Hospitalised children positive for RSV either born at < 33 weeks GA or with birth weight < 2500 g (and/or of indigenous origin or with siblings) or with CLD or CHD, ex-NICU	Not specified	Palivizumab	No prophylaxis	Provider	Not specified	Not specified
Roeckl-Wiedmann et al., 200336	Germany	CEA	Born at ≤ 35 weeks GA with or without CLD	0	Palivizumab	No prophylaxis	Societal	Decision-analytical model	1 year
Chiroli, 200537	Italy	CEA	CHD ≤ 2 years	46	Palivizumab	No prophylaxis	Third payer	Decision-analytical model	Life time
Vogel et al., 200238	New Zealand	CEA	Born at ≤ 32 weeks GA	Not specified	Palivizumab	No prophylaxis	Societal	Not specified	Not specified
de Armentia, 200339	Spain	CEA	Born at ≤ 32 weeks GA	Not specified, about 50% because of cohort	Palivizumab	No prophylaxis	Health service	Not specified	2 years
Lazaro et al., 200640	Spain	CUA	Born at 32–35 weeks GA	Not specified	Palivizumab	No prophylaxis	Provider, societal	Decision-analytical model	Life time
Raya et al., 200618	Spain	CEA	Born at 32–35 weeks GA inclusive and two or more risk factorsa	Not specified	Palivizumab	No prophylaxis	Hospital	Decision-analytical model	1 year
Simpson and Burls, 20019	UK	CEA	Born at ≤ 35 weeks GA (≤ 6 months), or CLD ≤ 2 years	43	Palivizumab	No prophylaxis	Provider	Decision-analytical model	Lifetime
Nuijten et al., 200725	UK	CUA	Born at ≤ 35 weeks GA (≤ 6 months), or CLD ≤ 2 years or CHD ≤2 years	43–46	Palivizumab	No prophylaxis	Provider, societal	Decision-analytical model	Lifetime
Joffe, 199941	USA	CEA	Born at ≤ 36 weeks GA	Not specified	Palivizumab	No prophylaxis	Societal, clinician, policy-maker	Decision-analytical model	Lifetime
Lofland et al., 200042	USA	CEA	Born at ≤ 35 weeks GA (≤ 6 months)	43	Palivizumab	No prophylaxis	Provider	Decision-analytical model	1 year
Stevens et al., 200043	USA	CEA	Born at ≤ 32 weeks GA	Not specified	Palivizumab	No prophylaxis	Provider	Not specified	Not specified
Shireman and Braman, 200244	USA	CBA	Born during RSV season ≤ 10 months	39	Palivizumab	No prophylaxis	Provider	Not specified	1 year
Strutton and Stang, 200345	USA	CEA	Born at ≤ 35 weeks GA	Not specified	Palivizumab	No prophylaxis	Payer, societal	Not specified	Not specified
Yount et al., 200446	USA	CUA	CHD ≤ 2 years	46	Palivizumab	No prophylaxis	Societal	Decision-analytical model	Life time
ElHassan et al., 200647	USA	CBA, CUA	Hypothetical cohort of children born at 26–32 weeks GA without CLD	Not specified	Palivizumab	No prophylaxis	Societal	Decision-analytical model	1 year without asthma, 8 years with asthma

The quality of the systematic reviews was moderate: none assessed the quality of the included primary economic evaluation studies. Details of the quality assessments are given in Table 45 (see Appendix 6). The three systematic reviews encompassed two, four and four primary economic evaluations that were identified in this report, respectively. All the reviews qualitatively summarised the results of the included economic evaluations and did not develop decision-analytical models to estimate the cost-effectiveness of prophylaxis with palivizumab.

All the systematic reviews stated that the potential costs of palivizumab were far in excess of any likely savings achieved by decreasing hospital admission rates, and that palivizumab is not cost-effective when used in all children for whom it is licensed at a willingness-to-pay threshold of £60,000/QALY or less, and that continued use of palivizumab for very high risk children may be justified. Details of the main findings of the systematic reviews are summarised in Table 8.

The 18 primary economic evaluation studies included were assessed and found to be of variable quality. Most of the studies clearly defined questions and described the competing alternatives, correctly established clinical effectiveness, performed incremental analysis of both costs and consequences, and clearly presented the results. However, some studies did not identify all relevant costs and consequences and others did not accurately measure or value the costs and consequences. More than half of the included studies did not consider discounting of costs and consequences for differential timing adjustment. Most of the studies did not carry out an adequate sensitivity analysis. Fewer than half of the studies used a lifetime time horizon; others did not specify the time horizon or used a time horizon of 1 year. Half of the studies did not report the price year. Full details of the quality of assessments can be found in Table 47 (see Appendix 8).

The characteristics of the included primary economic evaluations are summarised in Table 9. Most studies performed cost-effectiveness or cost–utility analyses, the remaining studies performed cost–benefit analysis. Most studies (n = 10) reported the ICER in terms of cost per hospital admission prevented (HAP), some studies (n = 5) reported the incremental cost per life-year gained (LYG), and others (n = 4) reported the incremental cost per quality-adjusted life-year (QALY). About half of the studies employed a societal perspective; others employed provider, or payer, or third-party perspectives.

The summary results of the included primary economic evaluations are given in Table 10.

TABLE 10 - Summary of results of economic evaluationsw

CHD, congenital heart disease; CLD, chronic lung disease; GA, gestational age; E-NICU, ex-neonatal care unit; HAP, hospital admission prevented; HDS, hospital day saved; IEA, infection episode avoided; LYG, life-year gained; NICU, neonatal intensive care unit; QALY, quality-adjusted life-year.

Cost year was not clearly defined, assumed to be the same as study year.

Incidence of RSV infection.

Author	Country	Price Year	Number of doses	Discount rate (%)	Hospitalisation rates (%)		Population	Reported in price year	Converted to £ (sterling) 2006
					Palivizumab	No prophylaxis
Farina et al., 200233	Argentina	2000	4	Not specified	10.71	23.8	Born at ≤ 35 weeks GA (≤ 6 months), or at ≤ 28 weeks GA (≤ 12 months), or CLD ≤ 2 years	$15,358/HAP	£8000/HAP
Numa, 200034	Australia	Not specified	5	Not specified	4.8	10.6	Born at ≤ 35 weeks GA (≤ 6 months), or CLD ≤ 2 years, weight < 6.7 kg	A$27,786/HDS	£14,400/HDSa
							Born at ≤ 35 weeks GA (≤ 6 months), or CLD ≤ 2 years, weight ≥ 6.7 kg	A$55,572/HDS	£28,900/HDSa
Reeve et al., 200635	Australia	Not specified	5	Not specified	2.0	4.0	Hospitalised children positive for RSV or born at ≤ 33 weeks GA	A$98,818/HAP	£42,000/HAPa
					2.3	4.4	Birth weight < 2500 g	A$88,547/HAP	£37,700/HAPa
					2.2	5.0	Indigenous and birth weight < 2500 g	A$73,294/HAP	£31,200/HAPa
					1.8	4.8	Birth weight < 2500 g and with siblings	A$69,861/HAP	£29,700/HAPa
					2.3	5.1	E-NICU	A$79,619/HAP	£33,900/HAPa
Roeckl-Wiedmann et al., 200336	Germany	2000	5	No discounting	24	54	Born at ≤ 35 weeks GA with CLD, siblings in day-care groups and discharge between October and December	€6639/HAP	£5300/HAP
					10	23	Born at ≤ 35 weeks GA with siblings in day-care groups and discharge between October and December	€25,288/HAP	£20,200/HAP
					6	12	Born at ≤ 35 weeks GA with siblings in day-care groups	€52,838/HAP	£42,200/HAP
					2	3	Born at ≤ 35 weeks GA without CLD, siblings in day-care groups and discharge between October and December	€204,68/4HAP	£162,800/HAP
Chiroli, 200537	Italy	2004	5	No discounting	5.3	9.7	CHD ≤ 2 years	€7186/LYG	£4300/LYG
Vogel et al., 200238	New Zealand	2000	5	Not specified	Not specified	42.1	Discharged home on oxygen	NZ$29,000/HAP	£12,000/HAP
					14.0	22.9	Born at ≤ 32 weeks GA, with CLD	NZ$65,000/HAP	£27,000/HAP
					4.1	18.5	Born at ≤ 32 weeks GA, without CLD	NZ$32,000/HAP	£13,300/HAP
					6.1	10	Born at 29–31 weeks GA, with CLD	NZ$167,000/HAP	£69,200/HAP
					1.8	8.2	Born at 29–31 weeks GA, without CLD	NZ$98,000/HAP	£40,600/HAP
de Armentia, 200339	Spain	Unclear	Unclear; up to 50 mg, full five doses in total	N/A	Unclear		Born at ≤ 30 weeks GA	€12,915/HAP	£9500/HAP
							Born at ≤ 32 weeks GA	€20,900/HAP	£15,400/HAP; appears to be data driven, states with 35 weeks GA, then treats only ≤ 32 weeks GA
Lázaro et al., 200640	Spain	2006	15 mg/kg, mean of 3.88 doses	3	1.8	8,1	Born at 32–35 weeks GA	€4605/QALY (societal)	£3200/QALY (societal)
								€13,849/QALY (provider)	£9500/QALY (provider)
Raya et al., 200618	Spain	2005	3.8 doses (mean), sharing vials	N/A	2.7	6.6	Born at 32–35 weeks GA	€42,761/HAP to €68,104/HAP	£29,400–46,800/HAP
Simpson and Burls9	UK	2000	6	1.5 for benefit	4.8	10.6	Born at ≤ 35 weeks GA (≤ 6 months), or CLD ≤ 2 years	£43,000/HAP, £96,000/LYG	£55,000/HAP, £122,800/LYG
Nuijten et al., 200725	UK	2003	4.87	3.5 for both cost and benefit	4.8	10.6	Born at ≤35 weeks GA (≤ 6 months), CLD ≤ 2 years	£16,720/QALY, £22,826/LYG	£18,900/QALY, £25,800/LYG
					5.3	9.7	CHD ≤ 2 years	£6664/QALY, £7002/LYG	£7500/QALY, £7900/LYG
Joffe, 199941	USA	1995	4	3 for both cost and benefit	11.1	24.6	Born at 23–32 weeks GA, length of oxygen ≥ 28 days, month of NICU discharge September to November	$33,000/LYG	£30,400/LYG
					4.8	10.7	Born at 23–32 weeks GA, length of oxygen ≥ 28 days, month of NICU discharge December to August	$110,000/LYG	£101,200/LYG
					3.6	8	Born at 23–32 weeks GA, length of oxygen < 28 days, month of NICU discharge September to November	$160,000/LYG	£147,200/LYG
					1.4	3.1	Born at 23–32 weeks GA, length of oxygen < 28 days, month of NICU discharge December to August	$440,000/LYG	£404,900/LYG
					5.0	11	Born at 33–36 weeks GA, length of oxygen ≥ 28 days, month of NICU discharge September to November	$110,000/LYG	£101,200/LYG
					2.0	4.4	Born at 33–36 weeks GA, length of oxygen ≥ 28 days, month of NICU discharge December to August	$300,000/LYG	£276,100/LYG
					1.4	3.2	Born at 33–36 weeks GA, length of oxygen < 28 days, month of NICU discharge September to November	$430,000/LYG	£395,700/LYG
					0.5	1.2	Born at 33–36 weeks GA, length of oxygen < 28 days, month of NICU discharge December to August	$1,200,000/LYG	£1,104,001/LYG
Lofland et al., 200042	USA	Not specified	5	Not specified	5b	10b	Born at ≤ 35 weeks GA (≤ 6 months)	$39,591/IEA if palivizumab therapy cost $2500	£31,300/IEAa if palivizumab therapy cost $2500
					5b	10b		$79,706/IEAa if palivizumab therapy cost $4500	£63,000/IEAa if palivizumab therapy cost $4500
Stevens et al., 200043	USA	Not specified	5	Not specified	9.3	20.6	Born at ≤ 26 weeks GA	$18,183/HAP	£14,400/HAPa
					6.6	14.6	Born at 27–28 weeks GA	$24,113/HAP	£19,100/HAPa
					5.1	11.3	Born at 29–30 weeks GA	$36,878/HAP	£29,200/HAPa
					2.9	6.4	Born at 31–32 weeks GA	$72,712/HAP	£57,500/HAPa
Shireman and Braman, 200244	USA	Not specified	Up to 6	Not specified	5.8	11.7	Born during RSV season ≤ 10 months	Cost–benefit ratio 6.67:1, drug cost $4,687, hospitalisation cost decreased by $703	Cost–benefit ratio 6.67:1, drug cost £3746a, hospitalisation cost decreased by £559a
Strutton and Stang, 200345	USA	2002	Not specified	5 for both cost and benefit	Not specified	Not specified	Born at ≤ 35 weeks GA	$66,200/LYG (societal)	£53,200/LYG (societal)
					Not specified	Not specified		$66,400/LYG (payer)	£53,300/LYG (payer)
Yount et al., 200446	USA	2002	5	3 for both cost and benefit	5.3	9.7	CHD ≤ 2 years	$114337/QALY	£91,800/QALY
ElHassan et al., 200647	USA	2002	5	3 for both cost and benefit	5.2	20.6	Hypothetical cohort of children born at 26 weeks GA without CLD	$830,152/QALY	£666,700/QALY
					3.7	14.6	Hypothetical cohort of children born at 27 weeks GA without CLD	$1,295,781/QALY	£1,040,600/QALY
					3.7	14.6	Hypothetical cohort of children born at 28 weeks GA without CLD	$1,500,351/QALY	£1,204,900/QALY
					2.8	11.3	Hypothetical cohort of children born at 29–30 weeks GA without CLD	$675,780/QALY	£542,700/QALY
					1.6	6.4	Hypothetical cohort of children born at 31 weeks GA without CLD	$1,212,497/QALY	£973,700/QALY
					1.1	6.4	Hypothetical cohort of children born at 32 weeks GA without CLD	$1,855,000/QALY	£1,489,700/QALY

