Personalized medicine: Looking beyond the science

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 It�s a pleasure to be here this afternoon. I want to thank the organizers of the event and staff of AAAS and FDLI for handling all of the arrangements so that we could come together and discuss what are indeed very important issues facing society today- how best to use to fashion the best health care system possible for the US and the role that personalized medicine might play in that work. It�s a pleasure to be here this afternoon. I want to thank the organizers of the event and staff of AAAS and FDLI for handling all of the arrangements so that we could come together and discuss what are indeed very important issues facing society today- how best to use to fashion the best health care system possible for the US and the role that personalized medicine might play in that work.

2. Ethical questions Beyond the science or in the science? What are the ethical questions. We are asked in this session to look beyond the science. And this is often the case with ethics. As it is also the case that we always seem to speak last. But this suggests seeing ethics as separate form the science. Asking what are the ethical issues once personalized medicine is established. Test oversight. Privacy and fair use of results. Reimbursement policies. What are the ethical questions. We are asked in this session to look beyond the science. And this is often the case with ethics. As it is also the case that we always seem to speak last. But this suggests seeing ethics as separate form the science. Asking what are the ethical issues once personalized medicine is established. Test oversight. Privacy and fair use of results. Reimbursement policies.

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/article (accessed 2009 Jan 28).

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

5. Challenges I If you look at the whole table, you�d see that consistently the only countries that the US out performs are Turkey and Mexico. On the total set of measures, countries such as Hungary, Portugal, Poland out perform us on at least one other measure-- and yet, as we all know, we spend the most amount of money.If you look at the whole table, you�d see that consistently the only countries that the US out performs are Turkey and Mexico. On the total set of measures, countries such as Hungary, Portugal, Poland out perform us on at least one other measure-- and yet, as we all know, we spend the most amount of money.

6. Challenges II: Percentage of children 6-16 years old with iron deficiency by family income, United States, 1988-94. (Source: NHANES III, 1996) Iron deficiency . The x-axis represents income levels and the classifications are based on poverty-income ratio, where low income is defined as a poverty-income ratio below 1.3, middle income level is a ratio between 1.3 and 3.5, and high income level is above 3.5. Iron deficiency . The x-axis represents income levels and the classifications are based on poverty-income ratio, where low income is defined as a poverty-income ratio below 1.3, middle income level is a ratio between 1.3 and 3.5, and high income level is above 3.5.

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

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)  Blood lead level is used as surrogate for substandard living conditions. These challenges are all fundamental structural issues effecting the well being of the US population. Genetics might play a role, but logically it would be a minor one. Blood lead level is used as surrogate for substandard living conditions. These challenges are all fundamental structural issues effecting the well being of the US population. Genetics might play a role, but logically it would be a minor one.

9. Custom tailoring? 2) Is personalized medicine a good tailor? Might be the wrong transition. The first is broad- general question The second concerns how well actual treatments based on the personalized medicine paradigm workMight be the wrong transition. The first is broad- general question The second concerns how well actual treatments based on the personalized medicine paradigm work

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 So this is the problem for personalized medicine. Logically it is compelling. It ought to work. But the question is does it work. And does it work in 2 ways-- will it contribute to the needed health reform that the US is now pursuing and if we were to adopt it, would it actually deliver-- or operate- behave the way it is predicted to. So this is the problem for personalized medicine. Logically it is compelling. It ought to work. But the question is does it work. And does it work in 2 ways-- will it contribute to the needed health reform that the US is now pursuing and if we were to adopt it, would it actually deliver-- or operate- behave the way it is predicted to.

11. 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 So lets look at some of the first tests that people had most hope for: -- the amplichip warfarin So lets look at some of the first tests that people had most hope for: -- the amplichip warfarin

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.

13. 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

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.

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.

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 And reports about other diseases that people thought would move quickly to personalized seem not to be doing well either. And reports about other diseases that people thought would move quickly to personalized seem not to be doing well either.

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 Speaking to attendees at a Personalized Medicine Coalition meeting just a few days ago, Francis Collins, former director of NHGRI offered a comment directed at pharmacogenomics that probably applies generally to the obstacles confronting personalized medicine: Collins said Speaking to attendees at a Personalized Medicine Coalition meeting just a few days ago, Francis Collins, former director of NHGRI offered a comment directed at pharmacogenomics that probably applies generally to the obstacles confronting personalized medicine: Collins said

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. This diagram illustrates intermediate factors that are known determinants of health and disease. We have identified �clues� at each level.This diagram illustrates intermediate factors that are known determinants of health and disease. We have identified �clues� at each level.

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 If you look at the whole table, you�d see that consistently the only countries that the US out performs are Turkey and Mexico. On the total set of measures, countries such as Hungary, Portugal, Poland out perform us on at least one other measure-- and yet, as we all know, we spend the most amount of money.If you look at the whole table, you�d see that consistently the only countries that the US out performs are Turkey and Mexico. On the total set of measures, countries such as Hungary, Portugal, Poland out perform us on at least one other measure-- and yet, as we all know, we spend the most amount of money.

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