Neonatal screening in Spain and cost–effectiveness

Abstract

Newborn screening (NBS) programs are subject to inter- and intra-country variations, especially after the introduction of tandem mass spectrometry (MS/MS). Access to MS/MS and variations in interpretation of available evidence seem to explain these differences. Cost considerations have had a minor role on funding decisions given the low direct costs to screen an additional disorder by MS/MS and their low frequency. In order to reduce the wide inter-regional observed variations in NBS in Spain, the Ministry of Health supported by the Spanish Network for Health Technology Assessment developed an evidence-based policy decision process guided by a series of effectiveness and cost–effectiveness reports.

Keywords:

• cost–effectiveness
• health policy variations
• inborn errors
• newborn screening
• tandem mass spectrometry

1. The heterogeneous scenario of newborn screening

Newborn screening (NBS) is recognized as an essential program with the aim of ensuring the best health outcomes for the nation’s newborn population. However, even in developed countries, health inequalities are present from the earlier stages of life due to the large variations in the contents of NBS programs. These inequalities occur regardless of the socio-economic level of individuals and populations and are not limited to international variations in the conditions subject to screening. Variations in NBS even exist in several developed countries of Europe with decentralized governmental jurisdictions, such as Belgium, Italy or Spain [1].

Although most NBS combines different laboratory methods, the progressive introduction of the tandem mass spectrometry (MS/MS) over the last 15 years has led to the use of NBS for an increasing number of disorders. At a population level, however, there is neither evidence nor consensus in that those receiving NBS for fewer disorders, as in the UK, France or Sweden, are at a higher risk of poorer health outcomes than the populations of Austria or Iceland, where NBS covers more than 25 different conditions [1].

Regardless of the development by Wilson and Jungner in 1968 of a framework to guide health policy decisions in NBS [2], the subjective character of some criteria such as the importance of the health problem, along with the accessibility to new screening methods, variations in the interpretation of available evidence for a given condition and the public advocacy by families, professionals and state legislators have led to the observed variations [1,3,4]. Economic considerations have been mainly based on cost estimates rather than on economic evaluations (EE) [4]. Costs have played a minor role on decisions because the direct costs of additional screening tests are relatively low and there is considerable uncertainty about the effects generated by available treatment options [5]. Apart from these criteria, additional variations in value judgments, which are not explicitly stated, could play a differential role regarding the maximization of societal benefits and the expected contributions to research advances [6].

2. Health policy initiatives to enhance equity and efficiency for NBS

The Spanish National Health Service (SNHS) is a public health insurance system fully financed by national taxes with universal coverage and free healthcare for every resident in Spain. The Spanish government created three health policy instruments to support decentralization of the health planning and management competences from the central government to each of the 17 Spanish Autonomous Communities (SAC) in 1981.The three aforementioned instruments are: Spanish General Law for Health Care guaranteeing free and universal access to healthcare for all Spanish residents, the National Benefits Catalog to ensure equity in the supply of healthcare services and the creation of the Inter-territorial Board of the SNHS (formed by the health authorities of the central and regional governments). Despite the fact that these health policies were established to ensure equity and efficiency in a decentralized SNHS, variations have occurred in the supply of healthcare services between the regions or SAC, including NBS. Consequently, a new Law 16/2003 for the Cohesion and Quality of the SNHS, operationalized by means of subsequent Quality Plans supported by the Spanish Network for Health Technology Assessment (HTA), was passed by the Spanish central government to support evidence-based health policies and to limit inequitable variations in the supply of healthcare services among the SAC.

