1. 1 Genetics and Individualized Therapies Jan C. Heller, PhD Bioethicist, Seattle, WA 4 March 2009

2. 2 Presentation Outline Introduction: Two disclaimers and key question… Introduction: Two disclaimers and key question… A very brief overview of selected individualized genetic therapies A very brief overview of selected individualized genetic therapies Review of some ethical issues raised by these therapies Review of some ethical issues raised by these therapies Discussion and questions Discussion and questions

3. 3 Introduction Two disclaimers… Two disclaimers… Pretty “heady stuff” and presenter has limited expertise on this subject Pretty “heady stuff” and presenter has limited expertise on this subject Yet another example of very rapid development in genetic research Yet another example of very rapid development in genetic research Limited time to cover a wealth of material Limited time to cover a wealth of material Genetic vaccines and anti-viral therapies Genetic vaccines and anti-viral therapies Transplantation therapies Transplantation therapies Pharmacogenetics and pharmacogenomics Pharmacogenetics and pharmacogenomics Dependent on new and individualized genetic tests Dependent on new and individualized genetic tests

4. 4 Introduction A key question… A key question… How are individualized genetic therapies morally relevantly different, if at all, than other genetic and non-genetic therapies? How are individualized genetic therapies morally relevantly different, if at all, than other genetic and non-genetic therapies? Two extremes to avoid Two extremes to avoid Genetic exceptionalism: That all genetic applications raise exceptionally serious ethical concerns that require special regulatory responses Genetic exceptionalism: That all genetic applications raise exceptionally serious ethical concerns that require special regulatory responses Genetic generalization: That all genetic tests raise the same ethical issues Genetic generalization: That all genetic tests raise the same ethical issues

5. 5 Vaccines and Anti-viral Therapies New treatments for emerging and re-emerging diseases New treatments for emerging and re-emerging diseases Immunizations against HIV, smallpox Immunizations against HIV, smallpox Correction of hereditary defects Correction of hereditary defects Anti-tumor therapies tailored to individuals Anti-tumor therapies tailored to individuals Preventive measures for degenerative diseases Preventive measures for degenerative diseases Unfortunately, these will only be available in the future (next decade?), if at all Unfortunately, these will only be available in the future (next decade?), if at all

6. 6 Transplantation Therapies Use of a patient’s own adult stem cells or somatic cells that are then cloned to create embryonic stem cells Use of a patient’s own adult stem cells or somatic cells that are then cloned to create embryonic stem cells Used to create tissues or organs that can then be transplanted into the patient without fear of rejection Used to create tissues or organs that can then be transplanted into the patient without fear of rejection Arguably, these are not genetic therapies, and in any case they raise the same ethical concerns raised by other stem cell therapies, which we’ve discussed many time before… Arguably, these are not genetic therapies, and in any case they raise the same ethical concerns raised by other stem cell therapies, which we’ve discussed many time before… Safety, efficacy, cost, and access, plus potential cooperation with destruction of cloned human embryos Safety, efficacy, cost, and access, plus potential cooperation with destruction of cloned human embryos

7. 7 Individualized Genetic Therapies Pharmacogenetics is the study of the effects of genotypic variations on drug-response (safety and efficacy) and drug-drug interaction Pharmacogenetics is the study of the effects of genotypic variations on drug-response (safety and efficacy) and drug-drug interaction Variations are not tissue-specific, but are properties of an individual’s genome Variations are not tissue-specific, but are properties of an individual’s genome Pharmacogenomics is the study of effects of variations in the expression of individual genes in the cells of particular tissues on drug-response Pharmacogenomics is the study of effects of variations in the expression of individual genes in the cells of particular tissues on drug-response Much more dynamic, since changes can originate with internal or external stimuli Much more dynamic, since changes can originate with internal or external stimuli

8. 8 Individualized Genetic Therapies An aside on pharmacogenetic and pharmacogenomic tests An aside on pharmacogenetic and pharmacogenomic tests Assays that determine an individual’s probable response to a drug or group of drugs Assays that determine an individual’s probable response to a drug or group of drugs Costs Costs Complete genome sequence: $350,000 Complete genome sequence: $350,000 ENCODE project may lower this to $10,000 ENCODE project may lower this to $10,000 Genome wide statistical association studies relate most common form of variation (single nucleotide polymorphisms* or SNPs) and diseases, incorporating more than 500,000 markers, for $1,000 Genome wide statistical association studies relate most common form of variation (single nucleotide polymorphisms* or SNPs) and diseases, incorporating more than 500,000 markers, for $1,000 * A stable mutation consisting of a single base in a DNA molecule * A stable mutation consisting of a single base in a DNA molecule

9. 9 Individualized Genetic Therapies Some potential benefits… Some potential benefits… Understand genetic basis of drug response mechanisms Understand genetic basis of drug response mechanisms Enhanced post-market surveillance (i.e., after a drug’s approval and widespread use) Enhanced post-market surveillance (i.e., after a drug’s approval and widespread use) Expediting drug development with smaller clinical trials Expediting drug development with smaller clinical trials

