On behalf of the Tender NBS team Facing the challenge of extending newborn screening in Europe: survey results Graz 15 April 2011 Martina Cornel, MD, PhD Professor of community genetics & public health genomics On behalf of the Tender NBS team Community Genetics, Dept Clinical Genetics

Introduction Survey Diseases screened Who decides Transparency How to contribute

Neonatal screening (heelprick)

Neonatal screening NL 2006-2007 PKU (1974) Congenital hypothyroidism (1981) Congenital Adrenal Hyperplasia (2001) Medication or diet to avoid mental retardation or sudden death Biotinidase deficiency Cystic fibrosis (conditional; pilot 2008; start 2011) Galactosemia Glutaric aciduria type I HMG-CoA-lyase deficiency Holocarboxylase synthase deficiency Homocystinuria Isovaleric acidemia Long-chain hydroxyacyl CoA dehydrogenase deficiency Maple syrup urine disease MCAD deficiency 3-methylcrotonyl-CoA carboxylase deficiency Sickle cell disease Tyrosinemia type I Very-long-chain acylCoA dehydrogenase deficiency

Why more diseases? More treatment available Early detection: less health damage More tests available (high throughput) MS/MS Many more promises in the age of genomics: how to proceed?

Sir Muir Gray (Nat Scr Comm UK) All screening programmes do harm. Some do good as well and, of these, some do more good than harm at reasonable cost.

To screen or not to screen? How to balance pros and cons?

Screening criteria: W&J still apply! When to screen? Wilson en Jungner WHO 1968. A variety of sets of criteria derived from W&J Important public health problem (prevalence & severity) Is treatment available? Does early treatment help? Course of disease known; frequency known Good test (high sensitivitity; high specificity, high positive predictive value) Uniform treatment protocol; knowing whom to treat Etc Decisions on screening build on the Wilson & Jungner framework, still the basis for the normative framework to assess population screening programmes, but they have been revised and made more specific.

Balancing pros and cons Good test available? False positives Specificity (1-FP) False negatives Sensitivity (1-FN) Positive predictive value Disease→ Test Result↓ Present Absent Positive A B Negative C D Some of the elements of “Wilson & Jungner” need to be made more explicit. Do we accept 5 false positives for 1 true positive? What is a “good test”?

Screening criteria (Grosse, Public Health Genomics 2010) Evidence Early treatment leads to less mortality, morbidity, loss of weight, days in hospital, pain, suffering, better QoL Economics Limited health care resources; cost per QALY under limit Ethics More pros (longer and healthier life) than cons (false positives; mild cases; incidental findings)

Neonatal screening NL: disease categories Considerable, irreparable damage can be prevented (category 1) Add 14 diseases (biotinidase deficiency, galactosemia, glutaric aciduria type I, HMG-CoA lyase deficiency, holocarboxylase synthase deficiency, homocystinuria, isovaleric acidemia, longchain hydroxyacyl- CoA dehydrogenase deficiency, maple syrup urine disease, MCAD deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, sickle cell disease, tyrosinemia type I and very-long-chain acyl-CoA dehydrogenase deficiency). Less substantial or insufficient evidence of prevention of damage to health (category 2) Consider adding cystic fibrosis if better test becomes available (improve specificity) No prevention of damage to health (category 3) An example of a transparent framework that came out of a Health Council committee on screening.

The role of the government (Health Council 2008) Duty of care: ensure worthwhile screening National population screening programme: provide facility itself Available in basic healthcare package Reproductive screening: special position: provide worthwhile options and guarantee both quality and informed decision making Duty of protection against unsound screening Guard citizens against health damage from risky or unsound forms of screening

Introduction Survey Diseases screened Who decides Transparency How to contribute

EU Tender “Evaluation of population newborn screening practices for rare disorders in Member States of the European Union” Deliver: Report on the practices of NBS for rare disorders implemented in all Member States Expert opinion document, including decision-making matrix, on the development of European policies in the field of newborn screening for rare diseases EU Network of Experts on NBS (EUNENBS) European Experts Consensus Workshop on NBS (June 2011)

European Commission decisions + actions Nov 11, 2008: adoption of Commission Communication nr 679 June 9, 2009: Council recommendation on a European Action in the field of Rare Diseases July 18, 2009: EAHC call for tender 2009/Health/09 concerning evaluation of population newborn screening practices for rare disorders in EU Member States

EU Tender, project group Luciano Vittozzi, Domenica Taruschio (ISS, Rome, Italy) Project leader, logistics Martina Cornel, Tessel Rigter, Stephanie Weinreich (VUmc, Amsterdam, Netherlands) Governance Gerard Loeber (RIVM, Bilthoven, Netherlands) Screening (blood sampling, assays, reports, storage) Georg Hoffmann, Peter Burgard, Kathryn Rupp (Univ Heidelberg, Heidelberg, Germany) Confirmatory diagnostics, treatment

