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(iii) a decision matrix for potential NBS expansion; (iv) a common quality-assurance process; (v) the
development of a common information system for assessment, linked to the NBS. This expert group
received scientific and technical support from RedETS through a series of HTA reports commissioned
by the expert group, pursuant to an iterative consultative process involving national experts and AR
health authorities. HTA reports delivered by RedETS provide appraised, evidence-based information on
the safety, effectiveness, cost-effectiveness, legal, ethical, organizational, and environmental aspects of all
[41]
non-pharmaceutical technologies .

COST-EFFECTIVENESS ISSUES IN NBS AND ITS DEVELOPMENT IN SPAIN
As previously reported, NBS cost estimates may be underestimated due to the relative inexpensiveness of
adding “just one more test” to an existing screening panel. However, the cumulative cost of screening is
beyond the test cost itself, in that it increases with the necessary acquisition of testing equipment, materials,
plant, and staff . According to the Hasting Reports , a health policy decision-making framework for NBS
[30]
[33]
should be based on scientific evidence, in addition to (1) taking overall opportunity costs into account;
[24]
(2) distributing the cost and benefits of the programme fairly; (3) respecting human rights . Beyond
cost estimates of the potential incorporation of new disorders into NBS programmes, the need for
cost-effectiveness analysis (CEA) results in the decision-making process is justified because the costs and
health outcomes per screened newborn (comprising follow-up testing and subsequent lifelong
treatment) are extended to all newborns at regional or national levels.

In 2012, Langer et al. drew up specific guidelines to assess and improve the methodological quality of
economic evaluations of NBS. The authors assessed 12 CEA studies on NBS for inherited metabolic
disorders by MS/MS, reporting differences in cost categories considered (from both health services and
societal perspectives) . When adopting the health services perspective, the costs should include those
[42]
pertaining to the NBS programme as well as treatment and follow-up. The societal perspective should
consider, in addition, the lost productivity of patients and informal caregivers . Furthermore, one of the
[42]
main problems confronting economic evaluations of NBS relates to the lack of epidemiological data and
[42]
health outcomes (in terms of morbidity and mortality) . In 2020, a scoping review on the challenges of
economic evaluations of NBS showed that the methodological quality of these types of studies continues to
be irregular .
[27]

In an economic evaluation, effectiveness is preferably measured by means of quality-adjusted life years
(QALYs) gained. A QALY measures the health state of a person or group by adjusting the length of life to
reflect the quality of life. The QALYs provide a common measure to compare the benefits gained from
different alternative interventions. The threshold of willingness to pay for an additional QALY in Spain has
been estimated at around €25,000/QALY . However, the low frequency of these disorders and the
[43]
methodological complexities of estimating QALYs justify the fact that life years (LY) gained are used as an
alternative outcome measure [42,44] .

The validity and robustness of CEA estimates are limited by the uncertainty of relevant parameters
(incidence of disorders, short-term screening effectiveness, and the long-term consequences of screening).
Addressing this uncertainty requires the use of simulation modelling techniques [42,44] and corresponding
sensitivity analyses that depend on arguable assumptions. Logistic and ethical considerations lead to the
absence of clinical trials on NBS, making it necessary to use effectiveness data from case series, mainly
short-term, very small, and subject to biases. Well-structured and completed population-based registries,
which include the necessary long-term follow-up of cases as well as comprehensive information on the
natural history of diseases, would seem a promising tool to improve the availability and validity of data.