The results of the included economic evaluation studies show that the ICERs vary from £5307/HAP to £69,240/HAP with mean of £33,190/HAP (SD £17,807/HAP), from £5288/LYG to £1,104,351/LYG with mean £202,104/LYG (SD £78,066/LYG), and from £3,164/QALY to £1,489,668/QALY with mean £547,817/QALY (SD £169,082/QALY).

In the UK study by Simpson and Burls9 values of £55,000/HAP and £122,800/LYG were reported for preterm infants or children with CLD (less than 2 years old). The most recent economic evaluation (2007) is a UK study by Nuijten et al. 25 funded by the manufacturer of palivizumab. This reported ICERs of £25,800/LYG and £18,900/QALY for preterm infants or children (less than 2 years old) with CLD, and £7900/LYG and £7,500/QALY for children with CHD.

An analysis of existing economic evaluations

The ICERs vary a lot from study to study. This makes it difficult for decision-makers to decide whether prophylaxis with palivizumab is effective. In order to find what is driving the differences between the ICERs we looked at the results for systematic differences in the populations, interventions, metrics, outcomes, time horizons and other parameters. These differed; for example, doses of palivizumab used in the economic evaluations were different, varying from four to six, while two studies did not specify dose. Studies also used different perspectives: half of the studies estimated ICERs from a societal perspective and others from a provider or hospital perspective. The time horizons were different, most varying from 1 year to 2 years, while two of the studies did not specify time horizon.

Population

The studies by Simpson and Burls9, Raya et al. 18, Farina et al. 33, Reeve et al. 35, Roeckl-Wiedmann et al. 36, Vogel et al. 38, de Armentia39, Lofland et al. 42 and Stevens et al. 43 assessed the cost-effectiveness of palivizumab in terms of cost per hospital admission prevented (HAP). Although the populations of these studies were preterm infants with gestational age less than 36 weeks, some studies reported cost-effectiveness for different subpopulations, such as preterm children with CLD and those born at different gestational ages, or with different risk factors, such as having a sibling in a day-care group. In general, prophylaxis with palivizumab was more cost-effective in those children with a higher risk of being admitted to hospital due to an RSV infection than in children from populations at lower risk. For example, Roeckl-Wiedmann et al. 36 reported that the ICER for preterm children born at a gestational age of less than 35 weeks and without other risk factors was £162,800/HAP and that the ICER for preterm children born at a gestational age of less than 35 weeks and with siblings in day-care groups was £42,200/HAP. It can be seen that ‘having a sibling in day care’ contributed to the 74% ICER reduction. Discharge between October and December reduced the ICER to £20,200/HAP, contributing to the 52% ICER reduction. CLD further reduced the ICER to £5300/HAP, contributing to the 74% of ICER reduction. Vogel et al. 38 reported that CLD increased the ICER from £13,300/HAP to £27,000/HAP for preterm children with a gestational age of less than 32 weeks, an increase of 103%, and from £40,600/HAP to £69,200/HAP for preterm children with a gestational age between 29 and 31 weeks, an increase of 70%. Stevens et al. 43 showed that the ICER was less than £30,000/HAP for those who were born at a gestational age of below 31 weeks, but was £57,500/HAP for those born at between 31 and 32 weeks gestational age. These risk factors were reflected in the RSV hospitalisation rates. These are listed in Table 10. The values of ICERs decrease as the risk difference of RSV hospitalisation between no prophylaxis and palivizumab become large (shown in Figure 6).

FIGURE 6.

Cost-effectiveness (£/HAP).

Outcomes and other model parameters

The studies by Simpson and Burls9, Nuijten et al. 25, Chiroli37, Joffe41 and Strutton and Stang45 assessed the cost-effectiveness of palivizumab in terms of cost per life-year gained. The cost-effectiveness for children with CHD was £4300/LYG in the study by Chiroli37 and £7900/LYG in the study by Nuijten et al. 25. The two studies used the same provider perspective and the same RSV hospitalisation rates, which was obtained from the RCT by Feltes et al. 12, the same time horizon. The study by Nuijten et al. 25 applied a discount of 3.5% and the price year was specified as 2003, whereas the study by Chiroli37 did not specify the price year and did not apply discounting. The studies by Simpson and Burls9, Nuijten et al. 25, Joffe41 and Strutton and Stang45 estimated the cost-effectiveness of palivizumab for preterm children. The values of ICER varied from £25,800/LYG to £404,900/LYG. The minimum ICER was reported in the study by Nuijten et al. 25 and the maximum ICER was reported in the study by Joffe. 41 The main variation in the ICER was caused by gestational age and NICU discharge seasons, which were reflected by RSV hospitalisation rates. The values of ICERs decrease as the risk difference of RSV hospitalisation between no prophylaxis and palivizumab becomes large (shown in Figure 7).

FIGURE 7.

Cost-effectiveness (£/LYG).

Mortality

The studies by Nuijten et al. 25, Lázaro et al. 40, Yount et al. 46, and ElHassan et al. 47 assessed the cost-effectiveness of palivizumab in terms of cost per QALY. The cost-effectiveness for children with CHD was £7500/QALY in the study by Nuijten et al. 25 and £91,800/QALY in the study by Yount et al. 46 The ICERs and the model parameters of the two studies are summarised in Table 11.

TABLE 11 - ICERs and the corresponding model parameters (children with CHD)

Author	Industry sponsored	Hospitalisation rates (%)		Population	Time horizon	Discount rate (%)	Number of doses	Mortality rate (%)	Perspective	Utility value	ICER (£/QALY)
		Palivizumab	No prophylaxis
Nuijten et al., 200725	Yes	5.3	9.7	CHD ≤ 2 years	Lifetime	3.5	4.87	4.5	Provider	0.88–0.95	7500
Yount et al., 200446	No	5.3	9.7	CHD ≤ 2 years	Lifetime	3	5	3	Societal	0.71	91,800

These two studies used the same RSV hospitalisation rates, a similar dose of palivizumab and the same time horizon. The differences between the two studies are that Yount et al. 46 used a societal perspective, an RSV mortality rate of 3% and a utility value of 0.71, whereas Nuijten et al. 25 used a provider perspective, an RSV mortality rate of 4.5% and utility values of 0.88–0.95. The ICER values for preterm children compared with the risk difference of RSV hospitalisation, which were collected from two studies25,47, are shown in Figure 8. The study by Lázaro et al. 40 was not included as the number of doses of palivizumab was too low (fewer than 4). In general, we can see that the values of ICERs decrease as the differences in RSV hospitalisation rates between no prophylaxis and palivizumab become large. However, there is an exception in the case of the study by Nuijten et al. 25, as shown at point A in Figure 8. The ICERs and the model parameters of the two studies are summarised in Table 12. Apart from the different perspectives, hospitalisation rates and time horizon, compared with the study by ElHassan et al. 47, the study by Nuijten25 assumed a higher mortality rate (8.11%). This is probably the main reason that Nuijten et al. 25 reported a very low ICER value. Three observational studies24,48,49 report mortality rates for children admitted to hospital because of RSV infection. Meta-analysis of these studies gives a mortality rate of 3.72% for RSV hospital admission, which is similar to the mortality rate of 3% used in the study by Yount et al. 46

FIGURE 8.

Cost-effectiveness (£/QALY).

