Ethical issues in genomics research

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Ethical issues in genomics research

• Bernard Lo, M.D.
• February 8, 2008

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Growth of genomics research

• High-throughput chips
• Availability of stored samples
• NIH emphasis on genome sequencing

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Issues to discuss

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

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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

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Genetics of neurological diseases

• Patients referred by PMDs and clinics
• Enrollment lagged
• How to increase enrollment?

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Genetics of neurological diseases

• To increase enrollment
• Identify eligible participants from computerized
  pharmacy records
• Contact them directly

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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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How is genetics ethically different

• Information about relatives and groups
• Genes viewed as highly predictive of future
  illness
• Future diaries
• Deserve stricter confidentiality?

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How is genetics ethically different

• Associated with controversial social beliefs and
  policies
• Controversial research projects
• Genetics of antisocial behavior

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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

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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

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Privacy in genome-wide association studies

• Rapid public release of sequencing data
• Use as controls for other studies

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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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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

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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

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Problems with general consentMight not understand

• Whole genome sequencing
• Public dissemination of sequencing
• Not feasible to withdraw from research
• Possibility of re-identification

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Problems with general consentMight not understand

• Potential patents
• Income from licensing and royalties
• Future studies might be considered objectionable

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Addressing consent issues

• Explicit consent for
• Whole genomic sequencing
• Public dissemination of sequencing data

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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

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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

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Addressing consent issues

• Tradeoff between research efficiency and respect
  for donors
• Researchers may exclude those who do not agree

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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

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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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Gene linked to sudden cardiac death

• Identified in high-risk families
• Should you disclose results to participants?
• Offer test to others in family?

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Characteristics of research tests

• Analytical validity
• DNA sequence accurate
• Association with phenotype?
• Clinical validity
• Correctly identify presence or absence of
  condition

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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

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Characteristics of research tests

• Clinical utility
• Change in clinical management
• If serious condition, may alter care even if no
  rigorous evidence
• Personal utility

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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

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CLIA

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

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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?

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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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Access to genomic tests and treatments

• Researcher who discovered BRCA1 and BRCA2
  patented genes
• Licensed test development to Myriad

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Access to genomic tests and treatments

• Myriad enforced patent
• Universities offering tests covering more
  mutations at lower cost

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Access to genomic tests and treatments

• European patent court overturned patents
• Another group claimed BRCA2 first, made public
• Technical errors in BRCA1 submission

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Canavan disease

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

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Canavan disease

• Property interest in sample evaporates once
  sample is given voluntarily to third party.
• Out of court settlement

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Patent system

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

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Concerns about genomic patents

• Expressed sequence tags of DNA whose function
  unknown
• Cannot invent around DNA sequence
• Patent and licensing essential for commercial
  development

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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

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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?

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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

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BiDil study

• Combination at that dose approved by FDA only for
  Blacks

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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

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Criticism of FDA approval

• Reinforce idea that racial categories have
  biological validity, rather than being social
  constructs

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Take home points
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