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Ethical issues in genomics research

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Identify eligible participants from computerized pharmacy records. Contact them directly ... Breaches of security with other databases ... – PowerPoint PPT presentation

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Title: 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
    Parkinsons, 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

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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

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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

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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

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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

44
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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
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