TABLE 12 - ICERs and the corresponding model parameters (preterm infants without CLD or children with CLD)

CLD, chronic lung disease; GA, gestational age; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Author	Industry sponsored	Hospitalisation rates (%)		Population	Time horizon	Discount rate (%)	Number of doses	Mortality rate (%)	Perspective	Utility value	ICER (£/QALY)
		Palivizumab	No prophylaxis
Nuijten et al., 200725	Yes	4.8	10.6	Born at ≤ 35 weeks GA (≤ 6 months), CLD ≤ 2 years	Lifetime	3.5	4.87	8.11	Provider	0.88–0.95	18,900
ElHassan et al., 200647	No	5.2	20.6	Hypothetical cohort of children born at 26 weeks GA without CLD	1 year without asthma, 8 years with asthma	3	5	Not considered	Societal	0.89–0.92	666,700
		3.7	14.6	Hypothetical cohort of children born at 27 weeks GA without CLD	1 year without asthma	3	5	Not considered	Societal	0.89–0.92	1,040,600
		3.7	14.6	Hypothetical cohort of children born at 28 weeks GA without CLD	1 year without asthma	3	5	Not considered	Societal	0.89–0.92	1,204,900
		2.8	11.3	Hypothetical cohort of children born at 29–30 weeks GA without CLD	1 year without asthma	3	5	Not considered	Societal	0.89–0.92	542,700
		1.6	6.4	Hypothetical cohort of children born at 31 weeks GA without CLD	1 year without asthma	3	5	Not considered	Societal	0.89–0.92	973,700
		1.1	6.4	Hypothetical cohort of children born at 32 weeks GA without CLD	1 year without asthma	3	5	Not considered	Societal	0.89–0.92	1,489,700

In order to evaluate the effect of the high mortality rate on the cost-effectiveness, we reconstructed the model described in the study by Nuijten et al. 25 and ran it using different mortality rates. The results are summarised in Table 13. The ICER changes from £29,200/LYG for a mortality rate of 7% to £195,500/LYG for a mortality rate of 1%, and changes from £20,200/QALY for a mortality rate of 7% to £41,700/QALY for a mortality rate of 1%. Note that the best estimate of mortality for premature children without CLD that we could find is smaller than any shown here and therefore the probable cost/QALY will be in excess of £41,000. Therefore, even given the other very optimistic assumptions favouring palivizumab used by Nuijten and colleagues in their model, palivizumab would not reach conventional UK levels of cost-effectiveness when a more representative mortality rate is used.

TABLE 16 - The results of cost-effectiveness versus different mortality rates using the model by Nuijten et al.23

ICER, incremental cost-effectiveness ratio; LYG, life-year gained; QALY, quality-adjusted life-year.

	Mortality rate (%)
	7	6	5	4	3	2	1
ICER (£/LYG)	29,200	33,800	40,300	50,000	66,200	98,500	195,500
ICER (£/QALY)	20,200	22,000	24,200	27,000	30,500	35,200	41,700

Methods of the BrumEE

The model was designed to estimate, from the UK NHS and societal perspectives, the incremental costs and outcomes in terms of QALYs of prophylaxis with palivizumab compared with no prophylaxis. The model also attempts to incorporate uncertainty in probabilities, resource use and utilities by incorporating the input parameters of the model as probability distributions. These distributions are used in a Monte Carlo simulation in order for uncertainty in the results of the model to be presented. The model is developed using the R programming language (http://cran.r-project.org). All costs are presented in 2006 UK pounds sterling (£). Both costs and benefits are discounted at 3.5%.

Structure of the model

The model structure is shown in Figure 9. The model follows high-risk children for their first RSV season. The high-risk children are divided into two groups: those receiving palivizumab prophylaxis and those not receiving prophylaxis. Children in either group may develop an RSV infection and be admitted to hospital. A proportion of them will require admission to a paediatric intensive care unit, the rest are managed in a general paediatric ward. A small proportion of children die. A time horizon of lifetime is used to take into account the impact of palivizumab on long-term morbidity and mortality of RSV infection. Cost-effectiveness is measured in terms of £ per QALY and £ per life-year gained. Adverse events are not taken into account in the model as the clinical trials did not show any important differences between the palivizumab and placebo groups. 12,16

FIGURE 9.

Base-case decision tree model for palivizumab versus no prophylaxis.

We do not consider sequelae (such as asthma, recurrent wheezing) in the base-case model. The relationship between RSV infections and the development of wheezing and asthma in children has been the subject of much debate. Most previous cohort studies have failed to identify a link between early RSV infection and atopic asthma. Recent cohort studies have indicated that wheezing in early childhood is associated with an increased incidence of atopic asthma, but that this risk is not increased by RSV infections. 50

Estimation of model pathway parameters

Prognostic factor studies in RSV

The limited RCT data (Tables 5 and 6) do not distinguish adequately between subgroups of risk within the ‘high-risk’ groups (e.g. groups defined by different gestational ages or age at the start of RSV season). It is therefore not possible to answer the core question of this review (For which high-risk subgroups may palivizumab be a cost-effective use of resources?) from the RCT data alone. Hence, supplementary evidence is needed to model different risk groups within the licensed indication.

Unfortunately, the scope of the commissioning brief does not permit us to undertake a full systematic review to look for studies about the development, course or outcome of infection in children with RSV so we took a pragmatic approach to seek the best available information. We systematically looked for prognostic studies identified during the search for the systematic review and undertook a further specific systematic search for prognostic studies (see Appendices for details). Based on scrutiny of title and abstract we selected those that were of most relevance to the current UK context and of highest quality. The studies selected as most relevant are summarised in Table 15.

Of these, the papers by Carbonell-Estrany et al. 51,52 and Rietveld et al. 53 were the most useful. All include large samples of children and use an appropriate method to investigate prognostic factors. Carbonell-Estrany et al. 51 and Rietveld et al. 53 estimate risk by gestational age (GA), which is a particularly important component of risk, and allows consideration of this important subgroup in the model. Carbonell-Estrany et al. 52 report a similar study for children with higher gestational age (> 32 weeks) and, along with Rietveld et al. 53, compare risk in children of different ages. Carbonell-Estrany et al. 52 use birth age for this comparison, whereas Rietveld et al. 53 use post-conceptional age. These papers also reported a significant impact of CLD/BPD and of having siblings at school (SAS) on the risk of RSV hospitalisation.The ORs and their confidence intervals for key prognostic factors are sumarised in Table 14.

TABLE 14 - Estimated ORs [and confidence intervals (CIs)] for key prognostic factors

BPD, bronchopulmonary dysplasia; CI, confidence interval.

Risk factor	Carbonell-Estrany et al., 200051	Carbonell-Estrany et al., 200452	Rietveld et al., 200653
Gestational age	0.85, 0.72–0.99/week	–	≤ 28 weeks: 3.2 (2.1–4.8)
			29–32 weeks: 2.8 (2.1–3.8)
			33–34 weeks: 2.3 (1.8–3.0)
			35–36 weeks: 1.6 (1.3–1.9)
			37+ weeks: 1.0
Chronic lung disease	3.1 (1.22–7.91)	–	2.2 (no CI reported)
Siblings at school	1.86 (1.01–3.4)	–	–
Age	–	0.55 (0.33, 0.92)	No BPD 0.8/month (0.8, 0.8) with BPD 0.9/month (0.9, 1.0)

TABLE 15 - Prognostic studies

CLD, chronic lung disease; CRIB, clinical risk index for babies; ICU, intensive care unit; LRTI, lower respiratory tract infection; PICU, paediatric intensive care unit; RDS, respiratory distress syndrome; RSV, respiratory syncytial virus.

Reference	Design	Population	Outcomes	Factors	Results
Arnold et al., 199956	Prospective multicentre cohort	1516 children with lung disease (CLD, cystic fibrosis, and others) hospitalised with RSV, 1993–1995 (159 only reported)	Duration of hospitalisation, ICU, duration of ICU, mechanical ventilation, duration of ventilation	CLD, cystic fibrosis, pneumonitis, pulmonary malformation, neurogenic disorders, tracheoesophageal fistula, other	No significant differences between groups; patients using home oxygen were more likely to be admitted to ICU (p = 0.03)
Carbonell-Estrany et al., 200051	Prospective multicentre cohort	680 children born ≤ 32 weeks gestation, 1998–1999 (584 evaluable)	Hospitalisation for RSV	Gestational age, birth weight, family history of asthma, CRIB score, age at start of RSV season, month of discharge, CLD, heart disease, neurological disease, ventilation at birth, breast-feeding, smoke exposure, day care, one or more siblings, school-age siblings	Gestational age (OR 0.85, 0.72–0.99), chronic lung disease (OR 3.1, CI 1.22–7.91), school-age siblings (OR 1.86, CI 1.01–3.4)
Carbonell-Estrany et al., 200452	Prospective multicentre cohort	1832 children born at 33–35 weeks gestation, 2000–2002	Hospitalisation for RSV	Multiple pregnancy, abnormal delivery, intubation, ICU at birth, ethnicity, month of birth, sex, small for gestational age, any chronic condition, crowding, two or more smokers at home, older siblings, preschool-age siblings in day care and not breast-feeding, eczema in a first-degree relative	Month of birth, sex, small for gestational age, any chronic condition, crowding, two or more smokers at home, older siblings, preschool-age siblings in day care and not breast-feeding, eczema in a first-degree relative
Clark et al., 200057	Prospective multicentre cohort	656 high-risk children, 1998–2000 (< 36 weeks gestation, < 24 months and discharged with supplemental oxygen)	Hospitalisation for RSV	Prematurity, discharge with oxygen	Premature infants at higher risk than those discharged with oxygen
Grimaldi et al., 200258	Prospective multicentre cohort	484 children admitted for RSV bronchiolitis, 1999–2000	PICU admission in children hospitalised for RSV-induced bronchiolitis	Prematurity, low birth weight, RDS, mechanical ventilation, CLD, CHD	Prematurity, low birth weight, RDS, mechanical ventilation, CLD, CHD
Holberg et al., 199159	Prospective multicentre cohort	1,179 healthy children 1980–1984	RSV-LRTI	Breast feeding, maternal education, sex, shared bedroom, birth month, ethnicity, maternal smoking, day care	Breast feeding, sex, shared bedroom
Rietveld et al., 200653	Retrospective multicentre cohort	143,130 (2469 hospitalised) children, 1996–1998	Hospitalisation for RSV	Sex, gestational age, birth weight, CLD, age	Sex, gestational age, birth weight, CLD, age
Kneyber et al., 200060	Quantitative review	10 studies	Asthma	Asthma associated with RSV infection	40% vs 11% (p < 0.001) up to 5 years follow-up, 22% vs 10% (p = 0.19) 5–10 years

For modelling prognosis, we decided to use the estimates for GA, CLD and SAS from Carbonell-Estrany et al. 51 These estimates are comparable to the odds ratios (OR) reported in the other papers, but the OR for GA in Rietveld et al. 53 is estimated by grouped GAs rather than as an OR/month, as in the Carbonell-Estrany et al. papers, and so is less flexible for modelling purposes; in addition, Rietveld et al. 53 report ORs to only one decimal place, which introduces a high rounding error. Similarly, Carbonell-Estrany et al. 52 report an OR only for age groups above and below 3 months, whereas Rietveld et al. 53 report an OR of 0.8/month for post-conceptional age without BPD and 0.9/month for post-conceptional age with BPD. The OR for birth age used in our prognostic model was 0.8, obtained by considering ORs of the correct order of magnitude according to Rietveld et al. 53 but which also corresponded well to data from the other paper. 54

Other significant prognostic factors reported by these papers include sex, birth weight, parents’ level of education and overcrowding at home. With additional resources it would be possible to build a more comprehensive prognostic model that includes these and other factors.