Universal NBS, introduced in 1968, is now a well-established program in Spain and is funded by every SAC. It is currently organized through a network of 20 regional labs with an overall coverage of over 98%. By the year 2000, the SAC of Galicia implemented an expanded NBS based on MS/MS for more than 40 conditions, while the rest of 16 SAC were only screening for phenylketonuria (PKU) and hypothyroidism (some SAC also included cystic fibrosis and sickle cell disease). An expert group was set up by the Inter-territorial Board of the SNHS involving experts in NBS from every SAC, scientific societies, representatives of the Spanish network of HTA and the Public Health Directorate of the Ministry of Health, Social Services and Equality to provide homogeneous evidence-based NBS and medical services to children and their families in Spain. The aim of this expert group was to develop recommendations to address: i) a uniform screening panel, ii) minimal standards for NBS in SACs, iii) a decision matrix for potential NBS expansion, iv) a national process for quality assurance and v) the development of a common Information System linked to the NBS [7]. This expert group received scientific and technical support from the Spanish network of HTA by means of a series of HTA reports on the effectiveness and cost–effectiveness for 16 different newborn disorders prioritized according to an iterative consultative process involving national experts and SAC health authorities [8].

3. Cost–effectiveness issues in NBS and their application in Spain

The need for EE in decision-making for national-level screening programs in Europe is becoming increasingly clear from a public health perspective because the costs and outcomes (including harms) per screened person (comprising follow-up testing and subsequent lifelong treatment) are extended to all eligible subjects at a national level. An HTA perspective with cost–effectiveness analysis (CEA) is required by the Spanish Ministry of Health for decision-making on the extension of NBS, even though Spain has yet not officially defined any incremental cost–effectiveness ratio as a threshold for funding new health interventions. Therefore, the Spanish Ministry of Health has recently commissioned a research project to explore and hopefully set a threshold of willingness to pay for an additional quality-adjusted life year (QALY) that will deliver results by the beginning of 2016, nonetheless health economists and HTA researchers in Spain generally agree that a cost-effective investment happens when the cost for a QALY is €30,000 or less [9].

As MS/MS-based screening is relatively new, and both health outcomes and economic data are scarce and uncertain, published CEA studies are limited and do not include all detectable conditions. A recent review by Langer et al. [10] assessed 12 CEA studies on NBS for inherited metabolic diseases, and 5 of them focused exclusively on medium-chain acyl-CoA dehydrogenase deficiency (MCADD).

CEA differs according to the perspective of the economic analysis used (health services or societal). As regards the health services perspective, the costs considered should include those related to the screening program and confirmation tests as well as treatment and follow-up of detected cases. The societal perspective additionally takes into account the patients’ and carers’ costs (days of work and productivity lost because of caring). Differences in costs between cases detected clinically or by screening are compared with effectiveness differences. In an economic evaluation, effectiveness is preferably measured by means of QALY. A QALY is a measure of a person’s or group health state in which the length of life is adjusted to reflect the quality of life. The combination of quality and length of life of newborns in QALYs provide a common currency to assess the extent of the benefits gained from different interventions. However, the low frequency of these disorders and the methodological complexities to estimate QALYs in newborns (the weights used for adjustment are based on preferences for different health states which are insufficiently assessed in the case of rare diseases) mean that life years gained (LY) is used as an alternative outcome measure [10].

Published CEAs on NBS share common limitations affecting relevant parameters such as incidence of disorders, short-term screening effectiveness and the long-term consequences of screening that are managed by simulation-modelling techniques [10]. The uncertainty concerning these parameters limits the validity and robustness of CEA estimations, making the results highly dependent on arguable assumptions. The lack of clinical trials on NBS, for logistic and ethical considerations, means a reliance on effectiveness data provided by very small and short-term case-series subject to several types of biases. Sensitivity analyses linked to modelling techniques allows the reliable management of uncertainty. The expected access to well-structured and completed national registries linked to NBS seems a promising tool to improve the availability and validity of data.

NBS might have a lifelong impact on health outcomes and health services. Therefore, much of the existing literature attempts to extrapolate short-term outcomes into the future, to grasp the effect of successful early identification of conditions through screening. However, there is inadequate information to quantify these parameters in adulthood. As a result, CEA restricts the assessment to a shorter timeframe for which information is available or alternatively relies on assumptions to incorporate an adequate time-horizon.

