Table 35, Summary of included economic evaluations, mucoactive or mucolytic agents - Cystic Fibrosis

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Table 35Summary of included economic evaluations, mucoactive or mucolytic agents

Study	Limitations	Applicability	Other comments	Inc. costs	Inc. effects	Inc. cost-effectiveness	Uncertainty
Christopher 1999	Very serious^a^,^b	Partially^c^,^d^,^e	Considered 2 populations: All participants Subgroup with FEV₁ ≤70% (and who demonstrate a sustained improvement in FEV₁ of ≥10%)	Daily dornase alfa may lead to average savings of £1,746 per person from reduced hospitalisations over a 6-month period compared to placebo	Continued use of dornase alfa over a lifetime may increase life expectancy by 2 years in all patients, or 7 in years in the subgroup, compared to placebo	All: £52,550 per LYG Subgroup: £16,110 per LYG	Explored changing the rate of decline in FEV₁, initial FEV₁, and the mean % improvement in FEV₁ with dornase alfa treatment. Varied the length of treatment and discount rate for costs and benefits. CIs not reported.
McIntyre 1999	Very serious^a^,^b^,^f	Partially^c^,^d^,^e	None	Assumed cost savings from RTI-related care would offset between 18.3% and 37.5% of the acquisition cost of dornase alfa based on Oster 1995.	FEV₁% improvement with daily dornase alfa assumed to be either 8%, 4.3%, or 20% based on different literature sources. Based on assumptions for disease progression and survival, 3 additional LYs would be gained by a patient on dornase alfa compared to no dornase alfa	Cost per LYG varying FEV₁% improvement as a result of dornase alfa and the cost offset possible with dornase alfa use. Improvement with daily dornase alfa: 8%; 4.3%; 20%: 18.3% cost offset: £27,269; £45,234; £10,311 37.5% cost offset: £20,318; £34,915; £7,226	Improvement with dornase alfa and cost offset varied to provide a range of results. An increase in the cost of annual care for CF severe patients (FEV₁<40%) from £19,995 (Robson 1992) to £30,000 (Fogarty 1996) explored. CIs not reported.
Menzin 1996	Very serious^a^,^g^,^h^,ⁱ	Partially^c^,^j	Measures of physical resource use were compared between participants who received daily dornase alfa versus placebo in the US trial (Oster 1995). Differences in RTI-related resource use were then evaluated using local (country specific) estimates of unit costs	Difference in the mean costs of RTI-related care over 24 weeks (placebo – daily dornase alfa) Inpatient care, days in hospital £300 Inpatient care, antibiotic therapy £50 Outpatient care £84 Total £434	Difference in mean health care utilisation over 24 weeks (placebo – daily dornase alfa) Hospital admission: +0.15 Inpatient days: +1.5 Days of inpatient IV antibiotic therapy: +1.4 Days of inpatient oral antibiotic therapy: −0.04 Days of outpatient IV antibiotic therapy: +1.5 Days of outpatient oral antibiotic therapy: +1.7	NR	Not assessed. CIs not reported.
Suri 2002	Minor^k	Partially^c	Undertook a prospective, open, randomised, crossover trial completed by 43 children aged 5 to 18 years, this trial included a 2 week wash-out period. Clinical effectiveness data from this trial was also used to inform Grieve 2003	Daily dornase alfa - HS, mean costs over 12 weeks Intervention: +£1,718 Total non-interventional drugs: −£90 Total hospital care: −£212 Total community care: −£3 Grand total: £1,409 Daily dornase alfa - alternate day dornase alfa over 12 weeks Intervention: +£892 Total non-intervention drugs: +£18 Total hospital care: −£397 Total community care: £0 Grand total: +£513	Mean FEV₁ increase at 12 weeks from baseline Daily dornase alfa 16% Alternate day dornase alfa 14% HS 3%	NR	Mean incremental costs and benefits reported with 95% CIs. Scenarios reducing the price of dornase alfa reported by the BNF by 10–30% and 20th and 80th percentiles of the costs per occupied bed day.
Grieve 2003	Minor^l	Directly^c^,^m	Clinical effectiveness data taken from Suri 2002	Over 12 weeks Daily dornase alfa - HS, £1,409 Daily - alternate day dornase alfa, £464 Alternate day dornase alfa - HS, £945	FEV₁% over 12 weeks Daily dornase alfa - HS, 14 Daily - alternate day dornase alfa, 2 Alternate day dornase alfa – HS, 12	£ per 1% gain in FEV Daily dornase alfa - HS, £110 Daily - alternate day dornase alfa, £214 Alternate day dornase alfa - HS, £89	Mean incremental costs and benefits reported with 95% CIs. Using 2,000 samples CE planes and CEACs are presented. Scenario reducing the price of dornase alfa reported by the BNF by 10–30%. Net benefits were calculated for a range of ceiling ratios per 1% increase in FEV₁
NICE TA266	Seriousⁿ^,^o^,^p	Directly^q	Results are based on 100,000 simulations over a lifetime horizon	Control (baseline) £180,188 Bronchitol £211,923 Control + dornase alfa £249,472 Bronchitol + dornase alfa £285,858	Control (baseline) 9.75 Bronchitol 10.52 Control + dornase alfa 9.75 Bronchitol + dornase alfa 10.52	Mannitol versus control, ICER £41,074 Mannitol + dornase alfa versus control + dornase alfa, ICER £47,095	Deterministic sensitivity analysis was undertaken using minimum and maximum input values The most sensitive parameters are displayed in a tornado diagram The time horizon (1, 5, 10 and 20 years) and CF mortality (increased by 20% and 50%) was varied PSA was undertaken and presented on a cost-effectiveness plane and CEAC Several scenario analyses have been performed on the relative risk of exacerbation and discontinuation rule, decline in lung function and exacerbation rate

