2. 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

3. Ethical considerations in human subjects research Sound research design without unnecessary risksSound research design without unnecessary risks Risks in proportion with benefits/knowledgeRisks in proportion with benefits/knowledge Safety is maximizedSafety is maximized Subject selection is equitableSubject selection is equitable Privacy and confidentiality is adequatePrivacy and confidentiality is adequate Informed consent is obtainedInformed consent is obtained

4. 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

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

6. Overview The concern about parental challenges in assessing benefits/harms is not about research per se, but about whether an effective clinical intervention is appropriateThe 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 settingThe 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.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.

7. Pediatric care decisions include parental convenience/reassurance Metoclopramide for gastroesophageal refluxMetoclopramide 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 DiapersDiapers –Benefits: convenience of care –Risks: diaper rash

8. Limitations to parental assessments AbilityAbility –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 dehydrationWeight for dehydration Ph probes for GERPh probes for GER Apnea monitors downloads for apneaApnea monitors downloads for apnea Evidence of aspiration pneumonia for swallowing dysfunctionEvidence of aspiration pneumonia for swallowing dysfunction WillingnessWillingness –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 childrenNo reason to think that foster parents are more likely to harm their children

9. 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 benefitsCurrently these children are exposed to potential harms without evidence of benefits Given the lack of evidence, there would be equipoise in a placebo controlled trialGiven the lack of evidence, there would be equipoise in a placebo controlled trial The potential knowledge gained is important to children with swallowing dysfunctionThe potential knowledge gained is important to children with swallowing dysfunction

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

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

12. Conclusion The potential clinical complications of drooling that are similar to those routinely addressed in children by medical and surgical interventionsThe 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 childrenThe 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 trialsThere 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