Ethical Considerations in Human Gene Transfer Research: The IBCs Role

1
Ethical Considerations in Human Gene Transfer
Research The IBCs Role

• Nancy M. P. King, JD
• Professor of Social Medicine
• University of North Carolina, Chapel Hill

2
You Already Know This!

• Pre-clinical data
• Risks of harm to subjects
• Risks of harm to study personnel (containment and
  handling precautions)
• Risks of harm to others (horizontal and
  vertical/germline transmission)
• How good are the tests used to detect risks of
  harm?
• Ethical implications of study design
• Novelty and uncertainty
• Study personnel guidelines, education,
  recordkeeping, and monitoring re agent handling
  and administration
• Subjects role expectations, disclosure, and
  consent
• IBCs relationship with IRB

3
Is Ethics Different?

• No, but.
• Different framework, same concepts
• Different vocabulary, same concerns
• Ethics as common ground for expert and community
  members of IBC (and IRB)

4
Human Research Ethics in a Nutshell

• Respect for persons
• Supporting autonomy of subjects
• Informed consent
• Nonmaleficence
• Minimizing risks of harm through study design
• Minimizing risks of harm in conduct of study
• Justice
• Subject selection
• Use of results

5
Are Human Studies Different?

• Yes, but not that different.
• Biological systems are messy and uncertain
• Biological agents have whole-body effects and
  beyond
• IBCs may understand this better than IRBs
• IBCs can apply preclinical experience to human
  studies

6
Production, Animals, Humans

• Safety How are you handling this stuff, from
  lab to receipt to injection?
• Safety inspection, monitoring, guidelines
• Safety What did you see in animals?
  biodistribution, whole body response to high
  doses, integration, replication

7
Bench, Animals, Humans

• Design surrogate markers for successful gene
  transfer in humans?
• Design consequences of targeting miss in
  humans?
• Design consequences of perfect targeting in
  humans -- overkill?

8
The IBC and Uncertainty

• When you cant engineer host, look to vector for
  containment
• Experience in animal issues
• Ask how rare events can be detected with
  increasing numbers and generations in animal and
  human studies
• Collection and testing to monitor shedding,
  biodistribution, vertical transmission risk
• Discuss uncertainties with potential subjects
• Discuss subjects role providing data to reduce
  uncertainty

9
Scientific Review of Human Gene Transfer

• assessing risk levels, harm-benefit calculus, and
  risk minimization all require scientific review
• assessing subject selection consent form
  requires scientific knowledge
• IBC never stands alone in review IRB needs you!
• IBC sees Appendix M responses IRB may not know
  they exist
• IRB may or may not have access to local experts
  IBC often does

10
Moving to Human Gene Transfer Research

• Has enough preclinical information been collected
  so that the only reasonable way to learn more is
  to move to humans?
• Has enough been done to reduce the risks of harm
  to humans, and to maximize the likelihood that
  the gene transfer intervention will ultimately
  show benefit in humans?
• Has the point of irreducible uncertainty been
  reached?
• Is the amount of irreducible uncertainty small
  enough that it is fair to subjects to ask them to
  become involved in the research?

11
Selection of Patients as Subjects Should Reflect
Research Goals

• minimizing risks of harm -- for which subjects
  can the risks of the intervention be meaningfully
  minimized?
• maximizing contribution to generalizable
  knowledge -- from which subjects can maximally
  useful data (amount, meaning, interpretability)
  be obtained?
• both goals must be met they can conflict this
  presents challenging ethical/design questions.

12
Who Should Be the First Subjects?

• Should subjects be more like healthy
  volunteers?
• adults with relatively stable disease
• informed and unpressured decisions about
  participation
• possible to minimize risks of harm
• reliable and interpretable data
• Should subjects be more like the sickest
  patients?
• most often asked in early-phase trials
• treatment possibilities exhausted
• not tempted to forgo a bird in the hand
• may perhaps value potential benefits more, or
  risks less

13
Issues in Human Studies for IBCs

• small subject populations present design issues
  for intervention research on rare diseases
• need to frame research question carefully
• need for statistical consultation on sample size,
  phase, and research objective
• surrogate endpoints present design issues in
  early-phase clinical trials
• smaller, shorter studies can provide more
  meaningful data
• clinically meaningful effects less likely for
  subjects
• acknowledge limitations of small early-phase
  studies to potential subjects

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The IBCs Unique Contributions

• Accustomed to ongoing monitoring (IRBs are not)
• Expects investigators to persuade using data
  (IRBs often less sure about the science)
• Experienced in infection control practices
• Used to considering horizontal and vertical
  transmission risks
• Used to working with Appendix M and OBA

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The IBC and Research Ethics

• Preclinical evidence supports research safety and
  validity?
• Value (safety, fairness, payoff) of moving to
  human subjects?
• Minimizing uncertainty and risks of harm
• Discussing uncertainty and reasonable
  expectations
• Ensuring nonmaleficence (to subjects and others)
  through guidelines and monitoring
• Emphasis subjects role in early-phase GTR