Ethical issues in genomics research

1. Ethical issues in genomics research Bernard Lo, M.D. February 8, 2008

2. Growth of genomics research • High-throughput chips • Availability of stored samples • NIH emphasis on genome sequencing

3. Issues to discuss • Recruitment of participants • Disclose results to participants • Access to genomics tests • Using self-identified race as variable

4. Recruitment for study on genetics of neurological diseases • Collect blood samples of 450 patients with Parkinson’s, epilepsy, tardive dyskinesia • Multiethnic study population • Study genetics of susceptibility, drug responsiveness • $5.6 million over 5 years

5. Genetics of neurological diseases • Patients referred by PMDs and clinics • Enrollment lagged • How to increase enrollment?

6. Genetics of neurological diseases • To increase enrollment • Identify eligible participants from computerized pharmacy records • Contact them directly

7. Genetics of neurological diseases • One socially prominent patient had kept diagnosis secret • Outraged that her diagnosis known • Research team also • Told participants their MDs had agreed • Conducted off-on testing without consent

9. How is genetics ethically different • Information about relatives and groups • Genes viewed as highly predictive of future illness • “Future diaries” • Deserve stricter confidentiality?

10. How is genetics ethically different • Associated with controversial social beliefs and policies • Controversial research projects • Genetics of antisocial behavior

11. How is genetics ethically different • Associated with controversial social beliefs and policies • Undermines traditional moral beliefs? • Identification of genes for addiction may undercut individual responsibility • Contract beliefs about group ancestry

12. Confidentiality in biobanks • Main risk in genomics research • Need to maintain identifying links to update clinical data • Breaches of security with other databases • If bankruptcy, creditors not bound by confidentiality arrangements • Although low probability, large impact

13. Privacy in genome-wide association studies • Rapid public release of sequencing data • Use as controls for other studies

14. Privacy concerns about public release of sequencing data • Use in objectionable studies • Cannot withdraw from research once data are released • Re-identification of anonymized specimens

16. Privacy in genome-wide association studies • Reference samples in forensic databases • DOJ has 4.3 million profiles • STRs at 13 locations • Full genome sequence can be matched • Re-identification low probability, high impact

17. Use of existing samples in research • Value for research • No consent required if anonymized • General consent for research or genetic research suffices • Donors not envisage that research might make sample identifiable

18. Problems with general consentMight not understand • Whole genome sequencing • Public dissemination of sequencing • Not feasible to withdraw from research • Possibility of re-identification

19. Problems with general consentMight not understand • Potential patents • Income from licensing and royalties • Future studies might be considered objectionable

20. Addressing consent issues • Explicit consent for • Whole genomic sequencing • Public dissemination of sequencing data

21. Addressing consent issues • Explicit consent for • Patents arising from discoveries • Specify financial arrangements • Sharing with individual donors not feasible • May need to negotiate with advocacy groups who recruited donors

22. Addressing consent issues • Explicit consent for • Future studies • Consent for all studies approved by IRB or oversight committee • Require specific consent for highly sensitive studies • Permission to recontact for sensitive studies

23. Addressing consent issues • Tradeoff between research efficiency and respect for donors • Researchers may exclude those who do not agree

24. Research oversight • Currently research on existing anonymized data and specimens does not require IRB review • Rationale is very low risk, no one would object • May not be appropriate for controversial genomic studies

25. Research oversight • Oversight may be appropriate for genomic research using anonymized specimens and sequencing data • Identify controversial studies to see if they fall within the scope of original consent

27. Gene linked to sudden cardiac death • Identified in high-risk families • Should you disclose results to participants? • Offer test to others in family?

28. Characteristics of research tests • Analytical validity • DNA sequence accurate • Association with phenotype? • Clinical validity • Correctly identify presence or absence of condition

29. Establish clinical validity • Validation in independent sample • Families with same mutation • Other high-risk families • False negative if another gene • Individuals at high risk, no family history • General population screening

30. Characteristics of research tests • Clinical utility • Change in clinical management • If serious condition, may alter care even if no rigorous evidence • Personal utility

31. Personal significance • Even if not change medical care, person may want information • Avoid certain activities • Modify lifestyle • Alter plans for education, work, family • Just want to know

32. CLIA • Requirements for quality control • Waiver for home-brews, but may be eliminated • Can test for specific DNA sequence in commercial lab

33. Approach to disclosure in research study • Present plan in protocol • Tell participants whether tests available • In whole genome studies, what will be disclosed? • Raw sequence data • List of validated associations?? • Place in medical record?

34. Approach to disclosure in research study • Provide counseling and information • Explain clinical uncertainty • Educate primary MDs • Assess comprehension of participants? • Involve IRB if new developments

36. Access to genomic tests and treatments • Researcher who discovered BRCA1 and BRCA2 patented genes • Licensed test development to Myriad

37. Access to genomic tests and treatments • Myriad enforced patent • Universities offering tests covering more mutations at lower cost

38. Access to genomic tests and treatments • European patent court overturned patents • Another group claimed BRCA2 first, made public • Technical errors in BRCA1 submission

39. Canavan disease • Progressive, fatal neurological disease • Families helped researchers collect samples • After gene identified and patented, licensing and royalty fees made test unaffordable

40. Canavan disease • “Property interest in sample … evaporates once sample is given voluntarily to third party.” • Out of court settlement

41. Patent system • Exclusive use provides incentives to develop and market products • Must disclose invention • Diffuses knowledge • Others may invent around

42. Concerns about genomic patents • Expressed sequence tags of DNA whose function unknown • Cannot invent around DNA sequence • Patent and licensing essential for commercial development

43. Sharing benefits of genome discoveries • Individuals not share in benefit • National biobanks negotiate payments from commercial companies • Advocacy groups negotiate access or share of profits in return for helping recruit donors

45. BiDil study • Hydralazine + isosorbide not effective in CHF • Post-hoc subgroup analysis showed effectiveness in Blacks • New RCT enrolling only Blacks • Would trial including Caucasians be ethically acceptable?

46. BiDil study • Mortality 6.2% in BiDil arm compared to 10.2% in control group • Also significant difference in primary composite end-point • Terminated at interim analysis

47. BiDil study • Combination at that dose approved by FDA only for Blacks

48. Criticism of FDA approval • Self-identified race a surrogate for unknown specific polymorphisms • Misclassifies patients • Little incentive for manufacturer to carry out mechanistic studies • Other useful surrogate categories (age) also misclassify

49. Criticism of FDA approval • Reinforce idea that racial categories have biological validity, rather than being social constructs

50. Take home points