Martina Cornel, MD, PhD and Carla van El, PhD

1. The promises of genomic screening: building a governance infrastructure Lund, Sweden Genetics & Democracy 5th October 2009 Martina Cornel, MD, PhD and Carla van El, PhD Community Genetics, Dept Clinical Genetics

2. Screening: Definition US Commission on Chronic Illness 1951: The presumptive identification of unrecognized disease or defect by the application of tests, examinations or other procedures which can be applied rapidly. Screening tests sort out apparently well persons who probably have a disease from those who probably do not. A screening test is not intended to be diagnostic. Persons with positive or suspicious findings must be referred to their physicians for diagnosis and necessary treatment.

3. Neonatal screening (heelprick)

5. Neonatal screening NL 2006-2007 • 2006 • PKU • Congenital hypothyroidism • Congenital Adrenal Hyperplasia • Medication or • diet to avoid • mental retardation or • sudden death • Biotinidase deficiency • Cystische fibrosis (conditional; pilot 2008) • 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

6. Why more diseases? • More treatment available • Early detection: less health damage • More tests available • MS/MS • Many more promises: governance needed?

8. Sources of presentation: • Health Council of the Netherlands. Screening: between hope and hype. The Hague: Health Council of the Netherlands, 2008; publication no. 2008/05E. Available from www.gr.nl. • Grosse SD, Rogowski WH, Ross LF, Cornel MC, Dondorp WJ, Khoury MJ. Population Screening for Genetic Disorders in the 21st Century: Evidence, Economics and Ethics. Public Health Genomics, Epub.

9. Screening: between hope and hype • the rate at which useful new screening opportunities become available is not as rapid as reports in the media might sometimes indicate. • cultural, social and economic factors contribute to a situation in which various types of screening (including self-testing kits) are placed on the market without any proper investigation having been conducted to ascertain whether the benefits for those affected outweigh the disadvantages that always also exist. www.gr.nl Screening between hope and hype. Presentation of report.

10. Definition Screening involves the clinical and laboratory examination of individuals who exhibit no health problems with the aim of detecting disease, predisposition to disease, or risk factors that can increase the risk of disease. (Health Council of the Netherlands, 2008) Note: “systematic offer” not in this definition

11. Social developments relevant for screening • Health care moving from a government-regulated health care sector to one which is driven to a greater or lesser extent by market forces. • Blurring distinction between collective prevention and individual client-focused care. • Clinical genetic family testing vs cascade screening for FH • Need for reassurance: people increasingly receptive to anything that promises to eliminate risk.

12. What does this mean for the government? • A fresh approach is needed to encourage sensible screening and to protect individuals against the risks of unsound screening. • Extending regulations??????? Not..most suitable • Independent body… nat screening committee UK • Establish a quality-mark for responsible screening, based on scientific assessments of new developments and aimed at promoting responsible provision and responsible choices. www.gr.nl Screening between hope and hype. Presentation of report

13. www.gr.nl, Screening: between hope and hype, p 34

14. New technological possibilities • Attunement between parties Achterbergh et al. Health Policy 2007; 83: 277-286.

15. Screening: • Presymptomatic (no symptoms or complaints yet) • Offer of health care • Systematic offer (all newborns or all women aged 50-75) • Sometimes voluntary, seldom “mandatory” • Often low risk population; similar to self tests What about self tests?

16. Neonatal screening NL Available from: www.gr.nl

17. Neonatal screening NL: the committee

18. 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)

19. 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

20. Balancing pros and cons • Treatment available? Effective? Available for all and for ever? Affordable? • Good test available? • False positives • Specificity (1-FP) • False negatives • Sensitivity (1-FN) • Positive predictive value • Unintended side effects • Mild phenotypes • Carriers identified

21. Screening criteria(Grosse et al, Public Health Genomics) • 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)

22. What’s new? (Grosse; Tab 1) • Quality of the overall screening program • monitored & assured • Informed choice • Equity in access • Acceptability

23. Balancing pros and cons; Grosse et al. • Technical issues of analytic and clinical validity • Clinical utility: • Scientific evidence – medical benefits & harms • Balance of economic costs & health outcomes • Ethical issues

24. Evidence • High quality observational evidence is lacking for most disorders-> little agreement between countries. • Systematical assessment EGAPP genetic tests: BRCA/Lynch • Systematical assessment neonatal screening: • CDC review 2004; • ACMG: clinical experts criticized by advocates of EBM

25. Evidence • Systematical assessment (neonatal) screening: • NL: Health Council: • 2005: endorsed 14 additional disorders for which acceptable test was available & early treatment could prevent irreparable damage • 2007: self test kits • 2008: new approaches to evaluate tests to avoid coverage of unsound screening tests .. promote.. worthwhile approaches.

26. Evidence • Discussion: CF & CAH • The number of deaths prevented through screening for either disorder is difficult to quantify. • Deaths before diagnosis? Case-control studies needed. • Evidence not convincing: population wide screening for HFE mutations

27. Economic criteria • Cost-effectiveness analysis • Net cost per death prevented or life-year gained • Cost-utility analysis • combine information on mortality & morbidity; cost per QALY • Limited in the ability to inform policy decisions-> alternative methods need to be explored

28. Economic criteria • Cost saving? Averted cost>> intervention cost? • If not, good value for money? • NICE-UK:GBP 30.000 per QALY Nat Health Service • €80.000 per QALY NL • USA: wide range of cost per QALY

29. Ethics • Informed consent; mandatory neonatal screening; parental consent or awareness required; opt out; • Promotion of informed participation • NL: always voluntary, but parents not informed of the option to decline screening • France: written consent for DNA (99,8%)

30. Ethics: informed consent • USA: Voluntary screening for disorders for which the evidence of benefit to the child is less compelling?

31. Conclusion Grosse et al. • Genetic screening policies have typically been determined by technological capability, advocacy, and medical opinion rather than through a rigorous, objective, evidence-based review process. • Ethical and economic evidence alongside scientific evidence. • Transparent and open to stakeholder engagement. • BUT WHO & HOW?

32. 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

33. Protection (Health Council 2008) • Population Screening Act: unique in the world • Some forms of screening must undergo independent quality test before Minister issues licence: • Population screening using ionising radiation • Population screening for cancer • Population screening for serious diseases or abnormalities for which no treatment or prevention exists

34. Protection – 2 (Health Council 2008) • Self testing: European IVD directive • Purpose clear? Works as it is supposed to? Does not endanger health or safety of patients and users? • Risk classes: high, medium, low • High & medium: must be assessed by notified body • Low: assessed by the manufacturer • NL: Marketing channel regulations: High risk only sold via professional intermediary

35. Protection – 3 - Bottlenecks (Health Council 2008) • Population screening act: arbitrary categories for licencing, inflexible. Why are some intensively evaluated while others are not? • Cardiovascular disease vs. cancer • Enforcement: prosecution only for parties who carry out screening, not those who offer it and carry it out over the German border • Do it yourself testing kits easily obtained from Internet or pharmacist • Ban=restriction on freedom?

36. Protection – 4 – Self regulation? • Quality control • Accreditation/certification • Standards • Recognition of competence www.epbs.net/brussels/

37. An active approach is needed (Health Council 2008) • Responsible screening should be available and accessible • Strong proactive engagement government • Protect citizens against risk of unsound screening • Quality mark: information, education, exposure, trust • Positive evaluation->public provision • No significant benefits, but no major drawbacks either-> leave to market forces • Negative evaluation->independent information; public exposure