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Cost-Effectiveness of Newborn Screening for Spinal Muscular Atrophy in The Netherlands

Open AccessPublished:August 11, 2022DOI:https://doi.org/10.1016/j.jval.2022.06.010

      Highlights

      • Detection of spinal muscular atrophy (SMA) immediately after birth and timely presymptomatic treatment increases patients’ chances for normal motor milestone development (eg, sitting, standing, walking).
      • This is the first economic evaluation of newborn screening for SMA followed by early treatment versus treatment after clinical diagnosis that considers the severity of SMA types 1 to 3, number of survival motor neuron 2 gene copies, and 2 available treatments.
      • Addition of SMA to the newborn screening program in The Netherlands would allow clinicians to identify and treat SMA before the onset of irreversible damage, resulting in improved outcomes for patients and lower costs.

      Abstract

      Objectives

      Spinal muscular atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and paralysis. In its most common and severe form, the majority of untreated infants die before 2 years of age. Early detection and treatment, ideally before symptom onset, maximize survival and achievement of age-appropriate motor milestones, with potentially substantial impact on health-related quality of life. Therefore, SMA is an ideal candidate for inclusion in newborn screening (NBS) programs. We evaluated the cost-effectiveness of including SMA in the NBS program in The Netherlands.

      Methods

      We developed a cost-utility model to estimate lifetime health effects and costs of NBS for SMA and subsequent treatment versus a treatment pathway without NBS (ie, diagnosis and treatment after presentation with overt symptoms). Model inputs were based on literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and validity of results.

      Results

      After detection of SMA by NBS in 17 patients, the number of quality-adjusted life-years gained per annual birth cohort was estimated at 320 with NBS followed by treatment compared with treatment after clinical SMA diagnosis. Total healthcare costs, including screening, diagnostics, treatment, and other healthcare resource use, were estimated to be €12 014 949 lower for patients identified by NBS.

      Conclusions

      NBS for early identification and treatment of SMA versus later symptomatic treatment after clinical diagnosis improves health outcomes and is less costly and, therefore, is a cost-effective use of resources. Results were robust in sensitivity and scenario analyses.

      Keywords

      Introduction

      Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by functional loss of the SMN1 gene. It leads to progressive, irreversible loss of motor neurons with a range of severe symptoms. In the first 6 months of life, untreated SMA type 1 patients have overt, rapidly progressing muscle weakness, leading to respiratory failure and death.
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      Chronic childhood-onset SMA variants are characterized by stalled gross motor development, causing inability to walk independently (SMA type 2) and ambulation loss later in life (SMA type 3). Rare adult-onset SMA type 4 primarily causes proximal weakness of arms and legs.
      • Piepers S.
      • van den Berg L.H.
      • Brugman F.
      • et al.
      A natural history study of late onset spinal muscular atrophy types 3b and 4.
      The reported incidence of SMA in the literature varies from 1:7000 to 1:11 000 births,
      • Vill K.
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      • Schwartz O.
      • et al.
      One year of newborn screening for SMA – results of a German pilot project.
      Richtlijn spinale musculaire atrofie (SMA) type 1 [Spinal muscular atrophy (SMA) type 1 guideline]. Spierziekten Nederland [Muscle diseases in The Netherlands].
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      and the estimated prevalence is approximately 1 to 2 per 100 000 population.
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      • et al.
      Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review.
      Three SMA treatments have been approved by the European Medicines Agency and the US Food and Drug Administration: nusinersen (Spinraza®), onasemnogene abeparvovec (Zolgensma®), and risdiplam (Evrysdi®). With different modes of action, these therapies aim to increase the availability of functional SMN protein. Clinical trial results demonstrate these treatments are effective against motor neuron loss and further disease progression. Earlier intervention has demonstrated better preservation of motor neurons and improved or preserved motor function.
      • Lowes L.P.
      • Alfano L.N.
      • Arnold W.D.
      • et al.
      Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy.
      • Finkel R.S.
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      • Darras B.T.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      • Gidaro T.
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      • Baranello G.
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      • Day J.W.
      • et al.
      Risdiplam in type 1 spinal muscular atrophy.
      Reports from presymptomatic treatments demonstrated greater potential for gain in motor performance and achievement of enhanced motor milestones.
      • Lowes L.P.
      • Alfano L.N.
      • Arnold W.D.
      • et al.
      Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy.
      ,
      • Al-Zaidy S.
      • Pickard A.S.
      • Kotha K.
      • et al.
      Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
      • De Vivo D.C.
      • Bertini E.
      • Swoboda K.J.
      • et al.
      Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
      • Day J.W.
      • Finkel R.S.
      • Chiriboga C.A.
      • et al.
      Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
      Diagnosis and treatment of SMA as early as possible, before onset of symptomatic disease, are crucial to prevent irreversible motor neuron loss and reduced motor function,
      • Soler-Botija C.
      • Ferrer I.
      • Gich I.
      • Baiget M.
      • Tizzano E.F.
      Neuronal death is enhanced and begins during foetal development in type I spinal muscular atrophy spinal cord.
      thus achieving the best possible outcomes.
      • Dangouloff T.
      • Burghes A.
      • Tizzano E.F.
      • Servais L.
      NBS SMA Study Group
      244th ENMC international workshop: newborn screening in spinal muscular atrophy May 10-12, 2019, Hoofdorp, The Netherlands.
      ,
      • Serra-Juhe C.
      • Tizzano E.F.
      Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors.
      Therefore, SMA is a good candidate for inclusion in newborn screening (NBS).
      Notably, several countries have already started NBS pilot and national programs for SMA, including Belgium, Germany, the United States, Australia, Italy, Spain, and Taiwan.
      • Dangouloff T.
      • Burghes A.
      • Tizzano E.F.
      • Servais L.
      NBS SMA Study Group
      244th ENMC international workshop: newborn screening in spinal muscular atrophy May 10-12, 2019, Hoofdorp, The Netherlands.
      ,
      • Chien Y.H.
      • Chiang S.C.
      • Weng W.C.
      • et al.
      Presymptomatic diagnosis of spinal muscular atrophy through newborn screening.
      • Kariyawasam D.S.T.
      • Russell J.S.
      • Wiley V.
      • Alexander I.E.
      • Farrar M.A.
      The implementation of newborn screening for spinal muscular atrophy: the Australian experience.
      • Kraszewski J.N.
      • Kay D.M.
      • Stevens C.F.
      • et al.
      Pilot study of population-based newborn screening for spinal muscular atrophy in New York state.
      • Boemer F.
      • Caberg J.H.
      • Dideberg V.
      • et al.
      Newborn screening for SMA in Southern Belgium.
      • Glascock J.
      • Sampson J.
      • Haidet-Phillips A.
      • et al.
      Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening.
      • Müller-Felber W.
      • Vill K.
      • Schwartz O.
      • et al.
      Infants diagnosed with spinal muscular atrophy and 4 SMN2 copies through newborn screening – opportunity or burden? [published correction appears in J Neuromuscul Dis. 2021;8(2):335-336].
      In July 2019, the National Health Council in The Netherlands positively advised inclusion of SMA screening in the NBS program,
      Neonatal screening for spinal muscular atrophy. Health Council of The Netherlands.
      and the National Institute for Public Health and the Environment recently published an implementation plan for SMA inclusion within the Dutch NBS program in 2022.
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      Cost-effectiveness evaluations can support the decision to implement an NBS program for SMA in The Netherlands. In particular, the cost, budgetary impact, and health gains compared with current practice need to be assessed in the context of generally limited healthcare budgets. The goal of this study was to assess the cost-effectiveness of NBS for SMA versus with SMA treatment after clinical diagnosis in The Netherlands.

