Francis P. Crawley European Forum for Good Clinical Practice & Member, Ethics Working Group Confederation of Europea

1. Ethical Concerns in Pediatric Placebo-controlled Trials from the European ExperienceEthics of Placebo-controlled Trials in ChildrenFDA Pediatric Advisory Sub-committeeBethesda, MD, USA11-12 September 2000 Francis P. CrawleyEuropean Forum for Good Clinical Practice & Member, Ethics Working GroupConfederation of European Specialists in Paediatrics

2. The Paediatrician’s (Physician’s) Concern • The duty of care • The standard of care • The bonus pater familias

3. The Child in the Controlled Trial • ‘. . . it is in the interest of children to evaluate medicinal products with scientifically proven methods. A precondition is minimising distress and risk due to studies.’ R. Kurz, The Paediatrician’s Approach to the “Best Interests” of Children, Slov. Pediatr 2000 5: 10-13.

4. ‘The Gold Standard’ ‘. . . Properly controlled RCTs form the only scientifically valid tools.’ PP De Deyn, J.Pharm.Med. June 2000 14

5. ‘Ethically Justified’ ‘The optimal (and therefore often placebo-controlled and ethically founded) RCT meets the duties of benefiting society and increasing knowledge without jeopardizing the well-being of the experimental subjects.’ PP De Deyn, J.Pharm.Med. June 2000 16

6. Justification of Randomisation • Scientific Equipoise • Personal Equipoise 17

7. Scientific Equipoise The medical community is genuinely uncertain as to which treatment is best. 18

8. Personal Equipoise The patient is herself in a situation of uncertainty as to which treatment is best. 19

9. Risk & Benefit ‘Benefit and risk are ethical commodities determined normatively on the basis of empirically proven preparation [product] characteristics occurring with a certain probability.’ Wagner & Herrmann, Int. J. Pharm. Med. June 2000 22

10. Uncertainty in Science & Ethics ‘For the management of uncertainty, ethical principles are important decision-/action-guiding tools.’ Wagner & Herrmann, Int. J. Pharm. Med. June 2000 23

11. A Question

12. Are placebos and controls ever justified in paediatric research? Yes Both are permissible in some circumstances. Where their use is justified in adults the same may be true in children, subject to consent.

13. Are placebos and controls ever justified in paediatric research? No New treatments should always be tested against old and there is no case for withholding established treatments from children even if the evidence for efficacy is thin. Furthermore, placebos mean deception and controls signify uncertainty of a kind to which children should not be exposed. TL Chambers, ‘Seven Questions about Paediatric Research, Journal of the Royal Society of Medicine 2000, 93: 320-321.

14. Conclusion Paediatric placebo-controlled trials can only be justified when the design, enrollment, and conduct of such trials are such that they address the best interests of the child-participant with a view toward his/her health and a concern with his/her dignity.