The risk of hospitalisation due to RSV was estimated for different subgroups, cross-tabulated by GA and age, using a simple Excel spreadsheet. The OR for a specific group compared with the reference group (GA = 28 weeks, age = 3 months, no CLD or SAS) was calculated using the ORs taken from the prognostic papers using the formula:

OR subgroup = exp ( − ln OR GA ( 28 − GA ) − ln OR age ( 3 − age ) + ( CLD * ln OR CLD ) + ( SAS * ln OR CLD )

where CLD and SAS are indicator variables for the presence/absence of these risk factors.

Note that the lnORs for GA and age are included as negative terms because our model uses increasing risk with lower values than the reference (OR > 1), whereas the ORs in the papers are reported the other way around (OR < 1).

The absolute risk for each group was then calculated from an estimated baseline risk for the reference group of 15.1%, obtained from considering the empirical data from the UK study by Deshpande et al. 55 An RSV-related hospitalisation rate of 12.5% was reported for children less than 6 months with a gestational age of less than 28 weeks. We assumed that this hospitalisation rate was obtained from children with a gestational age of 26 weeks, 27 weeks and 28 weeks. The odds ratio of 0.85 was applied to gestational ages and the hospitalisation rate of children with a gestational age of 28 weeks was estimated to be 10.8%. The odds ratio of 0.8 was applied to birth ages and the hospitalisation rate of infants under 3 months with a gestational age of 28 weeks was estimated to be 15.1%, which was used to estimate the hospitalisation rates for children with different gestational ages and different birth ages.

The average of the derived absolute risks of hospitalisation for different subgroups across gestational age and birth age is estimated to be 11.3%. This is consistent with a hospitalisation rate of 10.6% reported in the RCT. 16

Estimation of model pathway parameters

RSV hospitalisation for infants born at ≤ 35 weeks of gestation or children with CLD

The IMpact-RSV16 RCT was conducted for infants born at ≤ 35 weeks of gestation or children with CLD. The results of the study showed that monthly prophylaxis with palivizumab was associated with a 55% (95% CI 38–72%) reduction in RSV hospitalisation compared with no prophylaxis (Table 8). Significant reductions were observed in both children with CLD (39%, 95% CI 20–58%) and premature children without CLD (78%, 95% CI 66–90%). 16 The RSV hospitalisation rate was 4.8% for prophylaxis with palivizumab and 10.6% for no prophylaxis. These rates were used in our model (Table 16).

TABLE 16 - Model pathway parameters for preterm infants without CLD or children with CLD

CLD, chronic lung disease; ICU, intensive care unit; RSV, respiratory syncytial virus.

Parameter	Estimate	Source
RSV-related mortality rate (without CLD)	0.0043	Chater et al., 200661
RSV-related mortality rate (with CLD)	0.04 (0.03–0.05)	Stensballe et al., 20035
Probability of ICU admission	0.107	Deshpande et al., 2003;55 Greenough et al., 2001;62 Clark et al., 2000;57 Broughton et al., 200563
Relative risk of RSV hospitalisation rate between palivizumab versus no prophylaxis	0.4519	The IMpact-RSV Study Group, 199816
Probability of RSV hospitalisation in palivizumab prophylaxis group (without CLD)	0.018	The IMpact-RSV Study Group, 199816
Probability of RSV hospitalisation in palivizumab prophylaxis group (with CLD)	0.079	The IMpact-RSV Study Group, 199816
Probability of RSV hospitalisation in no prophylaxis group (without CLD)	0.081	The IMpact-RSV Study Group, 199816
Probability of RSV hospitalisation in no prophylaxis group (with CLD)	0.128	The IMpact-RSV Study Group, 199816

RSV hospitalisation for CHD children

One RCT study, by Feltes et al. ,12 compared RSV hospitalisation rate in children with CHD receiving or not receiving prophylaxis with palivizumab. The results showed that monthly prophylaxis with palivizumab was associated with a 45% reduction in RSV hospitalisation rate (Table 5). RSV hospitalisation rates were 5.3% in the palivizumab group and 9.72% in the no prophylaxis group (Table 17). One Switzerland cohort study by Duppenthaler et al. 24 has been identified for RSV hospitalisation rates in children < 24 months of age with CHD. This study reported that RSV hospitalisation rates in CHD patients less than 24 months of age varied from 0.5% to 2.5%, which is fourfold lower than that reported from the RCT study. The latitude and location of Switzerland suggest that RSV seasons might be expected to be similar to those experienced in the UK. However, it is unclear whether demographic characteristics were the same between the cohort study and the RCT study (Tables 2 and 4). The RSV-hospitalisation rates obtained from the RCT study are used in the base case model. The RSV-hospitalisation rates of 0.5% to 2.5% from the cohort study are used in sensitivity analysis. RSV-hospitalisation rates of 5.6% for prophylaxis with palivizumab and 7.9% for no prophylaxis in the cyanotic stratum, and 5% vs 11.8% in the acyanotic stratum reported from the RCT study are also used for sensitivity analysis.

TABLE 17 - Model pathway parameters for children with CHD

ICU, intensive care unit; RSV, respiratory syncytial virus.

Parameter	Estimate	Source
RSV-related mortality rate	0.0372	Wang et al., 1995;24 Moler et al., 1992;48 Navas et al., 199249
Probability of ICU admission	0.387	Feltes et al., 200312
Relative risk of RSV hospitalisation rate between palivizumab and no prophylaxis	0.5473	Feltes et al., 200312
Probability of RSV hospitalisation in palivizumab prophylaxis group	0.0532	Feltes et al., 200312
Probability of RSV hospitalisation in no prophylaxis group	0.0972	Feltes et al., 200312

Probability of ICU admission

Four UK studies, by Greenough et al. ,62 Clark et al. ,57, Broughton et al. 63 and Deshpande et al. ,55 were meta-analysed to estimate the ICU rate. The individual and pooled results are shown in Table 18.

TABLE 18 - Probability of ICU stay for preterm infants

ICU, intensive care unit; RSV, respiratory syncytial virus.

Study	N (RSV hospitalisation)	N (ICU)	%
Greenough et al., 200162	45	6	13.33
Clark et al., 200057	53	5	9.43
Broughton et al., 200563	44	4	9.09
Deshpande et al., 200355	53	6	11.32
Pooled result			10.71

Feltes et al. 14 reported that 13 out of 34 palivizumab recipients who were hospitalised due to RSV infection were admitted to the ICU, compared with 24 out of 63 placebo recipients who were admitted to hospital because of RSV infection (Table 6). This gives an average ICU admission rate of 38.7% for CHD children. This is consistent with the ICU admission rate (38.2%) reported in the study by Chiroli. 37

Mortality rates for children born ≤ 35 weeks of gestation or children with CLD

Mortality rates of 0.4% in the prophylaxis with palivizumab group and 1% in the no prophylaxis group were reported in the RCT study (Table 6). 16 However, the study was not powered to estimate mortality rates25 because it was designed to evaluate RSV hospitalisation rates associated with prophylaxis with palivizumab and no prophylaxis. Furthermore, they are not the mortality rates required by the decision-analytical model. The model needs estimates of mortality rates for those who were admitted to hospital due to RSV infection. The mortality rates reported in the RCT are the total death rates for those in either arm. Therefore, these cannot be directly used in the model.

The study by Sampalis and Sampalis23 reported a mortality rate of 8.11% (196/2415) for RSV hospitalisation. This mortality rate in a cohort of children generally considered to be less high risk (32–35 weeks’ gestation) is exceptionally high, and is far greater than reported among more high-risk children. Moreover, this mortality rate is all-cause mortality during follow-up subsequent to RSV hospitalisation, and does not necessarily relate to RSV hospitalisation per se. The author reported a significantly higher rate of sudden or otherwise unexplained death among RSV-hospitalised children than among controls, possibly an artefact from the use of poorly coded, routinely collected discharge data or selection bias. Since the median age at RSV hospitalisation among the preterm cohort was 6.9 months, and as the risk of sudden infant death syndrome greatly reduces by 6 months of age, use of the mortality figure from this study for model estimates is inappropriate. Wang et al. 24 reported RSV hospitalisation rates of 5.06% (4/79) for CLD and 3.38% (5/148) for gestation < 37 weeks. The subgroups in this study were not mutually exclusive, e.g. children with gestation < 37 weeks could also have had other risk factors such as CLD, cardiac disease, immunocompromise, etc. As the authors mentioned, there were only six deaths in the entire cohort of 689 hospitalised children; four of the children who died had underlying illnesses while one was premature and one was less than 6 weeks of age. Again, it is inappropriate to use these mortality rates in the model because it is not clear whether the deaths were due to RSV or to underlying disease.

The RSV-related mortality rate among preterm infants without CLD derived from the study by Chater et al. 61 was 0.43%. Stensballe et al. 5 reported high mortality rates of 3 –5% among children with CLD. Therefore, a mortality rate of 4% was used in the base-case model for preterm children with CLD.

Mortality rates for CHD children

The economic evaluation study by Yount et al. 46 used a mortality rate of 3% for both the prophylaxis with palivizumab and no prophylaxis groups. The study by Nuijten et al. 25 used a mortality rate of 4.5% for RSV hospitalisation. The RCT by Feltes et al. 12 reported a total mortality rate of 3.3% for the palivizumab prophylaxis group and of 4.2% for the no prophylaxis group (Table 6). They are not the mortality rates required by the decision-analytical model as the model requires mortality rates of those who were admitted to hospital because of RSV infection.

Three studies24,48,49 that reported a mortality rate for those who were admitted to hospital due to RSV infection were identified. The study by Moler et al. 48 reported a mortality rate of 2.53% (2/79), that by Navas et al. 49 a mortality rate of 3.46% (9/260) and that by Wang et al. 24 a mortality rate of 5.26% (3/57). Meta-analysis of these studies gives a mortality rate of 3.72% for those who were admitted to hospital due to RSV infection. This value of the mortality rate was used in the base-case model for children with CHD (Table 17).

Resource use and costs

The UK NHS perspective is adopted for the base-case evaluation and the cost-effectiveness is expressed in terms of incremental cost per QALY or per LYG. In the non-base-case analysis, we also include cost implications for a societal perspective which includes parent work loss costs due to infant’s hospitalisation or for administrating prophylaxis with palivizumab. Thus, the identification of costs for the model was conducted from both an NHS perspective and a societal perspective.