      Methods

      Model Structure

      Our cost-utility model was developed to evaluate the lifetime costs and health effects of 2 alternatives: treatment of SMA after identification by NBS versus treatment after clinical SMA diagnosis. The model framework is a combination of a decision tree and a Markov state-transition model (Fig. 1). A short-term decision tree was designed to capture the initial NBS outcomes and treatment options. Subsequently, a Markov model was linked to simulate the health outcomes and costs. In line with published health-economic models on SMA treatment, the Markov model includes the following health states: being within a broad range of normal development (BRND), walking, sitting, not sitting, and requiring permanent assisted ventilation (PAV).
      • Malone D.C.
      • Dean R.
      • Arjunji R.
      • et al.
      Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.
      Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value. Final evidence report. Institute for Clinical and Economic Review (ICER).
      • Thokala P.
      • Stevenson M.
      • Kumar V.M.
      • Ren S.
      • Ellis A.G.
      • Chapman R.H.
      Cost effectiveness of nusinersen for patients with infantile-onset spinal muscular atrophy in US.
      • Dean R.
      • Jensen I.
      • Cyr P.
      • et al.
      An updated cost-utility model for onasemnogene abeparvovec (Zolgensma®) in spinal muscular atrophy type 1 patients and comparison with evaluation by the Institute for Clinical and Effectiveness Review (ICER).
      These health states align with major developmental milestones of healthy infants and clinical outcomes assessed in SMA clinical studies. Motor milestones were described based on tests listed in Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010.
      Figure thumbnail gr1
      Figure 1Model structure. Note: After NBS, patients with negative results leave the decision tree and patients with positive results undergo genetic testing to confirm the SMA type and identify the severity of disease by estimating the SMN2 copy numbers. Patients with SMN1 gene mutation and positive patients in the without NBS scenario will be identified symptomatically based on the SMA type. Once an SMA type is identified, patients transition into a Markov model and are treated and modeled until they transition to the death health state (lifetime horizon). Patients enter the Markov model 6 months after SMA diagnosis. The exact health state in which a patient enters the model depends on the SMA type, with corresponding severity of disease progression as derived from the clinical trials. The transition through the health states is reflected by the arrows. The square, circle, triangle, and pentagon represent a decision, chance, terminal, and obligatory node, respectively.
      BRND indicates broad range of normal development; D+, patients with SMA; D−, patients without SMA; M(…), transition to a Markov model; NBS, newborn screening; PAV, permanent assisted ventilation; SMA, spinal muscular atrophy; T+, positive heel-prick test; T−, negative heel-prick test.
      The cost-effectiveness analysis was conducted in accordance with Dutch pharmacoeconomic guidelines, following both the payer and societal perspectives.
      Guideline for economic evaluations in healthcare. Zorginstituut Nederland.
      Notably, a lifetime time horizon (100 years) and annual discount rates of 4% for costs and 1.5% for health outcomes were applied. Costs were expressed at 2019 price levels.
      Consumer prices price index 2015=100. Centraal Bureau voor de statistiek [Central Bureau of Statistics]. StatLine.

      Population Cohort

      The modeled cohort size was based on 169 680 newborns in The Netherlands in 2019. A cycle length of 6 months was applied for the first 3 years, followed by 12 months for the remainder of the model, to adequately reflect the rapid rate of motor development change in the first 3 years of a child’s life while also allowing treatment cycles to be appropriately costed. After the first 3 years of life, by which time healthy children would have achieved the milestone of walking, a longer cycle length was applied, reflecting the reduced likelihood of developmental change.

