Martina%20Cornel,%20MD,%20PhD%20and%20Carla%20van%20El,%20PhD

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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
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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.

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Neonatal screening (heelprick)
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Neonatal screening NL 2006-2007

• 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

• 2006
• PKU
• Congenital hypothyroidism
• Congenital Adrenal Hyperplasia
• Medication or
• diet to avoid
• mental retardation or
• sudden death

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Why more diseases?

• More treatment available
• Early detection less health damage
• More tests available
• MS/MS
• Many more promises governance needed?

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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.

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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.
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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

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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.

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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
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www.gr.nl, Screening between hope and hype, p 34
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New technological possibilities

• Attunement between parties

Achterbergh et al. Health Policy 2007 83
277-286.
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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?
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Neonatal screening NL
Available from www.gr.nl
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Neonatal screening NL the committee
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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)

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Screening criteria WJ still apply!

• When to screen?
• Wilson en Jungner WHO 1968.
• A variety of sets of criteria derived from WJ
• 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

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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

Disease? Test Result? Present Absent
Positive A B
Negative C D
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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)

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Whats new? (Grosse Tab 1)

• Quality of the overall screening program
• monitored assured
• Informed choice
• Equity in access
• Acceptability

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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

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Evidence

• High quality observational evidence is lacking
  for most disorders-gt 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

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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.

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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

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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-gt alternative methods need to be
  explored

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Economic criteria

• Cost saving? Averted costgtgt intervention cost?
• If not, good value for money?
• NICE-UKGBP 30.000 per QALY Nat Health Service
• 80.000 per QALY NL
• USA wide range of cost per QALY

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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)

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Ethics informed consent

• USA Voluntary screening for disorders for which
  the evidence of benefit to the child is less
  compelling?

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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?

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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

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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

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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

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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
• Banrestriction on freedom?

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Protection 4 Self regulation?

• Quality control
• Accreditation/certification
• Standards
• Recognition of competence

www.epbs.net/brussels/
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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-gtpublic provision
• No significant benefits, but no major drawbacks
  either-gt leave to market forces
• Negative evaluation-gtindependent information
  public exposure