Personalized medicine: Looking beyond the science

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Personalized medicine Looking beyond the science

• Pamela Sankar, PhD
• Department of Medical Ethics
• University of Pennsylvania
• AAAS-FDLI Personalized Medicine Planning for the
  Future Colloquium I Diagnostics and Diagnoses
  Paths to Personalized Medicine June 1-2, 2009
  Washington, DC

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Ethical questions

• Beyond the science
• or
• in the science?

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Personalized medicine as High end shopping

• In the same way you can walk into a high end
  clothing store and be fitted for a
  custom-tailored suit, you may soon have the
  opportunity to go to your doctor's office and
  receive a custom-tailored treatment for your
  ailments.
• www.deloitte.com/dtt/article (accessed 2009 Jan
  28).

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Custom tailoring?

• Will a custom tailored suit help US health care?

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Challenges I
Measuring America 2008-2009 American Human
Development Project
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Challenges II Percentage of children 6-16 years
old with iron deficiency by family income, United
States, 1988-94. (Source NHANES III, 1996)
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Challenges III Percentage of children age 16 or
younger w/ food insufficiency by family income,
United States, 1988-94. (Source NHANES III,
1996)
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Challenges IV - Percentage of children 1-5 years
old with blood lead levels 10 ug/dl by family
income, United States, 1991-94. (Source NHANES
III, 1996)
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Custom tailoring?

• 2) Is personalized medicine a good tailor?

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A custom tailored suit should fit, but does this
one?

• The most important thing about a treatment is
  that it is effective,
• not merely that it ought to be
  effective.
• R. Asher, 1961 Lancet

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Personalized medicineThe future is now

• By 2010 predictive genetic tests will be
  available for as many as a dozen common
  conditions
• Francis Collins, July 2005
• Personalized medicine is not a promise of the
  future it is fast emerging as the current state
  in diagnosticstherapeutics Deloitte 01.27.09

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CIGNA Coverage Policy

• Subject Drug Metabolizing Enzyme Genotyping
  Systems (AmpliChip, Invader) Effective
  Date..........................12/15/2008
• The specific enzymes that are analyzed by this
  test play a role in the metabolism of about 25
  of all prescription drugs, including
  antidepressants, antipsychotics, beta-blockers,
  and some chemotherapy drugs. AmpliChip laboratory
  test system as designed may allow physicians to
  consider unique genetic information from a
  patient when selecting medication and doses of
  medication for a variety of common conditions
  such as cardiac disease, psychiatric disease, and
  cancer.

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CIGNA Coverage Policy

• CIGNA does not cover Drug
• Metabolizing Enzyme Genotyping
• Systems (e.g., AmpliChip
• CytochromeP450 Genotyping
• Test Invader UGT1A1 Molecular
• Assay because they are considered
• experimental, investigational or
• unproven. 12.15.2008

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Use of genetic testing to guide the initiation of
warfarin therapy

• California Technology Assessment Forum 12/15/2008
• TA Criterion 3 The technology must improve net
  health outcomes.
• TA Criterion 3 is not met.
• TA Criterion 4 The technology must be as
  beneficial as any established alternatives.
• TA Criterion 4 is not met.
• TA Criterion 5 The improvement must be
  attainable outside of the investigational
  setting.
• TA Criterion 5 is not met.

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Use of genetic testing to guide the initiation of
warfarin therapy

• California Technology Assessment Forum 12/15/2008
• Conclusion
• the use of genetic testing to guide initial
  warfarin dosing does not meet Technology
  Assessment Criteria 3 through 5 for safety,
  effectiveness and improvement in health outcomes.

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Diabetes and ARMD Off the rack will have to do

• Diabetes
• As compared with clinical risk factors alone,
  common genetic variants associated with the risk
  of diabetes had a small effect on the ability to
  predict the future development of type 2
  diabetes. The value of genetic factors increased
  with an increasing duration of follow-up.
  Lyssenko NEJM 2008
• A genotype score based on 18 risk alleles
  predicted new cases of diabetes in the community
  but provided only a slightly better prediction of
  risk than knowledge of common risk factors alone.
  Meigs NEJM 2008
• Age-related macular degeneration
• ...although genotype can identifyindividuals
  with extreme risk or extreme protection the
  majority of the population inherits some of each
  category, resulting in the lifetime risk of AMD
  that is only modestly different from the overall
  population average. Maller 2006

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Extremely complicated

• "Pharmacogenomics, which from my perspective
  has been one of the most promising areas of
  personalized medicine, has also turned out to be
  extremely complicated, not that we shouldn't have
  known that.
• Francis Collins, former director of NHGRI,
• Personalized Medicine Coalition Meeting
• January 30, 2009

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What we should have known one size does not fit
all

• Environment
• One size does not fit all applies
• not only to traditional drugs but
• also to challenge of accurately
• modeling the environment of
• different subjects

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Non-genetic factors drug response

• Environmental influences
• Diet alcohol intake
• Cigarette smoking
• Diseases
• Liver and kidney diseases which effect
  metabolism
• Interaction with other drugs
• Patient compliance

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Non-genetic factors disease

• Geographic Location
• Housing Conditions
• Occupational Risks
• Access to Services

Environmental Influences

• Social Class
• Age
• Gender
• Ethnicity

Social Structure

• Smoking
• Nutrition
• Physical Activity
• Psychosocial Factors

Lifestyle Influences

• Blood Pressure
• Cholesterol
• Obesity

Physiological Influences
Source McKinlay J, AJPH 1999
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What we should have known one size does not fit
all

• Genotype-phenotype relationship
• Understood only imperfectly and
• becomes more complex as more is learned
• about factors such as
• relations among genes
• relations between the human genome and the human
  microbiome
• features such as copy number variation
• epigenetic modifications

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Where is heritable risk hiding?

• Alleles with small size effects
• Rare variants
• Population differences
• Epistatic interactions (where combined risk is
  greater (or lesser) than the sum of the risk form
  individual genes)
• Copy number variation
• Epigenetic inheritance (chemical modifications of
  DNA that can alter the expression of genes --and
  thus physical traits--without changing the
  sequence)
• D. MacArthur GeneticFuture, Blog 2008

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We have our work cut out for us
Measuring America 2008-2009 American Human
Development Project
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Is custom tailoring the best answer?

• As long as there are cold and nakedness in the
  land around you,
• so long can there be no question at all but
  that splendor of dress is a crime.
• John Ruskin