EU Tender, action plan (2010) Set up surveys stratified to parts of the neonatal screening programme (2010) Compile lists of experts (DoH, laboratories, paediatricians) (2010-2011) Receive and evaluate results of survey (2010-2011) Workshops (March 2010, Dec 2010) (2011) Draft documents sent out for comments (2011) Finalisation of documents (May-June) (2011) Consensus workshop (June)

We covered modules A&B, which are on assesment and governance of NBS programs. Scope of our workpackage: - Data collection on current NBS policies - Comparative analysis of current NBS strategies and policies - Development of a decision tool

Austrian experts: Module A&B: Renate Fally-Kausek (Ministry of Health) David Kasper (Medical University of Viena) Bernhard Wieser (Inter-University Research Center (IFZ)) Module C&D: Module E: Barbara Plecko (Medical University Graz (Peadiatrics)) Klaus Kapelari (Endocrinological Center)

Introduction Survey Diseases screened Who decides Transparency How to contribute

Phenylketonuria Source: dr. G. Loeber, RIVM

Congenital Hypothyroidism Source: dr. G. Loeber, RIVM

Congenital Adrenal Hyperplasia Source: dr. G. Loeber, RIVM

Galactosemia Source: dr. G. Loeber, RIVM

Cystic Fibrosis Source: dr. G. Loeber, RIVM

Biotinidase deficiency Source: dr. G. Loeber, RIVM

MS / MS (MCADD etc.) Source: dr. G. Loeber, RIVM

Other conditions Source: dr. G. Loeber, RIVM DMD SCD G6PD HCY

Screened conditions Large variation Relatively few countries have started ms/ms analysis Some countries test “all” ms/ms possibilities Technology driven Only report where health gain for infant

Introduction Survey Diseases screened Who decides Transparency How to contribute

Governance Attunement between parties Achterbergh et al. Health Policy 2007; 83: 277-286. Technology developed by Scientists; Organisation by physicians?; Demand from patients(organizations)?; Acceptability to be assessed by Regulatory, advisory and governmental agencies. Many parties/ actors; potential for different views & priorities; how to attune?? Co-evolution, collective learing processes. Andermann et al. Journal of Health Services Research & Policy 2010; 15: 90-97.

Attunement between parties Health regions Society, medicine, industry, government Countries EU? Some aspects of attunement are not country specific-> room for collaboration Learn from others?

Governance 17 of 35 jurisdictions surveyed reported to have laws or regulations on newborn screening 18 have a body which oversees newborn screening (“steering committee”) 21 have changed NBS program in last 5 years health authorities almost always involved physicians specialized in paediatrics and clinical chemistry in one case (Sweden) health technology assessors sometimes patient organisations sometimes

Laws

Transparency: extend further? Reports of committees (HTA) Review of literature Expert hearings Pilot studies Lists of evaluation criteria International recommendations; professional societies Decision of ministry in official statement

Transparency: information to parents Website in 19 out of 35 countries where anyone can get information about the newborn screening program 7 out of 35 of the responding jurisdictions do not actively inform prospective parents No country specifically informs prospective parents in the first or second trimester of the pregnancy 13 countries inform prospective parents only after birth at the time of blood sampling 12 out of 35 countries parents are informed at two or even three time points

Transparency: information to parents Material to support the first communication of the meaning of consequences of a positive NBS result is available in 41% of the countries. Predominantly the material is authored by local heads or directors (68%), but apparently applied on a national level (83%). Printed or digital material on treatment is available in 69% of the countries. Across all disorders printed or digital material is available in 69% of the countries. Authors predominantly are local heads or directors (61%).

Informed consent 20 of the 37 responding jurisdictions report to ask for informed consent (or dissent). 17 of them also have the possibility to opt-out. 17 of the 37 report that they do not ask informed consent (or dissent) from parents before the blood sampling 6 out of 17 report that they do have the possibility to opt-out from screening 7 said not to have informed consent (or dissent) nor to allow opting out

Fireworks disaster Enschede 13 mei 2000 Children amongst 23 victims Identification? Heelprick cards? -> discussion in media undermining trust

Research? In 15 out of 33 countries parents are informed about the fact that bloodspots are retained

Information on blood spot retention More than half of countries do not inform parents of blood spot retention This is an easy topic; information should be available in all countries Large variation in length of storage (1 y till >20 y) Striking number of countries with no defined length Variation within countries e.g. Spain and Italy Discussion is needed on storage

Conclusion Challenging field, fast changes in most EU countries Huge variety Not all patients with rare diseases profit from optimal NBS programs Collaboration needed Training Exchange of experiences, materials, etc

Comments to drafts (Dr. Wolfgang Sperl) potential member of EUNENBS Introduction Survey Diseases screened Who decides Transparency How to contribute TenderNBS@iss.it Comments to drafts (Dr. Wolfgang Sperl) potential member of EUNENBS

Thanks !!!