Medical costs

The utilisation of palivizumab reported in the study by Nuijten et al. 25 is used in the base-case model. It was based on assumptions about the number of 50-mg and 100-mg vials used in the RCT studies. 12,16 Among preterm infants without CLD or children with CLD, 38.7% used a 50-mg vial and 91.3% used a 100-mg vial. Among children with CHD, 39.6% of children used a 50-mg vial and 100% of infants used 100-mg vial; in 3.8% of cases a second 100-mg vial was used. 25

The cost of a 50-mg vial of palivizumab is £360.40 and the cost of a 100-mg vial of palivizumab is £600.10. 64 The recommended dose of palivizumab is 15 mg/kg body weight administered once monthly throughout the RSV season. We assume that each infant received five doses. Palivizumab utilisation and unit cost for preterm infants are listed in Table 19 and for children with CHD in Table 20.

TABLE 19 - NHS perspective or societal perspective resource use and costs for preterm infants

ESRC, Economic and Social Research Council; ONS, Office for National Statistics.

	Resource use	Source	Unit cost	Source	Total
Palivizumab	Five doses; 38.7% 50 mg, 91.3% 100 mg	Numa, 2000;34 Chiroli, 2005;37 Nuijten et al., 200725	£360.40/50 mg; £600.10/100 mg	BNF64	£3436.83
Palivizumab administration	1 × 8.4 min GP	Yount et al., 200446	£2.45	Curtis and Netten, 200631	£20.58
Palivizumab administration	5 × 15 min nurse	Yount et al., 200446	£0.52	Curtis and Netten, 200631	£39.00
Hospitalisation (intensive care unit)	1.37 days	The IMpact-RSV Study Group, 199816	£1723	Nuijten et al., 200725	£3183.24
Hospitalisation (non-intensive care unit)	6.47 days	The IMpact-RSV Study Group, 199816	£492	Nuijten et al., 200725	£2360.57
Parents’ work loss due to administration of prophylaxis	5 × 3 hours	Yount et al., 200446	£13.98	ONS;66 ESRC67	£209.70
Parents’ work loss due to children in hospital	7.84 × 8 hours	The IMpact-RSV Study Group, 1998;16 Yount et al., 200446	£13.98	ONS;66 ESRC67	£876.83

TABLE 20 - NHS perspective or societal perspective resource use and costs for children with CHD

ESRC, Economic and Social Research Council; ONS, Office for National Statistics.

	Resource use	Source	Unit cost	Source	Total
Palivizumab	Five doses, 39.6% 50 mg, 100% 100 mg. 3.8% 200 mg	Numa, 2000;34 Chiroli, 2005;37 Nuijten et al., 200725	£360.40/50 mg; £600.10/100 mg	BNF64	£3736.90
Palivizumab administration	1 × 8.4 min GP	Yount et al., 200446	£2.45	Curtis and Nettern, 200631	£20.58
Palivizumab administration	5 × 15 min nurse	Yount et al., 200446	£0.52	Nuijten et al., 200725	£39.00
Hospitalisation (intensive care unit)	6.14 days	The IMpact-RSV Study Group, 199816	£1723	Nuijten et al., 200725	£10,579.22
Hospitalisation (non-intensive care unit)	6.25 days	The IMpact-RSV Study Group, 199816	£492	Nuijten et al., 200725	£3075
Parents’ work loss due to administration of prophylaxis	5 × 3 hours	Yount et al., 200446	£13.98	ONS;66 ESRC67	£209.70
Parents’ work loss due to children in hospital	12.39 × 8 hours	The IMpact-RSV Study Group, 1998;16 Yount et al., 200446	£13.98	ONS;66 ESRC67	£1385.70

Administration costs

We assumed that palivizumab is routinely administered in a outpatient setting and that the costs of palivizumab administration consist of the following components:

• 8.4 min of GP time and 15 min of nurse time at the first visit to see the patient and discuss RSV prophylaxis with palivizumab

• 15 min of nurse time in the following visits.

The resource use for palivizumab administration and unit cost for preterm infants are listed in Table 19 and for children with CHD in Table 20.

Hospitalisation costs

The two RCT studies12,16 reported the number of patients who were admitted to paediatric wards and ICUs and the total of days in paediatric wards and in ICUs. For preterm infants without CLD or children with CLD, the average ICU stay is calculated to be 1.37 days and the average of non-ICU stay is calculated to be 6.47 days. 25 Two UK cohort studies57,65 reported length of stay in hospital due to RSV infection. However, the study by Clark et al. 57 reported only median of length of hospital stay (4 days with a range of 2–7 days), making it difficult to combine the length of stay in hospital with the RCT study. The other study by Thomas et al. 65 reported a total of 26 ICU days for three RSV-positive admissions and three admissions with RSV status unknown, but did not report the length of ICU stay for the three RSV-positive patients, making it difficult to estimate the average ICU days for RSV admission. We used the average number of days in a paediatric ward and in ICU estimated from the RCTs in the model. The hospitalisation resource use and unit cost for preterm children are listed in Table 19. For children with CHD, the average ICU stay is calculated to be 6.14 days and the average non-ICU stay was calculated to be 6.25 days. 25 The hospitalisation resource use and unit cost for children with CHD are listed in Table 20.

Parent work loss costs

Parent work loss costs consist of two parts, that due to the infant’s hospitalisation and that due to administrating prophylaxis with palivizumab. We assumed that in each case the infant was accompanied by one parent and that 3 hours of work was missed for each visit to administer palivizumab and 8 hours of work was lost in accompanying the infant to hospital. 46 The weekly wage in the UK in 2002 was estimated to be £442,67 which is equivalent to £516.58 in 2006. The average number of hours worked in the UK is estimated to be 36.96 hours per week. 66 This gives a unit cost of £13.98/hour for estimating parent work loss cost. The parent work loss and unit costs for preterm children are listed in Table 19 and for children with CHD in Table 20.

Estimation of QALYs

Life expectancy

National statistics (1997–2001) reported average life expectancy to be 79.4, 77.8, 76.8, 74.6, 73.3, and 71 years for men and 82.2, 81.7, 81.3 79.3, 78.6, and 77.6 year for women in different social classes. 68 The life expectancy for children at risk of RSV infection is calculated by averaging the life expectancies for men and women in different social classes using the assumption that men and women are equally represented in each social group. The mean life expectancy is estimated to be 77.8 with a standard deviation of 3.44. For preterm infants without CLD or children with CLD, the life expectancy at the age of 1 year was assumed to be 76.8 years. In the case of children with CHD, 95.3% of children were predicted to be survived to age 16 years if they had survived to age of 1 year. 25,69 Therefore, life expectancy at the age of 1 year was assumed to be 76.1 years for children with CHD.

Utilities

The study by Greenough et al. 70 assessed the health-related quality of life (HRQoL) for preterm children at the age of 5 years using the Health Utilities Index (HUI). The HUI describes a family of generic health status and HRQoL measures. Parents were sent the HUI2/3 and asked to complete the 15 questions to reflect their child’s health over the previous 4 weeks. The HUI2 measures seven attributes of health status describing 24,000 unique health states, while HUI3 describes 972,000 unique health states. The HUI2 was originally developed for paediatric application and clinical evaluation studies, whereas HUI3 was developed for use in adults and population surveys. The median HUI2 multiattribute utility function was 0.88 (range 0.16–1.00) in the RSV-positive children, while the median HUI2 multiattribute utility function was 0.95 (range 0.03–1.00) in the non-RSV-positive children. The median HUI 3 multiattribute scores were 0.93 (range –0.05 to 1.00) for RSV-positive children and 0.97 (range –0.32 to 1.00) for non-RSV-positive children. These utility values are used in the model for preterm children with or without CLD and are listed in Table 21. As mentioned above, the utility estimate was made by asking parents (rather than children themselves) to complete the questions to reflect their child’s health. This might introduce a bias in utility estimate. However, because the utility estimates for children hospitalised for RSV infection or not hospitalised for RSV infection were evaluated in the same way (i.e. parents completed the questionnaire) the effect of utility estimate made by parents for a child on the overall results is likely to be small and the conclusions unaltered.

TABLE 21 - Estimated utilities

CHD, congenital heart disease; CLD, chronic lung disease; RSV, respiratory syncytial virus.

	Utility values		Source
	RSV hospitalisation	Not RSV hospitalisation
Preterm with or without CLD	0.88	0.95	Greenough et al., 2004;70 Nuijten et al., 200725
Children with CHD	0.88	0.95	Greenough et al., 2004;70 Nuijten et al., 200725

Utility data for children and adults with CHD are lacking. The economic evaluation study by Yount et al. 46 extrapolated data from congestive heart failure to the CHD population and used a utility of 0.71 for children with CHD. We use the same utility values for children with CHD as those for preterm children with or without CLD (Table 21).

Assessment of cost-effectiveness using the base-case model

The results of cost-effectiveness are presented in three ways. Firstly, mean costs and QALYs for prophylaxis with palivizumab and no prophylaxis are presented and the incremental cost per QALY is calculated. For the base-case analysis, the incremental costs per LYG and per HAP are also presented. Secondly, cost-effectiveness–acceptability curves (CEACs) and scatterplots of incremental costs and outcomes generated from PSAs are presented. CEACs are used to illustrate uncertainty in results due to statistical variability around the parameter estimates. The curves demonstrate the likelihood that a strategy is cost-effective at different threshold values of willingness to pay for an additional QALY. The PSA is undertaken using appropriate distributions for all model variables. The model is run for 10,000 simulations. The results are summarised as the mean ICER for all simulations. Thirdly, the results of deterministic sensitivity analyses are presented for subgroups of the premature population and for specific RSV hospitalisation rates for children with CHD.

In order to consider the wider costs and benefits of prophylaxis with palivizumab to society, cost-effectiveness analyses are also undertaken from a societal perspective, taking into account the cost of parent work loss.

Assessment of cost-effectiveness using an extended model

It can be seen from the results of using realistic mortality rate estimates as parameters in the industry-sponsored model by Nuijten et al. 25 (which makes other assumptions favourable to palivizumab, such as the 100% occurrence of asthma in children admitted to hospital) that palivizumab does not meet conventional UK levels of cost-effectiveness in all children who meet the licensed indication.

Nonetheless, if there were evidence that by preventing RSV hospitalisations we might reduce asthma morbidity, then this would improve the cost-effectiveness of palivizumab. Although there is no evidence to show a causal link between early RSV infection and atopic asthma, a recent cohort study showed that wheezing in early childhood is associated with an increased incidence of atopic asthma. 50 It is difficult to know whether children who are prone to asthma are more likely to become symptomatic when infected by RSV or whether RSV may increase the risk of asthma. We found five studies60,71–74 that reported asthma/wheezing rates for children who were admitted to hospital due to RSV infection and children who were not admitted to hospital due to RSV infection. The follow-up period varied from 2 to 15 years. The pooled sequelae rates were 0.23 for RSV hospitalisation and 0.12 for non-hospitalisation, giving a pooled odds ratio (OR) of 2.3 (95% CI 1.74–3.02). The studies suffered from various biases.

Because our clinical experts advised us that it was more likely that children prone to asthma were likely to get more symptomatic RSV infections rather than RSV infections causing asthma, we decided not to include asthma in our base-case model. Therefore, in order to model the possible effect of including increased asthma as a consequence of RSV infection, we undertook a separate analysis. To do this the BrumEE was extended to take sequelae (asthma/wheezing) into account. The structure of the extended model is shown in Figure 10.

