1. 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

2. Ethical questions Beyond the science or in the science?

3. 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/articlewww.deloitte.com/dtt/article (accessed 2009 Jan 28).

4. Custom tailoring? 1)Will a custom tailored suit help US health care?

5. Challenges I Human development dimension US Rank/ 30 peer nations LIFE EXPECTANCY AT BIRTH 23 INFANT 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 2008-2009 American Human Development Project

6. 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 MiddleHigh 0

7. 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 MiddleHigh 0

8. 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 MiddleHigh 0

9. Custom tailoring? 2) Is personalized medicine a good tailor?

10. 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

11. Personalized medicine The 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

12. 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

13. 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

14. 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

15. 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

16. 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 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

17. 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

18. 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

19. 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

20. Social Class Age Gender Ethnicity Social Structure Lifestyle Influences Physiological Influences 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

21. 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

23. 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

24. We have our work cut out for us Human development dimension US Rank/ 30 peer nations LIFE EXPECTANCY AT BIRTH 23 INFANT 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 2008-2009 American Human Development Project

25. 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