      Model Inputs

      Model inputs consisted of screening parameters, epidemiologic parameters, clinical aspects, costs, and utilities (Table 1
      • Vill K.
      • Kölbel H.
      • Schwartz O.
      • et al.
      One year of newborn screening for SMA – results of a German pilot project.
      ,
      • Ogino S.
      • Leonard D.G.B.
      • Rennert H.
      • Ewens W.J.
      • Wilson R.B.
      Genetic risk assessment in carrier testing for spinal muscular atrophy.
      ,
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      ,
      • Servais L.
      • Dangouloff T.
      Sun may arise on SMA: newborn screening of SMA.
      Open data van de Nederlandse Zorgautoriteit [Open data from the Dutch Healthcare Authority]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      Germany first in EU to get Novartis’ SMA gene therapy, costing almost 2m euros. Pharmaphorum.
      NZa zorgproductapplicatie [NZa Heathcare Product Application]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      • Hakkaart-van Roijen L.
      • van der Linden N.
      • Bouwmans C.
      • Kanters T.
      • Swan Tan S.
      Kostenhandleiding: Methodologie van Kostenonderzoek en Referentieprijzen voor Economische Evaluaties in de Gezondheidszorg. Diemen.
      • Tappenden P.
      • Hamilton J.
      • Kaltenthaler E.
      • et al.
      Nusinersen for Treating Spinal Muscular Atrophy: A Single Technology Appraisal Erratum.
      • Thompson R.
      • Vaidya S.
      • Teynor M.
      The utility of different approaches to developing health utilities data in childhood rare diseases – a case study in spinal muscular atrophy (SMA).
      • Lin C.W.
      • Kolb S.J.
      • Yeh W.S.
      Delay in diagnosis of spinal muscular atrophy: a systematic literature review.
      Appendix Methods in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010 and Appendix Table 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010).
      • Vill K.
      • Kölbel H.
      • Schwartz O.
      • et al.
      One year of newborn screening for SMA – results of a German pilot project.
      ,
      • Ogino S.
      • Leonard D.G.B.
      • Rennert H.
      • Ewens W.J.
      • Wilson R.B.
      Genetic risk assessment in carrier testing for spinal muscular atrophy.
      ,
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      ,
      • Servais L.
      • Dangouloff T.
      Sun may arise on SMA: newborn screening of SMA.
      Open data van de Nederlandse Zorgautoriteit [Open data from the Dutch Healthcare Authority]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      Germany first in EU to get Novartis’ SMA gene therapy, costing almost 2m euros. Pharmaphorum.
      NZa zorgproductapplicatie [NZa Heathcare Product Application]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      • Hakkaart-van Roijen L.
      • van der Linden N.
      • Bouwmans C.
      • Kanters T.
      • Swan Tan S.
      Kostenhandleiding: Methodologie van Kostenonderzoek en Referentieprijzen voor Economische Evaluaties in de Gezondheidszorg. Diemen.
      • Tappenden P.
      • Hamilton J.
      • Kaltenthaler E.
      • et al.
      Nusinersen for Treating Spinal Muscular Atrophy: A Single Technology Appraisal Erratum.
      • Thompson R.
      • Vaidya S.
      • Teynor M.
      The utility of different approaches to developing health utilities data in childhood rare diseases – a case study in spinal muscular atrophy (SMA).
      ,
      Pakketadvies sluisgeneesmiddel nusinersen (Spinraza®) voor de behandeling van spinale musculaire atrofie (SMA). Zorginstituut Nederland [Packaging information for nusinersen (Spinraza®) for the treatment of spinal muscular atrophy (SMA)]. Zorginstituut Nederland [Healthcare Institute of The Netherlands].
      These were derived from published literature, health technology assessment agencies’ reports, databases, and Dutch clinical expert opinion (see Acknowledgments section; hereafter referred to as expert opinion). In cases of disagreement regarding model inputs, consensus was reached by discussion with the authors and experts.
      Table 1Model parameters and values for the base-case analysis and sensitivity analyses.
      EstimateValueLower to upper boundDistributionSource
      Epidemiologic inputs
      Incidence of SMA0.0001
      1 in 10 000 population.
      Dirichlet6
      Incidence of SMA deletion
      Homozygous deletion0.99Dirichlet25
      Heterozygote deletion0.01Dirichlet25
      SMA types (detected without NBS)
      Type 158%Dirichlet6
      Type 229%Dirichlet6
      Type 313%Dirichlet6
      SMN2 copy numbers (detected with NBS)
      SMN2—2 copies45%Dirichlet4,32
      SMN2—3 copies33%Dirichlet4,32
      SMN2—4 copies22%Dirichlet4,32
      Cost parameters
      Based on 2019 pricing.
      Screening costs
      Costs of the screening test (within NBS program)€4.95€3.96-€ 5.94Gamma25
      Tariff for diagnostics for referred children€1600€1280-€ 1920Gamma33
      Treatment costs per dose
      Onasemnogene abeparvovec€1 945 000Gamma34
      Nusinersen€83 300Gamma25
      Administration costs
      Onasemnogene abeparvovec€3278€2622-€3933Gamma35,36
      Nusinersen€3278€2622-€3933Gamma36
      Utility values
      Parameters of general population utilities are presented in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010.
      Sitting health state0.600.50-0.71Beta37
      Not-sitting health state0.190.16-0.22Beta38
      PAV health state0.000.00-0.00Beta39
      NBS indicates newborn screening; PAV, permanent assisted ventilation; SMA, spinal muscular atrophy.
      1 in 10 000 population.
      Based on 2019 pricing.
      Parameters of general population utilities are presented in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010.

      Screening parameters

      In the model, the heel-prick test (as routinely used in Dutch NBS), in which a drop of blood is taken from the baby, is assumed to be used to identify the SMA genotype.
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      A real-time polymerase chain reaction genotyping assay for SMN1 is then performed on a dried blood spot to detect homozygous SMN1 deletion.
      • Glascock J.
      • Sampson J.
      • Haidet-Phillips A.
      • et al.
      Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening.
      If the result is positive, SMA status can be confirmed and SMN2 copy number, as a marker of the severity, can be determined by either droplet digital polymerase chain reaction or multiplex ligation-dependent probe amplification.
      • Glascock J.
      • Sampson J.
      • Haidet-Phillips A.
      • et al.
      Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening.
      ,
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      Coverage with heel-prick screening is >99% in The Netherlands.
      • Johnson N.B.
      • Paradis A.D.
      • Naoshy S.
      • Wong J.
      • Montes J.
      • Krasinski D.C.
      Evaluation of nusinersen on impact of caregiver experience and HRQOL in later-onset spinal muscular atrophy (SMA): results from the phase 3 CHERISH trial.

      Epidemiological inputs

      Our model base included the incidence of SMA patients detected by NBS. Nevertheless, because NBS does not identify SMN1 point mutations, this patient group is assumed to be diagnosed clinically when symptoms occur. According to a feasibility study
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      and Dutch expert opinion, a maximum of 1% of patients with SMA have an SMN1 point mutation, might therefore not be identified with NBS, and may be labeled as false-negatives. No false-positive results should be expected because all NBS tests are validated with a subsequent genetic test.
      • Chien Y.H.
      • Chiang S.C.
      • Weng W.C.
      • et al.
      Presymptomatic diagnosis of spinal muscular atrophy through newborn screening.
      ,
      • Lin C.W.
      • Kolb S.J.
      • Yeh W.S.
      Delay in diagnosis of spinal muscular atrophy: a systematic literature review.
      In addition, according to clinical results from an NBS study for SMA in Germany, no false-positives or false-negatives occurred during a 2-year period.
      Hielprikscreening: deelname. De staat van volksgezondheid en zorg [Heel prick screening: participation. The state of public health and care].
      Because motor development and survival vary widely by SMA phenotype, which is largely influenced by SMN2 gene copy number, our model included symptomatic patients with SMA types 1, 2, and 3, and presymptomatic newborns with specific SMN2 gene copy numbers. It was estimated that 45%, 33%, and 22% of newborn patients had SMA with 2, 3, or 4 SMN2 copies, respectively.
      • Vill K.
      • Kölbel H.
      • Schwartz O.
      • et al.
      One year of newborn screening for SMA – results of a German pilot project.
      ,
      • Servais L.
      • Dangouloff T.
      Sun may arise on SMA: newborn screening of SMA.
      The percentage of symptomatic patients diagnosed of SMA types 1, 2, or 3 was estimated as 58%, 29%, and 13%, respectively.
      • Ogino S.
      • Leonard D.G.B.
      • Rennert H.
      • Ewens W.J.
      • Wilson R.B.
      Genetic risk assessment in carrier testing for spinal muscular atrophy.

