Experiments with Static Electricity in the Nursery: Ethical Complexities in Pediatric Research

1. Experiments with Static Electricity in the Nursery:Ethical Complexities in Pediatric Research Benjamin S. Wilfond MD Seattle Children’s Hospital Treuman Katz Center for Pediatric Bioethics Center for Clinical and Translational Research University of Washington Division of Bioethics, Department of Pediatrics Center for Genomics and Healthcare Equality, Department of Bioethics and Humanities Regulatory Support and Bioethics Core, Institute of Translational Health Sciences

3. When are randomized controlled trials appropriate in pediatrics? • Placebo controlled trials of controller medications for asthma?

4. NHLBI asthma guideline adherence in clinical asthma trials including children (n = 70) Coffey, M. J. et al. Pediatrics 2004;113:87-94

5. When are randomized controlled trials appropriate in pediatrics? • Placebo controlled trials of controller medications for asthma? • RCT of newborn screening for cystic fibrosis?

6. Impact of cystic fibrosis newborn screening on height and weight in a trial involving 650,000 randomized children Farrell, P. M. et al. Pediatrics 2001;107:1-13

7. When are randomized controlled trials appropriate for surgical interventions? • Video-assisted thoracoscopic surgery and fibrinolytics for empyema?

8. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema Am J Respir Crit Care Med. 2006 Jul 15;174(2):221-7

9. When are randomized controlled trials appropriate for surgical interventions • Video-assisted thorascopic surgery and fibrinolytics for empyema • Arthroscopic surgery vs placebo surgery for osteoarthritis

10. A controlled trial of arthroscopic surgery for osteoarthritis of the knee N Engl J Med. 2002 Jul 11;347(2):81-8.

11. What is special about pediatric research? • Historically both “understudied” and “overstudied” • Children may be vulnerable to • Not understand the risks and benefits of research • Not be able to object to enrollment • Children may enroll in research • Not in their interest • Against their wishes • “Protecting” children in 45 CFR 46 • Limiting risks • Parental Permission • Adolescent consent • Child Assent

12. 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 404 405 405 Commensurate experiences Address serious problem affecting children Vital knowledge about subjects disorder 404 406 407 Limiting pediatric research based on risks and benefits (45 CFR 46.404-407) No prospect of direct benefit

13. What is Minimal Risk? • The US regulations define minimal risk as: “Probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” 45CFR 46.102(i)

14. Use of minimal risk as criterion for: • IRB review (expedited) • Waiver of consent • Waiver of documentation of consent • Prohibition of some research

15. Survey of IRB Chairs (N=188) Shah S, et al. JAMA 2004 291:476-482

16. Risks of Research Procedures(Wendler and Emanuel 2005)

17. Charitable Participation Standard as a normative interpretation of minimal risk (Wendler and Emanuel 2005) • Children are exposed to risk for the benefit of parents, siblings, and neighbors • Children are exposed to risk for their own psychological benefit in doing charity • Habitat for Humanity, • Shoveling snow for a neighbor • Research is like this type of charity • Minimal risk standard should expose children to the same risks that would be permitted for charitable activities

18. 8 Ethical Benchmarks of Research Collaborative Partnership Social Value Scientific Validity Fair Subject Selection Favorable Risk-Benefit Ratio Independent Review Informed Consent Respect for Human Subjects Emanuel et al. (2000) JAMA; (2004) J Infect Dis

19. Justifications of placebos • Scientific validity • Social value • Risks and benefits • Each arm compared to standard approach • Minimizing risks • Inclusion criteria • Study duration • monitoring

20. Goals are different and constrained by ethical obligations Promote scientific knowledge Benefit to patient and family Clinical Care Research Joffe and Miller. Hastings Center Report 2008

21. Decisional Capacity Ability to understand options Ability to understand consequences of actions Ability to relate consequences to set of personal values Disclosure Reasonable practitioner Reasonable patient Particular patient Comprehension Context dependent Voluntariness Persuasion Coercion Elements of Informed Consent

22. Approaching informed consent • Content • Inverse relationship between disclosure and comprehension • Context • Communication style • Communication setting • Family’s life circumstance and situation • Clinical • Cultural

23. Consent/Assent/Permission • Parental Permission • Not the same as consent • More limited scope and authority than consent • Adolescent Consent • In addition to parental permission • In place of parental permission in some contexts • Child Assent • Not necessary in all research • Not “mini-consent” • Obtaining assent vs respecting “dissent” • Limited disclosure and volunatiness

24. Assent for a blood draw? • Can the parents tell his child she should do it? • What if the child does not understand what the blood will be used for? • What if the child does not know she has a disease? • What if the child says she doesn’t want it? • What if the researchers pays $20 • What if the parents gives his child $20 • What should happened when the child is older: can the research continue?

26. Conclusions • The ethical principles for research are not the same as for clinical care • Randomized controlled trials can be justified based on scientific need/social value and risk/benefit • In pediatric research • Limit exposure to risks • Attention to parental permission • The goal of assent is engage with children in a developmentally appropriate manner: not “mini” assent • Don’t hang babies from ceilings (without a net)