Presentación empleada por Pedro serrano Aguilar durante su charla en el encuentro Genetic insidER (Sevilla, 16-17 abril 2015). Más info: http://www.genetic-insider.com/es/index.php

1. Neonatal screening
for Inborn errors of metabolism
Pedro Serrano Aguilar
Iván Castilla Rodríguez
Laura Vallejo-Torres
Lidia García Pérez
Cristina Valcárcel Nazco
SESCS

2. Contenidos de la presentación
• Threats, challenges and opportunities for Health Systems
• Heterogeinity in newborn screening programs (NSP)
• Towards uniformity of NSP in developed countries
• The role of Health Technology Assessment and ecomomic
evaluation to guide NSP development

3. • Aging and chronicity
• Exponential growing of technological development and
adoption
• Societal increasing expectations and demands
• Variations in practices and inappropriate use of medical
resources
• Making room for rare diseases
Current Oportunities, challenges and threats for Health Systems

4. Medical practice
variations Evidence Based
Medicine
Health Technology Assessment
Systematic Rewiews
Meta-analysis
Cost-effectiveness
Clinical Practice Guidelines
Computarized decission support
tools
Tools for shared decision making
Risk-sharing contracts
Payment by results
20 years of Concepts, Disciplines and Tools development
to reduce uncertainty in decission making

5. Variations in Newborn screening in developed countries (2012)
Country Screening Panel (Number of disorders)
Metabolic Endocrinological Cystic Fibrosis Hemoglob.
Austria 26 2 Yes -
Belgium-Flemish 9 2 - -
Belgium-French 6 1 - -
Finland - 1 - -
France 1 2 Yes 1
Germany 12 2 Yes -
Spain-Galicia 39 2 Yes -
Spain
Canary Islands
1 1 Yes -
UK 2 1 Yes 3
USA 22 2 Yes 3

6. Procedural variations among Newbon Screening
Programs
• Place (Hospital vs. Primary Care) for sample taking
• Time after birht for sample taking
• MS/MS vs conventional technical procedures
• Cut-off points for screening tests
• Organizational
• Quality control programs

7. Wilson and Jungner classic screening criteria (WHO-1968)
1. The condition sought should be an important health problem.
2. There should be an accepted treatment for patients with recognized disease.
3. Facilities for diagnosis and treatment should be available.
4. There should be a recognizable latent or early symptomatic stage.
5. There should be a suitable test or examination.
6. The test should be acceptable to the population.
7. The natural history of the condition should be adequately understood.
8. There should be an agreed policy on whom to treat as patients.
9. Costs of case-finding (with diagnosis and treatment) should be balanced to medical care.
10. Case-finding should be a continuing process.
Wide variations despite sharing the same guiding criteria

8. Why so wide variations in health policy decisions ?
• High degree of uncertainty for all countries
• Differences in interpretation and management of these uncertainties
• Specific epidemiological scenarios
• Pre-existing regional differences
• Differences in availability of technical means and clinical expertise
• Differences in economic resources to ensure sustainability
• Differences in overall health priorities
• Pressure groups
• Technological imperative

9. Why so wide variations in neonatal screening ?
Overall scientific basis for decisions:
Wilson and Jungner criteria (general to guide decisions)
Guidelines of scientific societies (scarce and consensus based)
Expert groups
Literature surveys (scarce and low validity)
National/regional research (scarce and limited validity)
Local availability of valid data:
Epidemiological evidence low availability
Course of disease not known for most diseases
Clinical management uncertain
Health / Social benefits uncertain
Cost-effectiveness uncertain (sensitivity analysis)
Implementation costs estimated