      Clinical inputs

      The Markov model is driven by short-term data on motor milestone achievement and long-term extrapolated survival estimates. In the model, both presymptomatic and symptomatic patients were assumed to be treated within the first 6 months, corresponding with the end of the first model cycle. Subsequently, patients achieving a motor milestone during a model cycle are transitioned into the next model cycle. Distinctive data sources were used to differentiate between health outcomes for presymptomatic and symptomatic patients. A targeted literature review was conducted to identify relevant clinical trials for approved SMA treatments used in both presymptomatic and symptomatic patients. Of the 6 single-arm trials and 2 trial extensions identified, some were considered to provide adequate input to represent the outcomes of presymptomatic treatment. In particular, the SHINE and ENDEAR studies were considered suitable for our model structure.
      • Finkel R.S.
      • Mercuri E.
      • Darras B.T.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      ,
      • Castro D.
      • Finkel R.S.
      • Farrar M.A.
      • et al.
      Nusinersen in infantile-onset spinal muscular atrophy: results from a longer-term treatment from the Open-label SHINE Extension Study (1640).
      For further details on the trial selection, see the Appendix Methods in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010 and Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010.
      Incorporating NBS for SMA will result in earlier diagnosis for patients by potentially 6 months for type 1, 1.7 years for type 2, and 4.2 years for type 3, based on the age of confirmed SMA genetic diagnosis.
      • Lin C.W.
      • Kolb S.J.
      • Yeh W.S.
      Delay in diagnosis of spinal muscular atrophy: a systematic literature review.
      After a diagnosis after NBS, a treatment decision should be made immediately to minimize the impact of loss of motor neurons and related symptoms.
      • Finkel R.S.
      • Mercuri E.
      • Darras B.T.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      In our model, early diagnosis and treatment initiation drives improvements in health-related quality of life through 2 mechanisms: (1) the absence of symptoms and (2) relevant delays in the occurrence of symptoms.
      • Lin C.W.
      • Kolb S.J.
      • Yeh W.S.
      Delay in diagnosis of spinal muscular atrophy: a systematic literature review.
      ,
      • Keinath M.C.
      • Prior D.E.
      • Prior T.W.
      Spinal muscular atrophy: mutations, testing, and clinical relevance.
      Treatment after early detection was modeled with data from the NURTURE trial. NURTURE enrolled presymptomatic newborns only, and the mean age at therapy initiation was 20.6 days.
      • De Vivo D.C.
      • Bertini E.
      • Swoboda K.J.
      • et al.
      Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
      Other studies were used to reflect the clinical diagnosis and efficacy of symptomatic treatment. All patients with SMA type 1 and patients identified by NBS entered the model in health state D (not sitting) and were assigned to a subsequent health state or remained in health state D based on transition probabilities or survival data. Symptomatic patients with SMA types 2 and 3 entered the model in health state C (sitting) and health state B (walking), respectively.
      The short-term data on milestone achievement were also based on clinical trials. Transition probabilities for presymptomatic children treated with either nusinersen or onasemnogene abeparvovec were based on the NURTURE clinical trial,
      • De Vivo D.C.
      • Bertini E.
      • Swoboda K.J.
      • et al.
      Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
      which enrolled only presymptomatic infants who were identified through affected sibling(s).
      • De Vivo D.C.
      • Bertini E.
      • Swoboda K.J.
      • et al.
      Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study.
      For symptomatic patients with SMA type 1, transition probabilities were calculated with data from START and STR1VE for those treated with onasemnogene abeparvovec and with data from ENDEAR and SHINE (an extension of ENDEAR) for patients treated with nusinersen.
      • Finkel R.S.
      • Mercuri E.
      • Darras B.T.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      ,
      • Al-Zaidy S.
      • Pickard A.S.
      • Kotha K.
      • et al.
      Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.
      ,
      • Day J.W.
      • Finkel R.S.
      • Chiriboga C.A.
      • et al.
      Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
      ,
      • Johnson N.B.
      • Paradis A.D.
      • Naoshy S.
      • Wong J.
      • Montes J.
      • Krasinski D.C.
      Evaluation of nusinersen on impact of caregiver experience and HRQOL in later-onset spinal muscular atrophy (SMA): results from the phase 3 CHERISH trial.
      ,
      • Castro D.
      • Finkel R.S.
      • Farrar M.A.
      • et al.
      Nusinersen in infantile-onset spinal muscular atrophy: results from a longer-term treatment from the Open-label SHINE Extension Study (1640).
      ,
      Highly specialised technology evaluation. Onasemnogene abeparvovec for treating spinal muscular atrophy [ID1473]. Evaluation report. National Institute for Health and Care Excellence (NICE).
      ,
      Single technology appraisal. Nusinersen for treating spinal muscular atrophy [ID1069]. National Institute for Health and Care Excellence.
      Transition probabilities for symptomatic treated patients with SMA types 2 and 3 were based on the CS2/CS12 clinical trial.
      • Darras B.T.
      • Chiriboga C.A.
      • Iannaccone S.T.
      • et al.
      Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies.
      Earlier diagnosis and treatment age in the model were based on assumptions and reflected symptom onset, diagnosis, and timely access to available treatments in clinical practice.
      • Finkel R.S.
      • Mercuri E.
      • Darras B.T.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      ,
      • Lin C.W.
      • Kolb S.J.
      • Yeh W.S.
      Delay in diagnosis of spinal muscular atrophy: a systematic literature review.
      ,
      • Tizzano E.F.
      Treating neonatal spinal muscular atrophy: a 21st century success story?.
      Compared with patients in ENDEAR/SHINE, patients in the START trial were younger at start of treatment, and fewer patients required ventilatory support.
      • Finkel R.S.
      • Mercuri E.
      • Darras B.T.
      • et al.
      Nusinersen versus sham control in infantile-onset spinal muscular atrophy.
      ,
      • Castro D.
      • Finkel R.S.
      • Farrar M.A.
      • et al.
      Nusinersen in infantile-onset spinal muscular atrophy: results from a longer-term treatment from the Open-label SHINE Extension Study (1640).
      ,
      • Mendell J.R.
      • Al-Zaidy S.
      • Shell R.
      • et al.
      Single-dose gene-replacement therapy for spinal muscular atrophy.
      Detailed information on the clinical trials is presented in Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010.
      In the model, it was assumed that the motor milestones achieved at the end of follow-up in the clinical trials (after 24 months for nusinersen and after 36 months for onasemnogene abeparvovec) were sustained until death.
      • Al-Zaidy S.A.
      • Mendell J.R.
      From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1.
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-year extension results of the Phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      • Mendell J.R.
      • Finkel R.S.
      • Mercuri E.
      • et al.
      Long-term follow-up (LTFU) of onasemnogene abeparvovec therapy in spinal muscular atrophy.
      No evidence exists that SMN protein expression stops or wanes over time, and data from the START trial and extension study demonstrated that patients treated with onasemnogene abeparvovec maintained achieved milestones up to 6 years and, in some cases, achieved additional milestones.
      • Al-Zaidy S.A.
      • Mendell J.R.
      From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1.
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-year extension results of the Phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      • Mendell J.R.
      • Finkel R.S.
      • Mercuri E.
      • et al.
      Long-term follow-up (LTFU) of onasemnogene abeparvovec therapy in spinal muscular atrophy.
      Survival for each health state was extrapolated over time using the method reported by Guyot et al
      • Guyot P.
      • Ades A.E.
      • Ouwens M.J.N.M.
      • Welton N.J.
      Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.
      (more detail is provided in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010). Extrapolations of the PAV, not-sitting, and sitting health states were based on published studies, such as Gregoretti et al
      • Gregoretti C.
      • Ottonello G.
      • Testa M.B.C.
      • et al.
      Survival of patients with spinal muscular atrophy type 1.
      for PAV. The NeuroNEXT study was used to estimate long-term survival in the not-sitting state (death as well as transition to health state PAV).
      • Kolb S.J.
      • Coffey C.S.
      • Yankey J.W.
      • et al.
      Natural history of infantile-onset spinal muscular atrophy.
      Survival for SMA type 1 patients in the sitting state was modeled from a 52-year targeted prospective, as well as a retrospective, study.
      • Zerres K.
      • Rudnik-Schöneborn S.
      • Forrest E.
      • Lusakowska A.
      • Borkowska J.
      • Hausmanowa-Petrusewicz I.
      A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients.
      For the walking and BRND health states, Dutch normal life expectancy was used.
      Life expectancy; sex, age (per year and period of five years). Statistics Netherlands (CBS).
      Survival curves obtained from the literature were aligned with the age of the modeled population. Ages at the start of cycle 1 were 6, 18, and 48 months for patients with SMA types 1, 2, and 3, respectively.
      In the base-case analysis, 94% of patients were treated with onasemnogene abeparvovec and 6% were treated with nusinersen. Percentages were based on expert opinion on ineligibility for onasemnogene abeparvovec. Risdiplam was not included in the model because clinical trial results were not available when the model was developed.

