Ethical Issues in Pediatric Research: Antimuscarinics to control the medical and psychosocial complications of drooling

1. Ethical Issues in Pediatric Research:Antimuscarinics to control the medical and psychosocial complications of drooling 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 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

4. Some concerns about studies related to studies of antimuscarinics in children with swallowing dysfunction • Risk/benefit • Who decides if “drooling” is severe enough to warrant study enrollment: • Might parents want an intervention for their convenience? • How are side effects assessed in children with limited ability to communicate: • Might children be harmed without others realizing it? • Might parents minimize side-effects to continue in the trial? • Equity: • Enrollment of children whose are not in the custody of their parents: • Is it wrong to exclude them? • Deny access to important intervention • Is it wrong to include them? • Take advantage of particularly vulnerable children

5. Overview • The concern about parental challenges in assessing benefits/harms is not about research per se, but about whether an effective clinical intervention is appropriate • The benefit/harms of enrolling a child in a study is as favorable as the alternative of using these unstudied drugs in a clinical setting • While there may not a compelling reason to exclude children who are not in the custody of parents from such trials, it would not be desirable to emphasize recruiting such subjects.

6. Pediatric care decisions include parental convenience/reassurance • Metoclopramide for gastroesophageal reflux • Benefits: decrease aspiration or apnea, less clothes to wash • Risks: sedation, dystonic reactions Apnea monitors for children with reflux associated apnea: • Benefits: reassurance • Risks: false alarms, parental distress • Diapers • Benefits: convenience of care • Risks: diaper rash

7. Limitations to parental assessments • Ability • It is routine to rely on parents to make observations about infants • Even well meaning parents may not provide accurate historical information about infants • Objective assessments can be helpful • Weight for dehydration • Ph probes for GER • Apnea monitors downloads for apnea • Evidence of aspiration pneumonia for swallowing dysfunction • Willingness • Most parents make reasonable decisions • Some parents take actions that harm their children • No reason to think that foster parents are more likely to harm their children

8. Antimuscarinics are routinely used in children with swallowing dysfunction without the benefits of clinical trials • Currently these children are exposed to potential harms without evidence of benefits • Given the lack of evidence, there would be equipoise in a placebo controlled trial • The potential knowledge gained is important to children with swallowing dysfunction

9. IRB evaluation • Clinical trials would be approved under 45CFR46.405 as this would be an intervention that offers a prospect of direct benefit • Special provisions for “wards of the state” only apply to 406 and 407 (no prospect of direct benefit and more than minimal risk)

10. Should IRBs limit enrollment decisions to children living with their parents? • It would avoid recruitment from more vulnerable settings, ie residential settings • Children in these settings already have access to these medications • Most children with swallowing dysfunction live with their parents • Scientific objectives can be met without enrolling children who do not live with their parents

11. Conclusion • The potential clinical complications of drooling that are similar to those routinely addressed in children by medical and surgical interventions • The challenges of assessing benefit and risk in inherent in any trial in young children • There is no reason to be more critical of parents of children with disabilities in making enrollment decisions or assessments than in for other pediatric trials