10. Watson MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Howell RR, American College of Medical Genetics Newborn Screening Expert Group. Newborn Screening:
Toward a Uniform Screening Panel and System—Executive Summary. PEDIATRICS Volume 117, Number 5, May 2006. ww.pediatrics.org/cgi/doi/10.1542/peds.2005-
2633I
Uniformity of Newborn Screening in the US of America (2006)
American Academy of Pediatrics
Maternal and Child Health Bureau of Health Resources and Services Administration
American College of Medical Genetics (ACMG)
American Academy of Pediatrics
Maternal and Child Health Bureau of Health Resources and Services Administration
American College of Medical Genetics (ACMG)
ACMG developed recommendations on state newborn screening programs :
1.- Uniform condition panel
2.- Policies and procedures
3.- Minimal standards
4.- Decision matrix for potential program expansion
5.- Value of a national process for quality assurance
ACMG developed recommendations on state newborn screening programs :
1.- Uniform condition panel
2.- Policies and procedures
3.- Minimal standards
4.- Decision matrix for potential program expansion
5.- Value of a national process for quality assurance
Work process:
Participative
Complex: stage-based and iterative
Evidence and opinion based
Marginal consideration of costs
Work process:
Participative
Complex: stage-based and iterative
Evidence and opinion based
Marginal consideration of costs
Main criteria for condition selection:
Identification at 24-48 h. after birth
Availability of valid test
Availability of efficacious treatment
Demonstration of benefits
Main criteria for condition selection:
Identification at 24-48 h. after birth
Availability of valid test
Availability of efficacious treatment
Demonstration of benefits
Natowicz M. Newborn screening—setting evidence-based policy for protection. N Engl J Med 2006;353(9):867–870.
Botkin JR, Clayton EW, Fost NC, et al. Newborn screening technology: proceed with caution. Pediatrics 2006;117:1793–1799. ISI

11. Slower and incomplete movements from the European Union

12. Towards health policies uniformity in Spain: Overall framework
• Law for the Cohesion and Quality Improvement in the NHS
• Quality Improvement Plan for the NHS
• Spanish network for Health Technology Assessment
• Inter-territorial Board of the National Health System.
• Benefits Catalog for the National Health System.

13. Towards uniformity in NSP in Spain: working groups
Inter-territorial Board of the National Health System
Ministry of Health, Social Services and Equality

14. Cost-effectiveness assessment for NSP in Spain

15. Uniformity of Newborn Screening in Spain
Sickle cell anemia

16. Spanish Newborn screening Information System

17. What is Health Technology Assessment (HTA) ?
Systematic evaluation of the characteristics and potential effects of
health care technologies on the populations health and the
sustainability of health services.
HTA reports include:
• Technical properties
• Efficacy / Effectiveness
• Safety
• Economic evaluation (cost/effectiveness)
• Impact on Organization, social, legal, ethical and political issues.

18. Main objective of HTA
• Guiding the introduction, diffussion and adequate use of HT
according to the best available scientific knowledge on efficacy,
safety and cost-effectiveness.
- To avoid the adoption of non effective technologies
- To promote the early incorporation and diffussion of cost-effective
technologies

19. Grupo
de
pacientes
Alternativa B
Alternativa A
Impacto sobre el estado de salud
Impacto sobre costes
Impacto sobre costes
Impacto sobre el estado de salud
i. Supervivencia
ii. Calidad de vida
iii. Capacidad para
trabajar
i. Hospitalizaciones
ii. Medicamentos
iii. Procesos médicos
iv. Costes para los familiares y
la comunidad
i. Hospitalizaciones
ii. Medicamentos
iii. Procesos médicos
iv. Costes para los
familiares y la
comunidad
i. Supervivencia
ii. Calidad de vida
iii. Capacidad para
trabajar
What is an economic evaluation ?
Ca – Cb €
ICER: -----------------------------
Ea – Eb LYG /QALYs

20. Simulation
modelling
Simulation
modelling
Sample
size
Sample
size
Ethical
problems
Ethical
problems
Time and
costs to
get results
Time and
costs to
get results
Methods for cost-effectiveness assessment?
Clinical trialClinical trial

21. Willingness to pay threshold
UK-NICE
20.000 – 30.000
£/QALY
UK-NICE
20.000 – 30.000
£/QALY
EE.UU.
50.000 $/QALY
EE.UU.
50.000 $/QALY
SPAIN
30.000 €/QALY
SPAIN
30.000 €/QALY