      Cost inputs

      The cost of NBS for SMA is based on various NBS components: the cost of the heel-prick test, the cost of performing the heel-prick test, and the cost of the laboratory analysis. The cost of performing the heel-prick test would not change with the addition of SMA screening because blood samples are already gathered for present screening purposes.
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      Laboratory analysis costs in NBS for SMA were the same as those for NBS for severe combined immunodeficiency at €4.95.
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      Infants who tested positive for SMA through NBS were recommended to receive genetic screening at a cost of €1600.
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      ,
      Open data van de Nederlandse Zorgautoriteit [Open data from the Dutch Healthcare Authority]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      In the absence of NBS for SMA, the cost of diagnostics consists of the present genetic screening costs (Table 1
      • Vill K.
      • Kölbel H.
      • Schwartz O.
      • et al.
      One year of newborn screening for SMA – results of a German pilot project.
      ,
      • Ogino S.
      • Leonard D.G.B.
      • Rennert H.
      • Ewens W.J.
      • Wilson R.B.
      Genetic risk assessment in carrier testing for spinal muscular atrophy.
      ,
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      ,
      • Servais L.
      • Dangouloff T.
      Sun may arise on SMA: newborn screening of SMA.
      Open data van de Nederlandse Zorgautoriteit [Open data from the Dutch Healthcare Authority]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      Germany first in EU to get Novartis’ SMA gene therapy, costing almost 2m euros. Pharmaphorum.
      NZa zorgproductapplicatie [NZa Heathcare Product Application]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      • Hakkaart-van Roijen L.
      • van der Linden N.
      • Bouwmans C.
      • Kanters T.
      • Swan Tan S.
      Kostenhandleiding: Methodologie van Kostenonderzoek en Referentieprijzen voor Economische Evaluaties in de Gezondheidszorg. Diemen.
      • Tappenden P.
      • Hamilton J.
      • Kaltenthaler E.
      • et al.
      Nusinersen for Treating Spinal Muscular Atrophy: A Single Technology Appraisal Erratum.
      • Thompson R.
      • Vaidya S.
      • Teynor M.
      The utility of different approaches to developing health utilities data in childhood rare diseases – a case study in spinal muscular atrophy (SMA).
      • Lin C.W.
      • Kolb S.J.
      • Yeh W.S.
      Delay in diagnosis of spinal muscular atrophy: a systematic literature review.
      ).
      The model includes the annual costs per health state. A literature search on resource use by patients with SMA was performed and discussed with the aforementioned Dutch SMA expert(s). We determined that UK healthcare resource use study data were the best source to estimate healthcare costs by applying Dutch cost estimates. This approach was also used for the Dutch reimbursement dossier for onasemnogene abeparvovec and was accepted and published by Dutch authorities.
      Pakketadvies sluisgeneesmiddel nusinersen (Spinraza®) voor de behandeling van spinale musculaire atrofie (SMA). Zorginstituut Nederland [Packaging information for nusinersen (Spinraza®) for the treatment of spinal muscular atrophy (SMA)]. Zorginstituut Nederland [Healthcare Institute of The Netherlands].
      Data were obtained from a UK healthcare resource use study, National Health Service Prescription Cost Analysis, Dutch cost guidelines, and the Dutch Health Authority.
      NZa zorgproductapplicatie [NZa Heathcare Product Application]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      ,
      • Hakkaart-van Roijen L.
      • van der Linden N.
      • Bouwmans C.
      • Kanters T.
      • Swan Tan S.
      Kostenhandleiding: Methodologie van Kostenonderzoek en Referentieprijzen voor Economische Evaluaties in de Gezondheidszorg. Diemen.
      ,
      Prescription cost analysis – England, 2018 [PAS]. NHS.
      ,
      Costs per health state were specified for drug costs, medical tests, medical visits, hospitalizations, general practitioner and emergency visits, health material, ventilation, and social services. In the model, it was assumed that patients in the BRND health state generally do not require any additional resources with associated costs.
      Treatment costs for nusinersen consisted of the cost of 4 loading doses administered within approximately 63 days of the initial dose and a maintenance dose administered once every 4 months thereafter (list price €83 300 per dose).
      Pakketadvies sluisgeneesmiddel nusinersen (Spinraza®) voor de behandeling van spinale musculaire atrofie (SMA). Zorginstituut Nederland [Packaging information for nusinersen (Spinraza®) for the treatment of spinal muscular atrophy (SMA)]. Zorginstituut Nederland [Healthcare Institute of The Netherlands].
      Administration costs were based on either inpatient or outpatient lumbar puncture at a cost of €3278 or €2473 per administration, respectively, and also dependent on the age of the patient.
      Pakketadvies sluisgeneesmiddel nusinersen (Spinraza®) voor de behandeling van spinale musculaire atrofie (SMA). Zorginstituut Nederland [Packaging information for nusinersen (Spinraza®) for the treatment of spinal muscular atrophy (SMA)]. Zorginstituut Nederland [Healthcare Institute of The Netherlands].
      Treatment costs for onasemnogene abeparvovec were based on the Dutch list price of the one-time treatment (€1 945 000),
      Germany first in EU to get Novartis’ SMA gene therapy, costing almost 2m euros. Pharmaphorum.
      and administration costs for the intravenous infusion were conservatively estimated at €3278 per administration.
      • Hakkaart-van Roijen L.
      • van der Linden N.
      • Bouwmans C.
      • Kanters T.
      • Swan Tan S.
      Kostenhandleiding: Methodologie van Kostenonderzoek en Referentieprijzen voor Economische Evaluaties in de Gezondheidszorg. Diemen.
      Societal perspective costs included the income lost per patient per health state, caregiver costs, and transportation costs (all based on Dutch cost guidelines).
      • Tappenden P.
      • Hamilton J.
      • Kaltenthaler E.
      • et al.
      Nusinersen for Treating Spinal Muscular Atrophy: A Single Technology Appraisal Erratum.
      Productivity losses from absences from paid work were included using the friction cost method for patients aged 18 to 65 years.
      • Versteegh M.
      • Knies S.
      • Brouwer W.
      From good to better: new Dutch guidelines for economic evaluations in healthcare.
      In the model, patients with SMA in the walking and BRND health states did not have additional absenteeism, except for those treated with nusinersen who must travel to receive treatment. It was assumed that 20% of patients with SMA in the sitting health state had paid employment. Patients with SMA who entered the not-sitting or PAV health states were assumed to never participate in the labor market. Unrelated medical costs, based on the Practical Application to Include future Disease costs method, were tested in scenario analysis.
      • Van Baal P.H.M.
      • Wong A.
      • Slobbe L.C.J.
      • Polder J.J.
      • Brouwer W.B.F.
      • de Wit G.A.
      Standardizing the inclusion of indirect medical costs in economic evaluations.

