1. Ethical Issues in Pediatric Research: Placebo 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

2. 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

3. Pediatric Risk Categories in 45 CFR 46 Prospect of direct benefit No prospect of direct benefit Commensurate experiences Vital knowledge about subjects disorder Risk/benefit is as favorable as alternatives Risk is justified by the benefits Minimal risk Minor increase over minimal risk Greater than minor increase over minimal risk Risk is justified by the benefits Risk/benefit is as favorable as alternatives

4. 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?

5. 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)

6. 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?

7. 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 ?

8. 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?

9. “ 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.