Ethical Issues in Pediatric Research: Placebo controlled trials for gastoesophogeal reflux

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Ethical Issues in Pediatric ResearchPlacebo
controlled trials for gastoesophogeal reflux

• Benjamin Wilfond MD
• Medical Genetics Branch
• National Human Genome Research Institute
• Department of Clinical Bioethics,
• Warren G Magnuson Clinical Center
• National Institutes of Health

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Ethical considerations in human subjects research

• Sound research design without unnecessary risks
• Risks in proportion with benefits/knowledge
• Safety is maximized
• Subject selection is equitable
• Privacy and confidentiality is adequate
• Informed consent is obtained

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Pediatric Risk Categories in 45 CFR 46
Greater than minor increase over minimal risk
Minor increase over minimal risk
Minimal risk
Risk is justified by the benefits
Risk is justified by the benefits
Prospect of direct benefit
Risk/benefit is as favorable as alternatives
Risk/benefit is as favorable as alternatives
Commensurate experiences
No prospect of direct benefit
Vital knowledge about subjects disorder
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Should risk categories be applied to the entire
study or to individual components?

• Should the risks/benefits of Ph probes, PPI
  placebo, blood draws be looked at as a group or
  separately?
• If they are looked at as a group, then the
  benefit of one component could justify the risks
  of other components.
• If they are looked at separately, how should the
  placebo arm be considered?

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Intuitions about Placebos

• Placebos arms are not acceptable particularly
  when there is an effective intervention to avoid
  significant morbidity or mortality
• Ie ALL, meningitis, status epilectus, status
  asthmaticus
• Placebo may be acceptable if
• No commonly accepted therapy
• Commonly used therapy is of questionable efficacy
• Commonly used therapy has significant side
  effects
• Disease has spontaneous exacerbations and
  remissions
• Placebo is an add-on to established therapy
• (AAP Committee on Drugs, 1995)

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Risks and benefits of placebos

• Need to clarify what what would happen without
  the trial.
• For purpose of assessing relatives benefits and
  risks
• Does the placebo arm offer prospect of direct
  benefit compared to the standard alternative?
  (405)
• Does the placebo arm pose more than minimal (406)
  or more than minor increase over minimal risk?

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Placebos and GER

• Standard treatment is to treat children with
  reflux symptoms with a range anti-reflux meds of
  uncertain efficacy.
• The side effects of the drugs are modest
• The placebo arm does not offer a prospect of
  direct benefit
• Are the risks of the placebo arm, more that a
  minor increase over minimal risk?

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Proposed research

• Study 2 - Pre term hospitalized infants
• Monitoring and interventions for apnea
• Withdrawal criteria
• Study 4 - infants 1 to 11 months
• Exclude children with ALTEs
• Need to define ALTE. (parental perception of
  color change)
• Withdrawal criteria
• Is the risk of being in a placebo arm, under
  these conditions, no more than a minor increase
  over minimal risk ?
• Is there any unnecessary risk?
• Can risk be further minimized?

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minor increase

• This is a judgment regarding what we expect will
  happen to children in the placebo group.
• Under the described conditions, reflux in both
  groups are would not be expected to cause
  significant harm to the children, in comparison
  to the the children in the active treatment
  groups.
• Thus the placebo arm does not pose greater than
  a minor increase over minimal risk to these
  children.