      Utility inputs

      Quality-adjusted life-years (QALYs) for patients with SMA were modeled as dependent on the specified health states. Health state utility values were sourced from the literature. Based on the Institute for Clinical and Economic Review analysis of nusinersen and onasemnogene abeparvovec and the National Institute for Health and Care Excellence single technology appraisal of nusinersen,
      Spinraza® and Zolgensma® for spinal muscular atrophy: effectiveness and value. Final evidence report. Institute for Clinical and Economic Review (ICER).
      ,
      Single technology appraisal. Nusinersen for treating spinal muscular atrophy [ID1069]. National Institute for Health and Care Excellence.
      the following health state utilities were identified: 0.00 was used for PAV as agreed to by the aforementioned Dutch clinical experts; 0.19 for not-sitting
      • Thompson R.
      • Vaidya S.
      • Teynor M.
      The utility of different approaches to developing health utilities data in childhood rare diseases – a case study in spinal muscular atrophy (SMA).
      ; and 0.60 was used for the sitting health state.
      • Tappenden P.
      • Hamilton J.
      • Kaltenthaler E.
      • et al.
      Nusinersen for Treating Spinal Muscular Atrophy: A Single Technology Appraisal Erratum.
      For more detail on utilities, please see the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010.
      The general population utility inputs for the walking and BRND health states were derived per cycle
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      and validated with Dutch utility values.
      • Versteegh M.M.
      • Vermeulen K.M.
      • Evers S.M.A.A.
      • de Wit G.A.
      • Prenger R.
      • Stolk E.A.
      Dutch tariff for the five-level version of EQ-5D.
      The approach used for utility estimation was reported and accepted in the Dutch reimbursement advice for onasemnogene abeparvovec.
      Pakketadvies sluisgeneesmiddel nusinersen (Spinraza®) voor de behandeling van spinale musculaire atrofie (SMA). Zorginstituut Nederland [Packaging information for nusinersen (Spinraza®) for the treatment of spinal muscular atrophy (SMA)]. Zorginstituut Nederland [Healthcare Institute of The Netherlands].

      Sensitivity Analyses

      A deterministic (univariate) sensitivity analysis (DSA) was conducted to evaluate the impact of parameter uncertainty by varying parameter values.
      Probabilistic sensitivity analysis (PSA) captured parametric uncertainty and assessed the robustness of the model.
      • Shih S.T.
      • Farrar M.A.
      • Wiley V.
      • Chambers G.
      Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis.
      When unavailable, a standard error of 15% was applied. For independent probabilities and utilities, the beta distribution was applied. For costs, the gamma distribution was used. For correlated probabilities and distribution parameters, the Dirichlet distribution and Cholesky decomposition were applied. The Cholesky decomposition algorithm was used to account for correlation between parameters in survival distributions.

      Scenario Analysis

      The scenario analysis tested key model assumptions and robustness of the base-case incremental cost-effectiveness ratio (ICER) of key parameter variations in the model. The model discount rate, time horizon, analysis perspective, incidence, treatment percentage, costs for NBS, and percentage SMN1 deletion were assessed in the scenario and combination analyses.

      Model Programming and Validation

      The model was programmed using Microsoft Excel (Microsoft Corporation, Richmond, VA). As validation, the model code was stress tested to generate results using a range of extreme parameter values.