: BNF, British National Formulary; CE plane, cost-effectiveness plane; CEAC, cost-effectiveness acceptability curve; CI, confidence interval; CF, cystic fibrosis; FEV, forced expiratory volume; HS, hypertonic saline; LYG, life years gained; NR, not reported; PSA, probabilistic sensitivity analysis; RTI, respiratory tract infection; control, best supportive care
: Note: dornase alfa was referred to as rhDNase in the studies, updated here to reflect the term used in current UK practice
(a): Clinical effectiveness data taken from old US trial(s) that may reflect outdated practices and practices that may not be generalisable to the UK, the short trial duration(s) questions if those effects can be sustained, resource utilisation recorded in the trial(s) did not include the full scope of possible costs
(b): Assumptions on survival and disease progression may reflect outdated practices, lung transplants were also not considered as part of the lifetime analysis
(c): QALY not used as an outcome measure
(d): Discount rate 6% for costs and 0% for benefits, whereas the NICE reference case specifies 3.5% for both costs and benefits
(e): Cost-effectiveness analysis based on outdated US practice
(f): Cost year unclear and costs are not reported to be inflated to the same year, insufficient detail on how costs taken from Robson 1992 were estimated
(g): Little detail regarding sources used for cost build up
(h): Uncertainty not assessed
(i): The cost of dornase alfa therapy was not included, as it was not being marketed at the time the assessment was undertaken, therefore we cannot know of the cost of treatment is offset by cost savings from improved clinical outcomes
(j): Practice-adjustment analyses were only undertaken for Italy and France in the likelihood of hospitalisation for a RTI as these patients were believed to be treated as outpatients rather than inpatients - the authors do not justify if this difference applies to the UK, overall, adjustments to reflect UK clinical practice are not sufficiently described
(k): Effectiveness based on a crossover trial
(l): Population not described, but said to be found in Suri 2002 who undertook a crossover trial
(m): Cost-effectiveness analysis informed from a UK clinical trial and methods closely follow the NICE reference case. The preferred measure of effects (QALYs) is not used, but is still thought to be useful for decision making, given that all other criteria are relevant and the alternative outcome measure reported is unlikely to change the conclusions about cost-effectiveness.
(n): Both comparisons use clinical effectiveness data taken from the whole adult population, irrespective of dornase alfa use which underestimates the effectiveness of dornase alfa use
(o): Due to a short trial duration they assumed the benefits if mannitol would be maintained over the patient’s life if they remained on treatment, this would affect the ICER favourably, but there is uncertainty around this assumption
(p): Costs and utilities applied in the model are treatment specific rather than health state specific which is inaccurate as this removes the dependency on time in each health state
(q): UK cost-utility analysis that closely follows the NICE reference case

From: Appendix K, Health Economics

Cystic Fibrosis: Diagnosis and management.

NICE Guideline, No. 78.

National Guideline Alliance (UK).

London: National Institute for Health and Care Excellence (NICE); 2017 Oct 25.

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