Limitations of standard cost-effectiveness methods for health technology assessment of treatments for rare, chronic diseases: a case study of treatment for cystic fibrosis

Figures & data

Table 1. Model inputs for disease progression, ELX/TEZ/IVA clinical efficacy, cost, and utility.

Disease progression parameter	BSC alone		ELX/TEZ/IVA + BSC		Source
Acute increase in ppFEV1	0		14.3-percentage point increase over 24 weeks		Middleton 2019^32
Annual change in ppFEV1 by age	12 years: −2.39 13–17 years: −2.34 18–24 years: −1.92 25+ years: −1.45		90% reduction relative to BSC alone (conservative estimate given lung function maintenance observed with ELX/TEZ/IVA over a period of more than 2 years) applied over the lifetime simulation 12 years: −0.24 13–17 years: −0.23 18–24 years: −0.19 25+ years: −0.15		Konstan 2007^53; Konstan 2012^54; Daines 2021^35
Rate of PEx requiring intravenous antibiotic administration and/or hospitalization	Predicted range is conditional on age and ppFEV1		78% reduction relative to BSC alone applied over the lifetime simulation		Whiting 2014^48; Goss 2007^55; Middleton 2019^32; Daines 2021^35; Vertex internal data
Acute increase in weight-for-age z score	0		0.30-unit increase over 24 weeks		Vertex internal data
Cost^a parameter	Input/assumption				Source
Annual ELX/TEZ/IVA cost	$311,715				Red Book 2020^56
ELX/TEZ/IVA compliance (applied to drug cost)	Weeks 1–24	98.8% (ELX/TEZ/IVA trial compliance)			Vertex internal data
	Weeks 24+	83.7% (TEZ/IVA real-world compliance)			Hu 2019^57
Disease management cost		ppFEV1 ≥70%	ppFEV1 40% to <70%	ppFEV1 <40%	Institute for Clinical and Economic Review 2020^44
	Annual non–PEx-related costs	$30,258	$39,914	$68,240
	PEx cost	$57,273	$91,037	$130,460
Lung transplant cost	Lung transplant			$948,437	Institute for Clinical and Economic Review 2020^44
	Annual post-transplant care (year 1)			$365,773
	Annual post-transplant care (year 2+)			$131,738
Other costs	Cost of treating adverse events and recommended monitoring measures for patients receiving ELX/TEZ/IVA were included				Trikafta PI 2019^58; CMS 2019^59
Utility parameter	Input/assumption				Source
Utilities	EQ-5D utility value assigned for each cycle based on ppFEV1 and occurrence of PEx (yes = 1), using an equation derived from an IVA clinical trial: EQ-5D = 0.686 + 0.535 (ppFEV1) − 0.274 (ppFEV1)^2 − 0.070 (PEx)				Solem 2016^24

^aAll costs are in 2019 values.

Abbreviations. BSC, best supportive care; ELX/TEZ/IVA, elexacaftor/tezacaftor/ivacaftor and ivacaftor; IVA, ivacaftor; PEx, pulmonary exacerbation; PI, prescribing information; ppFEV₁, percent predicted forced expiratory volume in 1 s; TEZ/IVA, tezacaftor/ivacaftor.

Table 2. Model assumptions varied in scenario analyses.

Parameter	Base-case assumption	Alternative scenario analysis assumption
Discount rate	3.0% discount rate applied to both costs and health benefits	3.0% discount rate applied to costs; 1.5% discount rate applied to health benefits, which is often considered an alternative discount rate^7^,^17^,^22
Utility value	EQ-5D utility values^a assigned based on ppFEV1 and PEx only^24	0.08 treatment-specific utility increment for patients receiving ELX/TEZ/IVA was added to the base-case utility equation, based on the treatment benefit observed in the CFQ-R-8D utility, after adjusting for ppFEV1 improvements^60 (see Appendix for additional details)
Disease management costs	All disease management costs, including those accrued during additional survival, contributed to the total costs	Disease management costs incurred as a consequence of extending life with the use of ELX/TEZ/IVA + BSC (compared with the patient-level trajectory for BSC alone) were omitted; ELX/TEZ/IVA drug costs were accumulated during the additional years of survival
Drug pricing	Static drug price is assumed for the full lifetime simulation	Price reduction following patent expiration, which occurs 17 years from the model start: 66% reduction in the first year, 80% reduction for all subsequent years^25

^aThe EQ-5D is a 5-dimension preference-based questionnaire that measures the generic quality of life; the EQ-5D is converted to a quantitative measure of health-related quality of life (utility scores) for health economic modeling.

Abbreviations. BSC, best supportive care; CFQ-R-8D, Cystic Fibrosis Questionnaire-Revised-8 Dimensions; ELX/TEZ/IVA, elexacaftor/tezacaftor/ivacaftor and ivacaftor; EQ-5D, EuroQol- 5 Dimension; PEx, pulmonary exacerbation; ppFEV₁, percent predicted forced expiratory volume in 1 s.

Figure 1. Projected impact of ELX/TEZ/IVA on survival. A comparison of the treatment-specific projected survival curves is presented. The incremental residual LYs (i.e. years since entering the model) is represented by the area between the two survival curves, whereas the incremental median predicted survival is represented by the distance between the two survival curves at the point where 50% of each cohort has died. Abbreviations. BSC, best supportive care; ELX/TEZ/IVA, elexacaftor/tezacaftor/ivacaftor and ivacaftor; LY, life-year.

Table 3. Pharmacoeconomic model results of base-case and scenario analyses^a.

Base-case analysis	BSC alone	ELX/TEZ/IVA + BSC	Incremental
Median predicted survival, years	40.8	70.4	29.7
Mean undiscounted LYs	17.4	42.5	25.0
Mean discounted LYs	12.4	21.5	9.1
Mean discounted QALYs	10.8	19.9	9.2
Mean discounted total costs	$2,193,000	$6,609,000	$4,416,000
Mean discounted ELX/TEZ/IVA costs	$0	$5,642,000	$5,642,000
Mean discounted direct medical costs^b	$2,193,000	$967,000	−$1,226,000
ICER (discounted cost/QALY)			$482,000
Scenario analyses	Incremental QALYs	Incremental costs	ICER (discounted cost/QALY)
Base case	9.2	$4,416,000	$482,000
Differential discounting alone	14.4	$4,416,000	$306,000 (36% reduction from base case)
Treatment-specific utility increment alone	10.6	$4,416,000	$415,000 (14% reduction from base case)
Omitting additional disease management costs alone	9.2	$3,989,000	$435,000 (10% reduction from base case)
Generic pricing alone	9.2	$2,435,000	$266,000 (45% reduction from base case)
All four alternative assumptions applied	16.4	$2,007,000	$122,000 (75% reduction from base case)

^aAll values are rounded; columns calculating differences reflect the changes in the true (unrounded) values.

^bBackground BSC costs (including other pharmacy costs) were included in the direct medical costs.

Abbreviations. BSC, best supportive care; ELX/TEZ/IVA, elexacaftor/tezacaftor/ivacaftor and ivacaftor; ICER, incremental cost-effectiveness ratio; LY, life-year; QALY, quality-adjusted life-year.

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