      Results

      Base-Case Results

      Tables 2 and 3 summarize the discounted cost outcomes and deterministic results, respectively, for the simulated cohort of 169 680 newborns in The Netherlands.
      Table 2Disaggregated costs per 169 680 newborns in a scenario with and without NBS for SMA (€2019, discounted).
      EstimateCosts with NBSCosts without NBS
      Costs of screening and diagnostics
      Costs of heel-prick testing€839 916€0
      Costs of genetic testing€27 149€27 149
      Costs of healthcare
      Costs of SMA treatment, including administration€37 682 058€34 951 898
      Medical costs€7 832 167€23 417 192
      Total healthcare costs€46 381 290€58 396 239
      NBS indicates newborn screening; SMA, spinal muscular atrophy.
      Table 3Deterministic results totals and per patient.
      StrategyTotal costsTotal LYsTotal QALYsIncremental costsIncremental LYsIncremental QALYsICER(ΔCostsΔQALYs)
      Results for the total cohort
      With NBS€46 381 290771660−€12 014 949283320−€37 564
      Without NBS€58 396 239488340
      Results per patient with SMA
      With NBS€2 733 45645.539−€708 0951719−€37 564
      Without NBS€3 441 5512920
      Note. All costs, LYs, and QALYs presented are discounted.
      ICER indicates incremental cost-effectiveness ratio; LY, life-year; NBS, newborn screening; QALY, quality-adjusted life-year; SMA, spinal muscular atrophy.
      Overall, the expected number of newborns with SMA is 16.97 among 169 680 newborns. With NBS for SMA, all patients with SMA and homozygous SMN1 deletion were detected. Patients with heterozygous SMN1 deletion were detected after symptom development. In the scenario without SMA screening in NBS, all patients with SMA were clinically diagnosed at a later stage: younger than 6 months for SMA type 1, age 1.5 years for SMA type 2, and age 4 years for SMA type 3.
      In the base-case analysis, the total cost of active screening was estimated at €839 916 per 169 680 newborns versus €0 without screening. The treatment costs (treatment acquisition and administration) for patients with SMA were €37 682 058 with NBS and €34 951 898 without NBS. Total healthcare costs, including costs of screening, diagnostics, treatment, and resource use, were €46 381 290 with NBS versus €58 396 239 without NBS. After NBS and treatment of presymptomatic infants with SMA, discounted life-years gained and QALYs gained were estimated at 771 and 660, respectively. In the scenario without NBS for SMA, discounted life-years gained and QALYs gained were estimated at 488 and 340, respectively.
      Compared with a no-NBS scenario, NBS saves €12 014 949 while increasing the patients’ health by 320 QALYs, resulting in NBS being dominant over a scenario without NBS.

      Sensitivity Analyses

      The DSA resulted in a range of ICERs, and all indicated dominance. The parameters with the largest impact on ICERs were general population utilities, percentage of patients dependent on ventilated intensive treatment in the sitting health state, hospitalization costs in the sitting health state, utility in the sitting health state, and costs per ventilation in the intensive treatment unit (Fig. 2).
      Figure thumbnail gr2
      Figure 2Tornado diagram with univariate sensitivity analysis results.
      ICER indicates incremental cost-effectiveness ratio; ITU, intensive treatment unit.
      The PSA demonstrates that, compared with no NBS, NBS has a 100% probability of being cost-saving. The analysis demonstrated that the conclusion was robust at a willingness-to-pay threshold of €20 000/QALY (Fig. 3).
      Figure thumbnail gr3
      Figure 3Incremental cost-effectiveness plane, including WTP thresholds.
      QALY indicates quality-adjusted life-year; WTP, willingness-to-pay.

      Scenario Analyses

      Several additional scenario analyses were performed on the discount rate, time horizon, perspective, incidence, treatment percentage, and cost of NBS and are summarized in Appendix Table 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010. Most scenarios analyzed demonstrated dominance, and all scenarios and respective incremental costs and QALYs are presented in Appendix Table 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.06.010. Non-dominance resulted if shares of nusinersen treatment were increased to 50% and 75%, resulting in ICERs of €19 426 and €46 105 per QALY gained, respectively. Results from the combined scenarios demonstrate that NBS is cost-effective, with an ICER of €20 727 and €15 792 per QALY gained.

