1 Ethical Concerns in Pediatric Placebo-controlled Trials from the European Experience Ethics of Placebo-controlled Trials in Children FDA Pediatric Advisory Sub-committee Bethesda, MD, USA September 2000 Francis P. Crawley European Forum for Good Clinical Practice & Member, Ethics Working Group Confederation of European Specialists in Paediatrics

2 The interests and the needs of the child should prevail over all other interests in the design, enrolment, and execution of clinical trials involving children.

3 A European Perspective Recent awareness and concern regarding the design and the descriptions of medicines for the paediatric population CPMP Note for Guidance on Clinical Investigation of Medicinal Products in Children (CPMP/EWP/462/95) (September 1997) EFPIA Concept Paper on Clinical Trials in Children (1998) The Ethics Working Group of the Confederation of European Specialists in Paediatrics The Ethics Working Party of the European Forum for Good Clinical Practice

4 An International Framework The Pediatric Rule (1994, 1999) The Food and Drug Administration Modernization Act (FDAMA) (1997) ICH E-11 (2000) WMA Declaration of Ottawa on the Right of the Child for Health Care (1998)

5 A General Position Research on and for children is needed. There should be a demonstrated need to engage children in research What can be learned in research on adults should not be repeated in children.

6 Ethical Dimensions Respect for the dignity and freedom of the child (even where autonomy is limited) Expression of the health interests, concerns, and needs of the child Articulation of the autonomy of the child The primacy of the child’s assent or consent

7 The Paediatrician Through vocation and training able to approach the best interests of the child A protector and an advocate of the rights and the needs of children R. Kurz, The Paediatrician’s Approach to the “Best Interests” of Children, Slov. Pediatr :

8 13 The 50th Anniversary of Randomised Controlled Trials BMA/BMJ November 1998

9 The Paediatrician’s (Physician’s) Concern The duty of care The standard of care The bonus pater familias

10 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 :

11 14 ‘The Gold Standard’ ‘... Properly controlled RCTs form the only scientifically valid tools.’ PP De Deyn, J.Pharm.Med. June 2000

12 16 ‘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

13 17 Justification of Randomisation Scientific Equipoise Personal Equipoise

14 18 Scientific Equipoise The medical community is genuinely uncertain as to which treatment is best.

15 19 Personal Equipoise The patient is herself in a situation of uncertainty as to which treatment is best.

16 20 Helsinki on Control Arms ‘In any medical study, every patient - including those of a control group, if any - should be assured of proven effective prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists.’ Declaration of Helsinki 17.C/WW2//2000

17 22 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

18 23 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

19 A Question

20 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.

21 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:

22 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.