FIGURE 10.

The extended decision tree model (taking sequelae into account).

Sequelae-associated costs

The study by Greenough et al. 62 compared the health care utilisation of children with CLD who had or had not been admitted to hospital with a proven RSV infection. A total of 235 children with a median gestational age of 27 weeks was included in this study. Forty-five of them had at least once been admitted to hospital for a proven RSV infection. The health care utilisation and the corresponding unit costs for children with proven RSV infection are shown in Table 22.

TABLE 22 - Resource use and costs of RSV hospitalisation (over 2 years)

ICU, intensive care unit; RSV, respiratory syncytial virus.

	Resource use	Source	Unit cost	Source	Total
Days in hospital	39.8	Greenough et al., 200162	£237	Nuijten et al., 200725	£9433
Days in ICU	2.9	Greenough et al., 200162	£1723	Nuijten et al., 200725	£4997
Days in paediatric ward	30.7	Greenough et al., 200162	£492	Nuijten et al., 200725	£15104
Outpatients paediatric attendance	11.9	Greenough et al., 200162	£148	Nuijten et al., 200725	£1761
GP contacts	16.3	Greenough et al., 200162	£22	Curtis and Netten, 200631	£352
Community care contacts	28.2	Greenough et al., 200162	£30	Nuijten et al., 200725	£846
Consultations with GP for respiratory illness	8.3	Greenough et al., 200162	£22	Curtis and Netten, 200631	£179

The sequelae-associated cost for those who were admitted to hospital due to RSV infection is estimated based on the health care utilisation of the children with a proven RSV infection and adjusted by subtracting the first-year RSV hospitalisation cost from the calculated 2-year costs.

Results of the BrumEE

Cost-effectiveness results using a deterministic model

The costs and outcomes for preterm infants without CLD, children with CLD and children with CHD are listed in Tables 23, 24 and 25 respectively.

TABLE 23 - Average costs and outcomes for prophylaxis in preterm infants without CLD

CLD, chronic lung disease; QALY, quality-adjusted life-year.

Parameters	Palivizumab	No prophylaxis	Cost difference	Outcome difference
Costs
Drug	£3437
Drug administration (GP)	£21
Drug administration (nurse)	£39
Hospital	£67	£301
Total cost (NHS)	£3564	£301	£3263
Sequelae	£279	£1255
Total cost (NHS), including sequelae	£3843	£1556	£2287
Parent work loss	£226	£72
Total cost (societal)	£3790	£373	£3417
Total cost (societal), including sequelae	£4069	£1628	£2441
Outcomes
No discounting life-year lost	0.0059	0.0267		0.0208
No discounting QALYs	76.3141	76.2934		0.0207
Discounting life-year lost	0.0021	0.0094		0.0073
Discounting QALYs	26.5163	26.5092		0.0072

TABLE 24 - Average costs and outcomes for prophylaxis in preterm children with CLD

CLD, chronic lung disease; QALY, quality-adjusted life-year.

Parameters	Palivizumab	No prophylaxis	Cost difference	Outcome difference
Costs
Drug	£3437
Drug administration (GP)	£21
Drug administration (nurse)	£39
Hospital	£293	£475
Total cost (NHS)	£3790	£475	£3315
Sequelae	£1180	£1912
Total cost (NHS), including sequelae	£4970	£2387	£2583
Parent work loss	£283	£120
Total cost (societal)	£4073	£595	£3478
Total cost (societal), including sequelae	£5253	£2507	£2746
Outcomes
No discounting life-year lost	0.2427	0.3932		0.1505
No discounting QALYs	76.0788	75.9292		0.1496
Discounting life-year lost	0.0853	0.1382		0.0529
Discounting QALYs	26.4346	26.3826		0.0520

TABLE 25 - Average costs and outcomes for prophylaxis in children with CHD

CHD, congenital heart disease; QALY, quality-adjusted life-year.

Parameters	Palivizumab	No prophylaxis	Cost difference	Outcome difference
Costs
Drug	£3714
Drug administration (GP)	£21
Drug administration (nurse)	£39
Hospital	£382	£697
Total cost (NHS)	£4155	£697	£3458
Sequelae	£799	£1461
Total cost (NHS), including sequelae	£4954	£2158	£2796
Parent work loss	£287	£140
Total cost (societal)	£4442	£837	£3605
Total cost (societal), including sequelae	£5241	£2298	£2943
Outcomes
No discounting life-year lost	0.1506	0.2752		0.1246
No discounting QALYs	75.4704	75.3466		0.1238
Discounting life-year lost	0.0533	0.0974		0.0441
Discounting QALYs	26.4156	26.3722		0.0434

Table 26 presents the cost-effectiveness results of the deterministic analysis using the base-case model (with no sequelae). The ICERs between prophylaxis with palivizumab and no prophylaxis are £454,100/QALY for preterm infants without CLD, £63,800/QALY for children with CLD and £79,800/QALY for children with CHD from the NHS perspective.

TABLE 26 - Cost-effectiveness (£/QALY) results of the base-case model (NHS perspective)

CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Preterm infants and children without CLD
No prophylaxis	£301		26.5092
Palivizumab	£3563	£3262	26.5163	0.0071	£454,100
Preterm infants and children with CLD
No prophylaxis	£475		26.3826
Palivizumab	£3789	£3314	26.4346	0.0520	£63,800
CHD children
No prophylaxis	£697		26.3722
Palivizumab	£4155	£3458	26.4156	0.0433	£79,800

In order to compare the results from the BrumEE with previous decision-analytical models, we also present the ICERs per LYG. These are, from an NHS perspective, £446,100/LYG for preterm infants without CLD, £62,600/LYG for children with CLD, and £78,400/LYG for children with CHD, as shown in Table 27.

TABLE 27 - Cost-effectiveness (£/LYG) results of the base-case model (NHS perspective)

CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; LYG, life-year gained.

Strategy	Cost	Cost difference	LYGs	LYG difference	ICER (£/LYG)
Preterm infants and children without CLD
No prophylaxis	£301		0.0094
Palivizumab	£3563	£3262	0.0021	0.0073	446,100
Preterm infants and children with CLD
No prophylaxis	£475		0.1382
Palivizumab	£3789	£3314	0.0853	0.0529	62,600
CHD children
No prophylaxis	£697		0.0974
Palivizumab	£4155	£3458	0.0533	0.0441	78,400

The ICERs for using palivizumab compared with no prophylaxis are £51,800/HAP for preterm infants without CLD, £67,600/HAP for children with CLD and £78,600/HAP for children with CHD (Table 28).

TABLE 28 - Cost-effectiveness (£/HAP) results of the base-case model (NHS perspective)

CLD, chronic lung disease; HAP, hospital admission prevented; ICER, incremental cost-effectiveness ratio.

Strategy	Cost	Cost difference	HAPs	HAPs difference	ICER (£/HAP)
Preterm infants and children without CLD
No prophylaxis	£301		0.081
Palivizumab	£3563	£3262	0.018	0.0063	51,800
Preterm infants and children with CLD
No prophylaxis	£475		0.128
Palivizumab	£3789	£3314	0.079	0.049	67,600
CHD children
No prophylaxis	£697		0.0972
Palivizumab	£4155	£3458	0.0532	0.0440	78,600

From a societal perspective, the ICERs for using palivizumab compared with no prophylaxis are £475,600/QALY for preterm infants without CLD, £66,900/QALY for children with CLD and £83,200/QALY for children with CHD, as shown in Table 29.

TABLE 29 - Cost-effectiveness (£/QALY) results of the base-case model (societal perspective)

CHD, congenital heart disease; CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Preterm infants without CLD
No prophylaxis	£372		26.5092
Palivizumab	£3789	£3417	26.5163	0.0071	475,600
Children with CLD
No prophylaxis	£596		26.3826
Palivizumab	£4074	£3478	26.4346	0.0520	66,900
CHD children
No prophylaxis	£838		26.3722
Palivizumab	£4442	£3604	26.4156	0.0433	83,200

Deterministic sensitivity analysis of cost-effectiveness (NHS perspective)

For preterm infants without CLD, deterministic sensitivity analyses were carried out with different mortality rates of 0.0005, 0.0013, 0.0073 and 0.0811. The cost-effectiveness results are shown in Table 30. The results show that prophylaxis with palivizumab for preterm infants without CLD becomes more cost-effective as the RSV-related mortality rate increases. When the mortality rate of 8.11% (used in the study by Nuijten et al. 25) is applied, the ICER is £24,100/QALY, which is below the UK cost-effectiveness threshold (£30,000/QALY).

TABLE 30 - Cost-effectiveness with different mortality rates for preterm infants without CLD (the base-case model, NHS perspective)

CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Mortality rate = 0.0005
No prophylaxis	£301		26.5173
Palivizumab	£3563	£3262	26.5182	0.0009	3,905,500
Mortality rate = 0.0013
No prophylaxis	£301		26.5156
Palivizumab	£3563	£3262	26.5178	0.0022	1,502,100
Mortality rate = 0.0043
No prophylaxis	£301		26.5092
Palivizumab	£3563	£3262	26.5163	0.0071	454,100
Mortality rate = 0.0073
No prophylaxis	£301		26.5027
Palivizumab	£3563	£3262	26.5149	0.0122	267,500
Mortality rate = 0.0811
No prophylaxis	£301		26.3442
Palivizumab	£3563	£3262	26.4797	0.1355	24,100

For children with CLD, deterministic sensitivity analyses were carried out with different mortality rates of 0.03 and 0.05. The cost-effectiveness results are shown in Table 31. The results show that prophylaxis with palivizumab for children with CLD becomes more cost-effective as the RSV-related mortality rate increases. However, none of the ICERs reaches the UK cost-effectiveness threshold (£30,000/QALY).

TABLE 31 - Cost-effectiveness with different mortality rates for children with CLD (the base-case model, NHS perspective)

CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Mortality rate = 0.03
No prophylaxis	£475		26.4166
Palivizumab	£3789	£3314	26.4556	0.0390	85,000
Mortality rate = 0.04
No prophylaxis	£475		26.3826
Palivizumab	£3789	£3314	26.4346	0.0520	63,800
Mortality rate = 0.05
No prophylaxis	£475		26.3487
Palivizumab	£3789	£3314	26.4137	0.0650	51,000

Table 32 shows the cost-effectiveness results for subpopulations of children with CHD. The ICER for prophylaxis with palivizumab versus no prophylaxis for children with cyanotic CHD is £159,400/QALY, which reflects the fact that the RSV hospitalisation rates are not significantly different between children with cyanotic CHD who do and those who do not receive prophylaxis with palivizumab. The ICER for prophylaxis with palivizumab compared with no prophylaxis for among with acyanotic CHD is £49,100/QALY, which is also above the conventional UK cost-effectiveness threshold.