      Discussion

      In the base-case analysis, adding NBS for SMA was associated with a gain of 320 QALYs and savings of €12 014 949 per annual cohort of newborns over a lifetime time horizon compared with no NBS in The Netherlands, resulting in a cost-saving ICER (−€37 564 per QALY). These results suggest that, in the base-case scenario, NBS for SMA is cost-saving compared with no NBS for patients with SMA at a willingness-to-pay threshold of €20 000/QALY. Although screening and treatment are associated with an investment, these additional costs were offset by savings that occur with the timely (presymptomatic) identification and treatment of patients with SMA. As these patients achieve additional and higher motor milestones, their lifetime health outcomes are improved and healthcare costs are reduced, indicating that NBS for SMA is not only cost-effective but cost-saving. The results were based on inputs from local Dutch data, the literature, and expert opinion.
      • Vill K.
      • Kölbel H.
      • Schwartz O.
      • et al.
      One year of newborn screening for SMA – results of a German pilot project.
      ,
      • Ogino S.
      • Leonard D.G.B.
      • Rennert H.
      • Ewens W.J.
      • Wilson R.B.
      Genetic risk assessment in carrier testing for spinal muscular atrophy.
      ,
      • Heijnen M.-L.
      • Jansen M.
      • van Gorp A.
      • et al.
      Uitvoeringstoets toevoeging Spinale Musculaire Atrofie aan de neonatale hielprikscreening [Additional test for spinal muscular atrophy at the neonatal heel prick screening].
      ,
      • Servais L.
      • Dangouloff T.
      Sun may arise on SMA: newborn screening of SMA.
      Open data van de Nederlandse Zorgautoriteit [Open data from the Dutch Healthcare Authority]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      Germany first in EU to get Novartis’ SMA gene therapy, costing almost 2m euros. Pharmaphorum.
      NZa zorgproductapplicatie [NZa Heathcare Product Application]. Nederlandse Zorgautoriteit [Dutch Healthcare Authority].
      • Hakkaart-van Roijen L.
      • van der Linden N.
      • Bouwmans C.
      • Kanters T.
      • Swan Tan S.
      Kostenhandleiding: Methodologie van Kostenonderzoek en Referentieprijzen voor Economische Evaluaties in de Gezondheidszorg. Diemen.
      • Tappenden P.
      • Hamilton J.
      • Kaltenthaler E.
      • et al.
      Nusinersen for Treating Spinal Muscular Atrophy: A Single Technology Appraisal Erratum.
      • Thompson R.
      • Vaidya S.
      • Teynor M.
      The utility of different approaches to developing health utilities data in childhood rare diseases – a case study in spinal muscular atrophy (SMA).
      ,
      Pakketadvies sluisgeneesmiddel nusinersen (Spinraza®) voor de behandeling van spinale musculaire atrofie (SMA). Zorginstituut Nederland [Packaging information for nusinersen (Spinraza®) for the treatment of spinal muscular atrophy (SMA)]. Zorginstituut Nederland [Healthcare Institute of The Netherlands].
      The QALY gains achieved through the screening strategy were driven by improved prognoses resulting from reduced disease progression (ie, patients achieved higher functioning motor milestones) and improved survival outcomes. Early diagnosis increased the relative discounted QALY gains by >94% (340 QALYs without NBS and 640 QALYs with NBS). The QALY gain represents the result of treatment after clinical diagnosis (without NBS) and the start of presymptomatic treatment (with NBS). Our model is applicable for other or updated screening/no-screening inputs. The one-way DSA and PSA demonstrated the robustness of the model and the cost-effectiveness outcomes, demonstrating that NBS for SMA is cost-saving in a variety of sensitivity analyses. Therefore, our findings support the inclusion of screening for SMA in the NBS program in The Netherlands. The scenario analyses substantiate this conclusion because most of the scenarios resulted in cost-savings. Of all the parameters included, varying the treatment percentage assumption demonstrated the greatest impact on the cost-effectiveness outcome. The scenario analysis of including variations of multiple parameters at once was cost-effective, which was demonstrated for most of the scenarios. Results from the sensitivity and scenario analyses support the robustness of the economic model.
      To the best of our knowledge, this is the first economic evaluation of NBS versus no NBS for SMA that accounts for the range in severity of SMA types 1, 2, and 3, the variable number of SMN2 gene copies, and 2 available treatments (onasemnogene abeparvovec and nusinersen). An Australian cost-effectiveness study considered 2 available treatments only in the NBS arm (onasemnogene abeparvovec and nusinersen) whereas only one treatment in the no NBS arm (nusinersen).
      • Shih S.T.
      • Farrar M.A.
      • Wiley V.
      • Chambers G.
      Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis.
      Our analysis also differs from Shih et al
      • Shih S.T.
      • Farrar M.A.
      • Wiley V.
      • Chambers G.
      Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis.
      who used different scenarios, including treatment patterns, and did not demonstrate cost-effectiveness of NBS compared with no-NBS scenarios. Therefore, direct comparison with our results should be interpreted with caution. Other studies considered either nusinersen and patients with SMA type 1 or onasemnogene abeparvovec alone.
      • Arjunji R.
      • Zhou J.
      • Patel A.
      • et al.
      PMU30 cost-effectiveness analysis of newborn screening for spinal muscular atrophy (SMA) in the United States.
      ,
      • Jalali A.
      • Rothwell E.
      • Botkin J.R.
      • Anderson R.A.
      • Butterfield R.J.
      • Nelson R.E.
      Cost-effectiveness of nusinersen and universal newborn screening for spinal muscular atrophy.
      Furthermore, parameters in this model were adapted to values applicable to the Dutch population. We expect that our model would demonstrate similar results for other countries that share comparable characteristics with The Netherlands.
      Ongoing follow-up studies demonstrated the long-term safety profile and sustained therapeutic effect of onasemnogene abeparvovec and support our assumption of lifelong durability of effect.
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-year extension results of the Phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      ,
      • Mendell J.R.
      • Finkel R.S.
      • Mercuri E.
      • et al.
      Long-term follow-up (LTFU) of onasemnogene abeparvovec therapy in spinal muscular atrophy.
      Lifelong transgene persistence and treatment effect were further supported by studies of adeno-associated virus vector-mediated gene delivery.
      • Choi J.
      • Yu G.
      • Bakes J.
      • et al.
      Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons.
      • Brommel C.M.
      • Cooney A.L.
      • Sinn P.L.
      Adeno-associated virus-based gene therapy for lifelong correction of genetic disease.
      • Colella P.
      • Ronzitti G.
      • Mingozzi F.
      Emerging issues in AAV-mediated in vivo gene therapy.
      To date, no clinical trial of a disease-modifying treatment for SMA has reported relapse. The uncertainty around this assumption is investigated in scenario analyses by limiting the lifetime time horizon to shorter periods.
      Because of limitations in published data (including a lack of head-to-head studies for onasemnogene abeparvovec and nusinersen), our model necessarily incorporated various assumptions, including that nusinersen and onasemnogene abeparvovec are equally effective, both over a lifetime time horizon. Obviously, current data can only support efficacy over a limited number of years; however, various data suggest sustained effect.
      • Al-Zaidy S.A.
      • Mendell J.R.
      From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1.
      • Mendell J.R.
      • Al-Zaidy S.A.
      • Lehman K.J.
      • et al.
      Five-year extension results of the Phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy.
      • Mendell J.R.
      • Finkel R.S.
      • Mercuri E.
      • et al.
      Long-term follow-up (LTFU) of onasemnogene abeparvovec therapy in spinal muscular atrophy.
      Data on costs for patients in the walking and sitting health states were also scarce. We accounted for this limitation by examining a wide range of cost values in the sensitivity analysis.
      Another limitation of our study is related to the clinical trials we identified that were only single-arm studies. As a result, real-world observations may differ from our partly trial-based model outcomes. Exact costs of adding the SMA test to an NBS panel will strongly depend on the outcome of a tender and negotiations with providers, generally resulting in lower costs and thus enhancing our favorable outcomes. Both the sensitivity and specificity of the NBS test for SMA were assumed to be 100% based on reported analyses. Even if false-positives occurred, diagnosis is confirmed by clinical follow-up, so physical complications or treatment for patients with false-positive results would not occur.

      Conclusions

      We found that NBS for SMA results in additional health benefits and cost-savings for The Netherlands. The outputs from sensitivity and scenario analyses indicate the robustness of these results.

      Article and Author Information

      Author Contributions: Concept and design: Velikanova, van der Schans, Bischof, Postma, Boersma
      Analysis and interpretation of data: Velikanova, van der Schans, Bischof, van Olden
      Drafting of the manuscript: Velikanova, van der Schans, Bischof
      Critical revision of paper for important intellectual content: Velikanova, van der Schans, Bischof, van Olden, Postma, Boersma
      Other (clinical assumptions, methods, model developments, parameter assumptions): Velikanova, van der Schans, Bischof, van Olden, Postma, Boersma
      Conflict of Interest Disclosures: As employees, Matthias Bischof and Rudolf Walther van Olden reported owning Novartis stock or other equities. Cornelis Boersma and Maarten Postma reported receiving grants from Novartis Gene Therapies. Dr Postma is an editor of Value in Health and had no role in the peer-review process of this article. No other disclosures were reported.
      Funding/Support: The project was financially supported by Novartis Gene Therapies, Inc . Editorial support, including copyediting and formatting of the manuscript and appendix, was provided by Laura Sitler, ELS, Kay Square Scientific, Newtown Square, Pennsylvania.
      Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study or collection, management, analysis, and interpretation of the data.

      Acknowledgment

      The authors acknowledge contributions to the development of this manuscript from Fay-Lynn Asselman, MSc (University Medical Center Utrecht), and Ludo van der Pol, MD, PhD (University Medical Center Utrecht), comprising, among other contributions, the validation of model assumptions, parameter inputs, and the results. The authors also thank Seren Phillips (Novartis Gene Therapies, Rotkreuz, Switzerland) for her critical review of the manuscript.

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