Personalized medicine: Looking beyond the science Pamela Sankar, PhD Department of Medical Ethics University of Pennsylvania AAAS-FDLI Personalized Medicine:

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?

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).

Custom tailoring?

1)Will a custom tailored suit help US health care?

Challenges IHuman development

dimension US Rank/ 30 peer nations

LIFE EXPECTANCY AT BIRTH 23INFANT MORTALITY RATE (per 1,000 live births)

25

TOTAL HEALTH EXPENDITURE (% of GDP)

1

NEW AIDS CASES (per million population)

1

OBESITY (% of adult population) 1

PRACTICING PHYSICIANS(per 1,000 inhabitants)

21

Measuring America 2008-2009American Human Development Project

Challenges II: Percentage of children 6-16 years old with iron deficiency by family income, United States, 1988-94. (Source: NHANES III, 1996)

Children with

iron deficiency (%)

Low Middle High0

5

10

6

3

1

0

Challenges III: Percentage of children age 16 or younger w/ food insufficiency by family income, United States, 1988-94. (Source: NHANES III, 1996)

Children with

food insufficiency

(%)

Low Middle High00

10

2016

20

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)

Children with high

blood lead levels (%)

Low Middle High0

5

108

21

0

Custom tailoring?

2) Is personalized medicine a good tailor?

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

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 diagnostics&therapeutics Deloitte 01.27.09

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.

CIGNA Coverage Policy

CIGNA Coverage Policy

CIGNA does not cover Drug Metabolizing Enzyme GenotypingSystems (e.g., AmpliChip™ CytochromeP450 GenotypingTest; Invader® UGT1A1 MolecularAssay because they are considered experimental, investigational or unproven. 12.15.2008

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.

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.

Use of genetic testing to guide the initiation of warfarin therapy

Diabetes and ARMD: Off the rack will have to do

DiabetesAs 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 identify…individuals 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

EnvironmentOne size does not fit all appliesnot only to traditional drugs but also to challenge of accurately modeling the environment of different subjects

Non-genetic factors & drug response

• Environmental influencesDiet alcohol intakeCigarette smoking

• Diseases Liver and kidney diseases

which effect metabolism• Interaction with other drugs• Patient compliance

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• Social Class• Age• Gender• Ethnicity

Social Structure

LifestyleInfluences

PhysiologicalInfluences

• Smoking• Nutrition• Physical Activity• Psychosocial Factors

• Blood Pressure• Cholesterol• Obesity

Non-genetic factors & disease

Environmental Influences

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

Source: McKinlay J, AJPH 1999

What we should have known: one size does not fit allGenotype-phenotype relationshipUnderstood 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

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

We have our work cut out for us

Human development dimension

US Rank/ 30 peer nations

LIFE EXPECTANCY AT BIRTH 23INFANT MORTALITY RATE (per 1,000 live births)

25

TOTAL HEALTH EXPENDITURE (% of GDP)

1

NEW AIDS CASES (per million population)

1

OBESITY (% of adult population) 1

PRACTICING PHYSICIANS(per 1,000 inhabitants)

21

Measuring America 2008-2009American Human Development Project

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