TABLE 32 - Cost-effectiveness for subpopulations of children with CHD (the base-case model, NHS perspective)

CHD, congenital heart disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
CHD, cyanotic, hospitalisation rates = 0.056/0.079 (palivizumab/no prophylaxis)
No prophylaxis	£567		26.3902
Palivizumab	£4175	£3608	26.4128	0.0226	159,400
CHD, acyanotic, hospitalisation rates = 0.050/0.118 (palivizumab/no prophylaxis)
No prophylaxis	£847		26.3518
Palivizumab	£4132	£3285	26.4187	0.0669	49,100

Sensitivity analyses are carried out using the RSV hospitalisation rates of 0.5–2.5% reported in the cohort study by Duppenthaler et al. 26 for children with CHD. Figure 11 shows the sensitivity analysis results of cost-effectiveness as RSV hospital admission rate in the no prophylaxis group changes. The ICER is £123,300/QALY with a RSV hospital admission rate of 0.5% and £91,000/QALY with a RSV hospital admission rate of 2.5%.

FIGURE 11.

ICERs vary as RSV hospital admission rate changes.

Table 33 shows the cost-effectiveness for children with CHD at different birth ages. The RSV hospitalisation rates reported in the study by Boyce et al. 75 were used (shown in Table 33). The value of ICER is £63,300/QALY for children with CHD at aged 0–6 months, £126,000/QALY for children aged 6–12 months and £457,900/QALY for children aged 12–24 months.

TABLE 33 - Cost-effectiveness with different mortality rates for children with CHD (the base-case model, NHS perspective)

CHD, congenital heart disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Age 0 to < 6 months, hospitalisation rate = 0.1208
No prophylaxis	£861		26.3498
Palivizumab	£4245	£3384	26.4033	0.0535	63,300
Age 6 to < 12 months, hospitalisation rate = 0.0635
No prophylaxis	£456		26.4054
Palivizumab	£4023	£3567	26.4337	0.0283	126,000
Age 12 to < 24 months, hospitalisation rate = 0.0182
No prophylaxis	£131		26.4500
Palivizumab	£3845	£3714	26.4581	0.0081	457,900

Cost-effectiveness (extended model in NHS and societal perspective)

Table 34 shows the cost-effectiveness results for preterm infants and children with CHD using the extended model (with consideration of sequelae) from the NHS perspective. The ICER for prophylaxis with palivizumab versus no prophylaxis for preterm infants without CLD is £318,200/QALY. The ICER for prophylaxis with palivizumab versus no prophylaxis for children with CLD is £49,700/QALY. The ICER for prophylaxis with palivizumab versus no prophylaxis for children with CHD is £64,600/QALY. These results demonstrate that prophylaxis with palivizumab for children with or without CLD tends to decrease ICER when sequelae are taken into account.

TABLE 34 - Cost-effectiveness (£/QALY), taking sequelae into account (NHS perspective)

CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Preterm infants without CLD
No prophylaxis	£1556		26.5092
Palivizumab	£3843	£2287	26.5163	0.0071	318,200
Children with CLD
No prophylaxis	£2387		26.3826
Palivizumab	£4970	£2583	26.4346	0.0520	49,700
Children with CHD
No prophylaxis	£2158		26.3722
Palivizumab	£4954	£2796	26.4156	0.0433	64,600

Table 35 shows the cost-effectiveness results for preterm infants and children with CHD using the extended model from societal perspective. The ICER for prophylaxis with palivizumab versus no prophylaxis for preterm infants without CLD is £339,700/QALY. The ICER for prophylaxis with palivizumab versus no prophylaxis for children with CLD is £52,800/QALY. The ICER for prophylaxis with palivizumab versus no prophylaxis for children with CHD is £67,900/QALY. These results demonstrate that prophylaxis with palivizumab for children with CHD tends to have a decreased ICER when potential sequelae are taken into account.

TABLE 38 - Cost-effectiveness (£/QALY), taking sequelae into account (societal perspective)

CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Preterm infants without CLD
No prophylaxis	£1628		26.5092
Palivizumab	£4069	£2441	26.5163	0.0071	339,700
Children with CLD
No prophylaxis	£2507		26.3826
Palivizumab	£5253	£2746	26.4346	0.0520	52,800
Children with CHD
No prophylaxis	£2298		26.3722
Palivizumab	£5241	£2943	26.4156	0.0433	67,900

Cost-effectiveness results using a PSA (NHS perspective)

The incremental cost-effectiveness plane for prophylaxis with palivizumab compared with no prophylaxis for preterm infants without CLD is shown in Figure 12 (the parameter values and their distributions used in this analysis are given in Table 48 in Appendix 9). This shows that, although the cost of palivizumab is always much higher than the cost of no prophylaxis, it always increases the QALY. The cost-effectiveness acceptability curve (CEAC) in Figure 13 shows that, compared with no prophylaxis, palivizumab has a probability of 50% of having an ICER below £460,000/QALY, a probability of 10% of having an ICER below £320,000/QALY and a probability of 90% of having an ICER below £690,000/QALY.

FIGURE 12.

Incremental cost-effectiveness plane for prophylaxis with palivizumab compared with no prophylaxis for preterm infants without CLD. The line represents the £30,000/QALY willingness-to-pay threshold.

FIGURE 13.

Cost-effectiveness–acceptability curve for prophylaxis with palivizumab compared with no prophylaxis for preterm infants without CLD.

The incremental cost-effectiveness plane for prophylaxis with palivizumab compared with no prophylaxis for children with CLD is shown in Figure 14 (the parameter values and their distributions used in this analysis are shown in Table 49 in Appendix 9). This also shows that the cost of prophylaxis with palivizumab is always much higher than the cost of no prophylaxis and always increases the QALY. The CEAC in Figure 15 shows that, compared with no prophylaxis, palivizumab has a probability of 50% of having an ICER below £64,000/QALY, a probability of 10% of having an ICER below £48,000/QALY and a probability of 90% of having an ICER below £86,000/QALY.

FIGURE 14.

Incremental cost-effectiveness plane for prophylaxis with palivizumab compared with no prophylaxis for children with CLD. The line represents the £30,000/QALY willingness-to-pay threshold.

FIGURE 15.

Cost-effectiveness–acceptability curve for prophylaxis with palivizumab compared with no prophylaxis for children with CLD.

The incremental cost-effectiveness plane for prophylaxis with palivizumab compared with no prophylaxis for children with CHD is shown in Figure 16 (the parameter values and their distributions used in this analysis are shown in Table 50). It demonstrates that the cost of prophylaxis with palivizumab is always much higher than the cost of no prophylaxis, and that in most cases prophylaxis with palivizumab increases the QALY. The CEAC in Figure 17 shows that, compared with no prophylaxis, palivizumab has a probability of 50% of having an ICER below £85,000/QALY, a probability of 10% of having an ICER below £50,000/QALY and a probability of 90% of having an ICER below £158,000/QALY.

FIGURE 16.

Incremental cost-effectiveness plane for prophylaxis with palivizumab compared with no prophylaxis for children with CHD. The line represents £30K/QALY willingness to pay threshold.

FIGURE 17.

Cost-effectiveness acceptability curve for prophylaxis with palivizumab compared with no prophylaxis for children with CHD.

As can be seen above, the deterministic model gives similar but slightly lower estimates for the ICERs for palivizumab compared with no prophylaxis than the median willingness-to-pay threshold of the PSA. The best summary estimate for policy-makers from the latter type of analysis (which incorporates more of the uncertainty than does a deterministic model with sensitivity analyses) is currently considered to be the average ICER from the PSA. These are summarised in the Table 36 and again are very similar. A comparison of the estimates from the different methods is given in Table 37.

TABLE 36 - Average ICER from PSA

CHD, chronic heart disease; CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Strategy	Cost	Cost difference	QALYs	QALY difference	ICER (£/QALY)
Preterm infants without CLD
No prophylaxis	£299		26.3239
Palivizumab	£3555	£3256	26.3310	0.0072	454,100
Children with CLD
No prophylaxis	£477		26.2079
Palivizumab	£3789	£3312	26.2595	0.0517	64,100
Children with CHD
No prophylaxis	£693		26.1997
Palivizumab	£4166	£3473	26.2423	0.0427	81,400

TABLE 37 - Comparative ICERs from different methods of BrumEE

CHD, chronic heart disease; CLD, chronic lung disease; ICER, incremental cost-effectiveness ratio; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life-year.

Strategy	Incremental cost/QALY (£)
	Deterministic analysis	10% probability of effectiveness from PSA	50% probability of effectiveness from PSA	90% probability of effectiveness from PSA	Average from PSA
Preterm infants without CLD	454,000	320,000	460,000	690,000	454,000
Children with CLD	64,000	48,000	64,000	86,000	64,000
Children with CHD	80,000	50,000	85,000	158,000	81,000

Summary

• The assessment group developed a decision tree with Monte Carlo simulation model to assess the cost-effectiveness of prophylaxis with palivizumab, compared with no prophylaxis. The model has been designed to estimate costs, from a UK NHS perspective and a societal perspective, and outcomes in terms of QALYs, for a lifetime time horizon.

• According to this model, prophylaxis with palivizumab is not a cost-effective strategy for preterm infants and children with CHD compared with no prophylaxis from both an NHS perspective and societal perspective. These findings are robust to probabilistic and other sensitivity analyses.

• Prophylaxis with palivizumab is also not a cost-effective strategy for preterm infants or infants with CLD who have no other risk factors.

• Subgroup analyses showed that prophylaxis with palivizumab for children with CLD may be cost-effective, at a willingness-to-pay threshold of £30,000/QALY, in

  • infants under 3 months old at the start of the RSV season who were born at 30 weeks gestational age or less

  • infants under 6 months old at the start of the RSV season who were born at 26 weeks gestational age or less.

• Further analyses showed that prophylaxis with palivizumab for children with CLD, and who also have a sibling in day care or school, may be cost-effective, at a willingness to pay threshold of £30,000/QALY, in

  • infants under 3 months old at the start of the RSV season who were born at 35 weeks gestational age or less

  • infants under 6 months old at the start of the RSV season who born at 30 weeks gestational age or less

  • infants under 9 months old at the start of the RSV season who born at 26 weeks gestational age or less.

Clinical effectiveness

Two good-quality trials provide evidence of the effectiveness of palivizumab in reducing the rate of RSV hospitalisation and RSV hospitalisation days in premature (≤ 35 weeks) infants and children with CLD and in children aged up to 2 years with CHD. Palivizumab appears to be safe and well tolerated.

Subgroup analysis suggested that palivizumab may be more effective in premature babies than in children with CLD. The reduction in RSV hospitalisation was greater in children with non-cyanotic rather than cyanotic CHD, but in this case there was no convincing evidence from subgroup analysis that the effect sizes were different.

Three systematic reviews9,17,20 assessed the clinical effectiveness of palivizumab based on the two RCTs. They gave the same conclusion: palivizumab is effective for the prevention of RSV infection in infants and children who are at high risk.