22. ECM Concepto Incremental [IC 95%] ICER [IC 95%]
Screening base: PKU +
MCADD
Costs 6,75 € [6,15 €; 7,45 €]
38.366,05 €/LYG
[23.490,84; 67.984,51]
LYG 0,00018
[0,00011; 0,00026]
Base + LCHADD
Costs 7,07 € [6,40 €; 7,77 €]
33.228,86 €/LYG
[20.832,09; 59.198,35]
LYG 0,00021
[0,00013; 0,00031]
Base + LCHADD + GA1
Costs 11,19 € [8,87 €; 14,61 €]
36.708,59 €/LYG
[21.223,01; 73.163,78]
LYG 0,00030
[0,00020; 0,00042]
Base + LCHADD + GA1 +
MSUD
Costs 14,85 € [10,56 €; 21,04 €]
41.229,84 €/LYG
[21.849,91; 88.010,25]
LYG 0,00036
[0,00024; 0,00048]
Base + LCHADD + GA1 +
MSUD + HCN
Costs 20,71 € [13,90 €; 27,50 €]
49.067,94 €/LYG
[25.508,50; 92.546,28]
LYG 0,00042
[0,00030; 0,00055]
Base + LCHADD + GA1 +
MSUD + HCN + IVA
Costs 21,47 € [14,85 €; 28,33 €]
50.315,21 €/LYG
[26.772,58; 95.042,27]
LYG 0,00043
[0,00030; 0,00055]
ICER for NSP from Health Services perspective (Spain)

23. ECM Concept Incremental [IC 95%] ICER [IC 95%]
Screning base: PKU +
MCADD
Costs 3,55 € [2,55 €; 4,31 €]
20.720,24 €/LYG
[10.041,37; 39.548,75]LYG 0,00017
[0,00011; 0,00025]
Base + LCHADD
Costs 3,11 € [1,92 €; 4,10 €]
15.031,14 €/LYG
[6.527,72; 32.289,76]LYG 0,00021
[0,00013; 0,00029]
Base + LCHADD + GA1
Costs 4,53 € [2,44 €; 7,39 €]
15.436,07 €/LYG
[5.920,19; 39.063,02]
LYG 0,00029
[0,00019; 0,00041]
Base + LCHADD + GA1 +
MSUD
Costs 7,03 € [3,30 €; 11,75 €]
20.091,26 €/LYG
[6.879,24; 50.646,71]
LYG 0,00035
[0,00023; 0,00048]
Base + LCHADD + GA1 +
MSUD + HCN
Costs 10,62 € [5,80 €; 15,68 €]
25.722,22 €/LYG
[10.609,77; 53.665,13]
LYG 0,00041
[0,00029; 0,00055]
Base + LCHADD + GA1 +
MSUD + HCN + IVA
Costs 11,20 € [6,56 €; 16,13 €]
26.718,68 €/LYG
[11.819,70; 56.933,91]
LYG 0,00042
[0,00028; 0,00055]
ICER for NSP from the Social perspective (Spain)

24. Limitations of Cost-effectiveness analyses
• Lack of valid data on transitional probabilities along the disease (Literature review)
• Sensitivity and especificity data from the NSP not robust for several disorders (literature
review).
• Conservative assumption based on just one clinical decompensation along the life
(expert judgment)
• Difficulties estimating the differential use of resources between screened and not
screened children (expert judgment)
• Lack of data on Quality of life as effectiveness measure precludes the use of QALYs
• Using Life Years Saved as effectiveness measure limits health benefit measurement to
very long time periods

25. Theoretical considerations on HTA for Rare Diseases
• Could screening criteria for RD be less demanding than for common
diseases?
• Is treatment availability an absolut requirement ?
• Value of the information for the families ?
• Value of the information for research ?
• Role of costs and Cost-effectiveness considerations
• Specific threshold of willingness to pay for RD and NSP?