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  • 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.