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Health technology assessment of the addition of spinal muscular atrophy (SMA) to the National Newborn Bloodspot Screening Programme

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SMA is a rare, genetic neuromuscular disorder. Clinically, there are five subtypes of SMA, distinguished by disease severity, with more severe forms typically presenting in infancy and early childhood, and milder forms presenting in later life. While the severity of SMA varies, it is characterised by irreversible degeneration of motor neurons in the spinal cord resulting in progressive muscle wasting and weakness. SMA was historically associated with supportive care only. However in recent years a number of disease-modifying treatments have been approved for use in the European Union.

In Ireland, cases of SMA are identified through clinical presentation and family history. Newborn bloodspot screening is provided in Ireland through the NNBSP. Newborn bloodspot screening for SMA aims to detect homozygous deletions of SMN1 (that is, deletions affecting both copies of the SMN1 gene). This form of screening has been implemented in a number of countries internationally. Given the pathophysiology associated with SMA, there is clinical rationale and emerging evidence to suggest that earlier identification and initiation of treatment may improve overall outcomes.  

This research was carried out in accordance with HIQA’s guidelines for the conduct of HTA. In summary:

  • The Terms of Reference of the HTA were agreed between HIQA and the NSAC Secretariat in the Department of Health.
  • A multidisciplinary expert advisory group (EAG) was convened by HIQA comprising representation from relevant stakeholders. These included the Department of Health, the Health Service Executive (HSE), the NNBSP, the National Newborn Bloodspot Screening Laboratory, clinical and laboratory science experts, patient and public representatives, and international experts. An evaluation team was appointed.
  • A protocol for the work to be undertaken was reviewed by the HIQA Expert Advisory Group, and published on the HIQA website (link).
  • The existing and proposed diagnostic and treatment pathways for SMA in Ireland were described.
  • An international review of the use of screening for SMA was completed.
  • The epidemiology and burden of disease associated with SMA was described. 
  • The test accuracy of newborn bloodspot screening for SMA was reviewed.
  • The clinical effectiveness of screening for SMA, and of the available disease-modifying treatment options in Ireland were described. 
  • A systematic review was undertaken to summarise the international literature on the cost effectiveness of newborn screening for SMA. 
  • The resource and budget implications of introducing newborn screening for SMA in Ireland were estimated.
  • Wider organisational, ethical, and societal implications that newborn screening for SMA may have for children, their families, the general public, and the healthcare system in Ireland were described.
  • A draft report summarising the findings of this HTA was produced and was circulated to the EAG for review. This was subsequently amended, where appropriate. 
  • The final draft of the HTA was submitted to the Board of HIQA for approval. Following its approval, the finalised HTA was submitted to NSAC for consideration and published on the HIQA website.

  • Spinal muscular atrophy (SMA) is a rare, serious genetic condition associated with irreversible motor neuron loss and disease progression. Clinically, the disease presents across a gradient of severity from type 0 (onset in utero, followed by early infant mortality) to type IV (adult-onset). 

    • Based on historical data, paediatric disease (types I to III) represents 99% of cases identified. 
    • In Ireland, the median age for diagnosis of type I SMA was six months (range 0 to 7.9 months), type II was 19 months (range 12 to 24 months), and type III was 144 months (range 42 to 192 months).
  • Estimates of incidence vary internationally. Data suggest an average of 6.5 cases (95% prediction interval (PI): 2.4 to 13.2) of types I to IV SMA a year in Ireland based on approximately 58,000 births. It is uncertain if screening would be associated with an increase in the number of diagnosed cases of SMA.
  • Newborn bloodspot screening for SMA typically targets identification of the homozygous deletion in the survival motor neuron 1 (SMN1) gene. This is a reliable and accurate test. 
    • This test will, however, not detect cases of SMA that do not involve homozygous SMN1 deletion (2 to 5% of cases). The addition of screening for SMA would enable earlier detection of infants that would otherwise present later with symptoms. Under screening, current clinical subtyping, which is determined by symptomatic presentation and age of onset, would generally no longer apply. Decisions on prognosis and treatment would instead rely on the individual’s survival motor neuron 2 (SMN2) gene copy number as a biomarker. 
  • Evidence suggests that earlier treatment with disease-modifying drugs may result in better clinical outcomes by preventing or reducing irreversible motor neuron loss and disease progression.
    • There are limited clinical effectiveness data for all relevant subgroups (for example, presymptomatic populations, and those with higher copy numbers of the SMN2 gene, indicative of less severe disease). There is also an absence of long-term effectiveness data. 
    • The limitations of the effectiveness evidence mean that any estimates of cost effectiveness are highly uncertain. 
  • While treatments are available for SMA, reimbursement arrangements have not been agreed in the context of screening and would need to be clarified. 
  • The incremental budget impact associated with the addition of screening for SMA to the National Newborn Bloodspot Screening Programme (that is, the budget impact over and above current expenditure in the absence of screening), was estimated at approximately €17.7 million (95% confidence interval (CI): €5.1 to €40.5 million) over a five-year time horizon. This was estimated using publicly available drug list prices. The results are subject to considerable uncertainty.
    • Approximately 90% of these costs relate to drug treatment (€16.3 million, 95% CI: €3.8 to €38.9).
    • Total laboratory costs, comprising equipment and consumables associated with screening, were estimated as representing less than 5% of costs (€0.7 million, 95% CI: €0.6 to €0.8). 
    • The costs of scheduled healthcare utilisation (€0.1 million, 95% CI: €0.02 to €0.3) and clinical staff (€0.5 million, 95% CI: €0.4 to €0.7) also comprised a small proportion of costs (less than 5%). 
  • Given the disease spectrum and variable potential to benefit, a decision to recommend screening should specify whether the aim is to identify all cases of SMA resulting from a homozygous deletion of SMN1 or to identify the subset of cases most likely to develop clinically significant disease. There are conflicting ethical implications associated with this decision. Limiting identification to a subset of cases, on the basis of SMN2 copy number, would:
    • risk harm in children who could otherwise have been identified through screening, given that SMN2 copy number is an imperfect biomarker of severity. This would apply specifically to those who may develop clinically significant disease in childhood despite having a higher SMN2 copy number.
    • potentially imply non-disclosure of a genetic diagnosis of SMA to a subset of individuals. This must be counterbalanced by the challenges for parents and clinicians of disclosing genetic information that is of uncertain value.  
  • Due to infrastructural constraints, implementation of screening by the National Newborn Bloodspot Screening Laboratory is unlikely to be feasible until the new children’s hospital on the St James’s campus is operational. Appropriate resourcing of the National Newborn Bloodspot Screening Programme is essential for the functioning of the programme as a whole.