10. 10 Individualized Genetic Therapies Three potential scientific limits… Three potential scientific limits… Will range of variability be enough to make testing worthwhile, yet not so much as to require an impractically large number of drugs and tests? Don’t know yet… Will range of variability be enough to make testing worthwhile, yet not so much as to require an impractically large number of drugs and tests? Don’t know yet… If multiple genes are involved in drug response and side effects, it may make testing more complex and less definitive If multiple genes are involved in drug response and side effects, it may make testing more complex and less definitive Drug response depends not only genotype but other factors as well, such as cellular and extra-cellular environments, general state of health, patient compliance with drug regimen Drug response depends not only genotype but other factors as well, such as cellular and extra-cellular environments, general state of health, patient compliance with drug regimen Thus, phramacogenetic tests will yield probabilistic results rather than definitive predictions (similar to other genetic tests) Thus, phramacogenetic tests will yield probabilistic results rather than definitive predictions (similar to other genetic tests)

11. 11 Individualized Genetic Therapies Potential limiting social factors… Potential limiting social factors… Health insurance and health care delivery system Health insurance and health care delivery system Public attitudes toward genetic research and testing Public attitudes toward genetic research and testing Knowledge of benefits and burdens of pharmacogenetics among payers, providers, and consumers Knowledge of benefits and burdens of pharmacogenetics among payers, providers, and consumers Regulatory practices Regulatory practices Industry investment in relevant technologies Industry investment in relevant technologies

12. 12 Ethical Issues Sufficient regulatory oversight to ensure safety and efficacy Sufficient regulatory oversight to ensure safety and efficacy Protection of privacy and confidentiality Protection of privacy and confidentiality Tests may reveal genetic disease or predisposition Tests may reveal genetic disease or predisposition May have implications for disease progression if test indicates negative drug response May have implications for disease progression if test indicates negative drug response Implications for insurance, employer, relatives Implications for insurance, employer, relatives

13. 13 Ethical Issues Informed consent Informed consent Provide counseling with test results Provide counseling with test results Educate patients re: meaning of tests Educate patients re: meaning of tests Educate clinicians re: importance of confidentiality Educate clinicians re: importance of confidentiality Coding technologies to create firewalls to test results Coding technologies to create firewalls to test results Legislation to protect patients from discrimination Legislation to protect patients from discrimination

14. 14 Ethical Issues Access issues Access issues Tests will create genotypic subgroups… Tests will create genotypic subgroups… If group is sufficiently large, pharmaceutical companies may have incentives to develop drugs for that group If group is sufficiently large, pharmaceutical companies may have incentives to develop drugs for that group Or, if not large enough…may create an “orphan” subgroup (could incent development with patent protections or subsidize development) Or, if not large enough…may create an “orphan” subgroup (could incent development with patent protections or subsidize development) Clinical access will depend on tests being included in standard insurance benefit packages, which may depend on whether tests prove cost-effective in the long run Clinical access will depend on tests being included in standard insurance benefit packages, which may depend on whether tests prove cost-effective in the long run

15. 15 Ethical Issues Clinical use Clinical use The less predictive the tests are, the more complicated the clinical decisions will be The less predictive the tests are, the more complicated the clinical decisions will be E.g., suppose a patent’s genotype indicates a 30% chance of adverse results? E.g., suppose a patent’s genotype indicates a 30% chance of adverse results? Requires clinician education or encourage willingness to be educated Requires clinician education or encourage willingness to be educated

16. 16 Discussion and Questions

17. 17 Sources Allen Buchanan, et al., “Pharmacogenetics: Ethical Issues and Policy Options,” Kennedy Institute of Ethics Journal 12, no. 1, 1-15, 2002. Allen Buchanan, et al., “Pharmacogenetics: Ethical Issues and Policy Options,” Kennedy Institute of Ethics Journal 12, no. 1, 1-15, 2002. W. Gregory Feero, et al., “The Genome Gets Personal—Almost,” JAMA 299, no.11 (March 19, 2008), 1351-1352. W. Gregory Feero, et al., “The Genome Gets Personal—Almost,” JAMA 299, no.11 (March 19, 2008), 1351-1352. Mechtild Schmedders, et al., “Individualized Pharmacogenetic Therapy: A Critical Analysis,” Community Genetics 6, no. 2, 2003, 114-119. Mechtild Schmedders, et al., “Individualized Pharmacogenetic Therapy: A Critical Analysis,” Community Genetics 6, no. 2, 2003, 114-119. GR Hellermann and SS Mohapatra, “Genetic Therapy: on the Brink of a New Future,” Genetic Vaccines and Therapy 1:1. GR Hellermann and SS Mohapatra, “Genetic Therapy: on the Brink of a New Future,” Genetic Vaccines and Therapy 1:1.