Genetics and Individualized Therapies

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

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

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

4. Introduction • A key question… • How are individualized genetic therapies morally relevantly different, if at all, than other genetic and non-genetic therapies? • Two extremes to avoid • 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

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

6. Transplantation Therapies • 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 • 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

7. Individualized Genetic Therapies • 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 • 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

8. Individualized Genetic Therapies • An aside on pharmacogenetic and pharmacogenomic tests • Assays that determine an individual’s probable response to a drug or group of drugs • Costs • Complete genome sequence: $350,000 • 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 • * A stable mutation consisting of a single base in a DNA molecule

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

10. Individualized Genetic Therapies • 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… • 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 • Thus, phramacogenetic tests will yield probabilistic results rather than definitive predictions (similar to other genetic tests)

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

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

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

14. Ethical Issues • Access issues • Tests will create genotypic subgroups… • 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) • 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. Ethical Issues • Clinical use • 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? • Requires clinician education or encourage willingness to be educated

16. Discussion and Questions

17. Sources • 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. • 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.