Cost-effectiveness

We have identified three systematic reviews and 18 primary studies for economic evaluations of prophylaxis with palivizumab.

The three systematic reviews on cost-effectiveness analysis came to similar conclusions. The study by Dunfield and Mierzwinski-Urban17 stated that the results of the included economic evaluation studies were variable due to different cost data sources, and that palivizumab was not cost-effective when used in all for whom it is recommended. Dunfield and Mierzwinski-Urban17 concluded that only children with a very high risk of RSV should be administered palivizumab owing to the high cost of palivizumab. The study by Embleton et al. 20 reported that none of the identified studies was a comprehensive economic analysis and that the costs of prophylaxis were far in excess of any likely savings achieved by decreasing hospital admission rates and concluded that continued use of palivizumab for high-risk infants, such as those with CLD, may appear justified in the absence of a comprehensive economic assessment. The study by Kamal et al. 32 reported that divergent results may be explained by differences in the study methods, assumptions and the poor quality of some economic evaluations and that the potential cost of palivizumab prophylaxis far exceeded the actual cost of hospitalisation; therefore, policy-makers, or providers, or payers need to critically appraise and judiciously interpret studies reporting the cost-effectiveness of palivizumab.

Four primary studies9,25,41,45 reported cost-effectiveness in terms of cost/LYG for preterm children with or without CLD. To make comparisons, we converted all ICERs into the UK pounds sterling at equivalent 2006 prices.

The ICERs varied from £25,800/LYG to £404,900/LYG:

• Two studies25,37 reported cost-effectiveness in terms of cost per LYG for children with CHD, with ICERs varying from £5300/LYG to £7900/LYG.

• Three studies25,40,47 reported cost-effectiveness in terms of cost per QALY for preterm children with or without CLD, with ICERs varying from £3200/QALY to £1,489,700/QALY.

• Two studies16,46 reported cost-effectiveness in terms of cost per QALY for children with CHD, with ICER varying from £7500/QALY to £68,700/QALY.

Other studies assessed cost-effectiveness in terms of cost/HAP for preterm children with or without CLD. The ICER varied from £5300/HAP to £69,200/HAP.

We have developed a decision-analytical model, the BrumEE, to assess the cost-effectiveness of prophylaxis with palivizumab.

The BrumEE shows that the ICERs for prophylaxis with palivizumab compared with no prophylaxis are £454,100/QALY for preterm infants without CLD, £63,800/QALY for children with CLD and £79,800/QALY for children with CHD, from an NHS perspective. The base-case model also shows that the ICERs between prophylaxis with palivizumab and no prophylaxis are £446,100/LYG for preterm infants without CLD, £62,600/LYG for children with CLD and £78,400/LYG for children with CHD from and NHS perspective, and that the ICERs between prophylaxis with palivizumab and no prophylaxis are £51,800/HAP for preterm infants without CLD, £67,600/HAP for children with CLD and £78,600/HAP for children with CHD from an NHS perspective. The similar cost-effectiveness results have been obtained from a societal perspective (£475,600/QALY for preterm infants without CLD, £66,900/QALY for children with CLD and £83,200/QALY for children with CHD). The probabilistic sensitivity analyses have shown that, compared with no prophylaxis, prophylaxis with palivizumab for preterm infants without CLD has a probability of 50% of having an ICER below £460,000/QALY, that prophylaxis with palivizumab for children with CLD has a probability of 50% of having an ICER below £64,000/QALY, and that prophylaxis with palivizumab for children with CHD has a probability of 50% of having an ICER below £85,000/QALY.

Strengths and limitations

The strengths of the assessment group economic model include the following aspects.

• Firstly, the cost-effectiveness of prophylaxis with palivizumab has been assessed in the time horizon of lifetime and expressed in terms of cost per LYG and cost per QALY (rather than in a 1-year time horizon and expressed only in cost per HAP, as in most previous models).

• Secondly, the mortality rates for those who admit to hospital due to RSV infection have been synthesised from meta-analysis of the available published evidence.

• Thirdly, analysis was conducted from both an NHS and a societal perspective.

• Finally, in addition to the base-case model, an extended model was used to assess the cost-effectiveness of prophylaxis with palivizumab when sequelae are taken into account.

The assessment group model has the following limitations.

• There is limited availability of good-quality scientific evidence to inform some of the parameters and some studies have quite a varied range of estimates.

• Evidence to inform the parameters of the model were sought and selected pragmatically rather than through a systematic review.

• The cost of sequelae was derived from only one study. It was estimated by subtracting the first-year cost due to RSV hospital admission from the total 2-year costs from a cohort study. The extended model was built with an assumption that the yearly sequelae costs are the same over several years.

• The utility values for children with CHD were assumed to be the same as those for preterm infants without CLD or children with CLD.

• Only one RSV season was considered in the models.

• The premature infants or children with CLD/CHD were assumed to have a normal full life expectancy.

Implications for decision and policy-making

Prophylaxis with palivizumab is clinically effective for the prevention of serious LRTI caused by RSV infection and requiring hospitalisation in high-risk children. This conclusion is based on two RCTs: the IMpact-RSV study16 found a 55% of reduction in RSV hospitalisation among preterm infants without CLD or children with CLD; and the Feltes et al. 12 study found a 45% reduction in RSV hospitalisation for children with CHD. There is some evidence that prophylaxis may be particularly effective in premature infants.

In terms of cost-effectiveness, prophylaxis with palivizumab does not represent good value based on any willingness-to pay-threshold below £60,000/QALY (the current UK ICER threshold is about £30,000/QALY) when used unselectively in preterm infants without CLD or children with CLD or CHD. This conclusion is in consistent with most previous economic evaluation studies, especially when only a short-term effect of RSV infection is considered (e.g. ICER is expressed as cost per HAP). However, our base-case model does show that prophylaxis with palivizumab may be cost-effective for some subgroups, such as young preterm infants with CLD.

The cost-effectiveness of prophylaxis with palivizumab is affected by the cost of palivizumab, and the length of stay and sequelae that RSV infection might have, in addition to the hospitalisation and mortality rates of RSV infection.

Suggested research priorities

Future research should be directed towards the following.

The body of evidence of the cost-effectiveness of prophylaxis with palivizumab is conditional on the quality of clinical evidence. Future research should focus on the major uncertainties in cost-effectiveness identified by the BrumEE, particularly in RSV-related mortality rate, and the length of effect of RSV infection on morbidity and mortality in the UK settings. Further large observational studies are desirable for the estimate of the mortality rate for children with CLD or preterm infants without CLD and who are admitted to hospital because of RSV infection. The health-related quality of life for RSV-infected children was assessed in the previous studies by measuring seven attributes of health status describing 24,000 unique health states for preterm children at the age of 5 years. Long-follow-up (> 5 years) observational studies will be useful for the estimate of the health-related quality of life and the period for which RSV infection has an effect on morbidity and mortality. In the first instance, a systematic review would more clearly identify gaps in knowledge and would inform the design of observational studies. A systematic review of the prognostic factors for hospital admission should be undertaken to permit the development of clinical guidelines to enable clinicians to identify the most appropriate children to be treated with palivizumab. Questions that could usefully be addressed in such research include:

• What are the prognostic factors for hospital admission due to RSV infection?

• What are the risks of these prognostic factors for hospital admission due to RSV infection?

Questions that could usefully be addressed in the systematic review and further observational research if the review confirmed that this was needed include:

• What is the mortality rate for children with CLD or preterm infants without CLD who are admitted to hospital due to RSV infection?

• What is the health-related quality of life for children with CLD or preterm infants without CLD who are admitted to hospital due to RSV infection?

• What is the health-related quality of life for children with CLD or preterm infants without CLD who are not admitted to hospital due to RSV infection?

• What is the health-related quality of life for children with CHD who are admitted to hospital due to RSV infection?

• What is the health-related quality of life for children with CHD who are not admitted to hospital due to RSV infection?

• For how long does RSV infection have an effect on morbidity and mortality in children with or without CLD or CHD?

The BrumEE models suggest that prophylaxis with palivizumab may be cost-effective for some subgroups, such as preterm infants with CLD. However, the hospital admission rates for these patient subgroups were obtained from subgroup analyses, and the mortality rates for these patient subgroups were assumed to be the same as those for the group considered as a whole. Future research should focus on the major uncertainties for patient subgroups, including preterm infants with different gestational ages. Further RCTs may be useful in estimating hospitalisation rates for children with CLD and/or who have a sibling in day care or at school, are under 6 months old at the start of the RSV season and who were born at 30 weeks gestational age or less. Questions that could usefully be addressed in such research include:

• What is the effect size of prophylaxis with palivizumab in terms of hospitalisation rates for children with CLD and/or who have a sibling in day care or at school, and who are under 6 months old at the start of the RSV season and who were born at 30 weeks gestational age or less?

Contributions of authors

Dechao Wang reviewed the economic evaluation studies, developed the decision-analytical model, and contributed to the drafting of the economic analysis, discussion and conclusion sections.

Carole Cummins applied the inclusion and exclusion criteria, extracted data, and contributed to the drafting of the clinical effectiveness section.

Sue Bayliss was information specialist to the team and devised and ran the search strategies.

Josie Sandercock contributed to the protocol development, selection of prognostic studies and modelling of risks for prognostic subgroups.

Dr Amanda Burls was the senior reviewer on this report. She contributed to the protocol development and design of the model and undertook data extraction for the systematic review of the effectiveness studies and the economic evaluations. She wrote the first draft of the report, read and commented on the final draft of the report and is guarantor.

About ‘home unit’

The West Midlands Health Technology Assessment Collaboration (WMHTAC) is an organisation involving several universities and academic groups who collaboratively undertake research synthesis to produce health technology assessments. Most of our members are based in the Department of Public Health and Epidemiology, University of Birmingham; however, other members are drawn from a wide field of expertise including economists and mathematical modellers from the Health Economics Facility, University of Birmingham, Leeds University and pharmacists and methodologists from the Department of Medicines Management, Keele University.

WMHTAC produces systematic reviews, health technology assessments and economic evaluations for NHS R&D HTA programme (NCCHTA), the National Institute for Health and Clinical Excellence (NICE), and for the health service in the West Midlands. WMHTAC also undertakes methodological research on research synthesis, and provides training in systematic reviews and health technology assessment.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health.

Health Technology Assessment reports published to date

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4. A cost–utility analysis of interferon beta for multiple sclerosis.

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6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

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9. Screening for speech and language delay: a systematic review of the literature.

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10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

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11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

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12. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

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13. Choosing between randomised and nonrandomised studies: a systematic review.

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14. Evaluating patient-based outcome measures for use in clinical trials.

    A review by Fitzpatrick R, Davey C, Buxton MJ, Jones DR.

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18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

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19. Systematic reviews of trials and other studies.

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20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

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   A review by Briggs AH, Gray AM.

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    By Payne N, Chilcott J, McGoogan E.

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    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

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    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Reimsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.