Prevalence figures and costs are likely to differ substantially among countries not only for the NBS itself, but also for all subsequent treatment and follow-up activities. These country specificities limit transferability of CEA to different contexts, thereby requiring revision and adaptation by using local data [11].

The implementation of evidence-based NBS by the Spanish Ministry of Health used and benefitted from the preliminary regional information provided by the SAC of Galicia about the incidence and prevalence of newborn disorders screened by MS/MS, their clinical course, resource utilization needs and their corresponding costs. These data, along with information from the literature review, were used by the Evaluation Department of the Canary Islands Health Service (SESCS) as part of the Spanish network of HTA to provide evidence on the cost–effectiveness of an expanded NBS for the whole country. A new national information system is under development in Spain to assess equity, coverage, performance and quality of NBS [12].

SESCS developed CEA for 16 different disorders to support decision making on NBS. All these CEA compared both costs and outcomes from the social and SNHS perspectives including the whole lifetime of the subjects. Overall, the results were subject to a high degree of uncertainty due to the limited availability and validity of the effectiveness of the screening. Our first report in 2006 confirmed the cost–effectiveness of adopting MS/MS to screen for PKU and MCADD in Spain with an incremental cost–effectiveness ratio (ICER) of 5757 €/LY. We then estimated the cost–effectiveness of adding homocystinuria, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), maple syrup urine disease, isovaleric acidemia and glutaric aciduria type 1 (GA-I) to the existing NBS based on MS/MS for MCADD and PKU. Incorporating these five new diseases to the NBS at a national level showed an ICER of 27,607.38 €/LY. At a later stage, a new set of CEA for a wider group of disorders were developed, not all of which subject to MS/MS; including sickle cell disease, cystic fibrosis, biotinidase deficiency, congenital adrenal hyperplasia, galactosemia, methylmalonic and propionic acidemia, tyrosinemia type I, primary carnitine deficiency (CUD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCAD). Some of the screened diseases under MS/MS that were found cost-effective in the Spanish context were: propionic and methylmalonic acidemia (ICER: 21,405.13 €/QALY), VLCAD (ICER: 10,723.97 €/LY) and CUD (ICER: 14,217.56 €/LY). A different case is tyrosinaemia type 1, whose ICER was of 40,670 €/QALY. Apart from MS/MS, cost–effectiveness of screening for biotinidase, congenital adrenal hyperplasia or cystic fibrosis obtained an ICER below 30,000 €/LY. Given the estimated birth prevalence of sickle cell disease in Spain, its screening would be cost-effective if the cost per screened newborn does not exceed €2.5. Screening of classic galactosemia was found not to be cost-effective with an ICER over 100,000 €/LY [8]. Based on this set of HTA reports, the Inter-territorial Board of the SNHS accepted the expert group’s recommendations of including the following common set of disorders for all Spanish SAC: hypothyroidism, PKU, cystic fibrosis, sickle cell disease, MCADD, LCHADD and GA-I [13]. As new HTA reports are being prepared, these recommendations could be extended in the next future.

4. Expert opinion

CEA are complex technical procedures to support, in a transparent and reliable manner, evidence-based health policies in general and population screening in particular. Despite the considerable uncertainty affecting the data needed for CEA in NBS, modelling techniques offer the possibility of reducing unexplained variations in NBS contents and guiding funding decisions under economic constraints. CEA might also be of help in guiding organizational issues in NBS and supporting best-practices organization according to cost–effectiveness criteria. CEA for NBS assumes that diagnostic confirmation, clinical care and follow-up are provided by experienced biochemical/genetics laboratories and reference clinics to maximize the health benefits linked to NBS while reducing potential risks [14].

Declaration of interest

This work was funded by the collaboration agreement between the Carlos III Health Institute, an autonomous organization of the Ministry of Economics and Competitiveness, and the Canary Islands Foundation of Research and Health (FUNCANIS). This work was undertaken by SESCS in the framework of the activities run by the Network of Health Technology Assessment Agencies funded by the Ministry of Health, Social Services and Equality. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.