Ethical Concerns in Pediatric Placebocontrolled Trials from the European Experience Ethics of Placeb

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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

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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.
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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

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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)

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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.

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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 childs assent or consent

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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 Paediatricians Approach to the
  Best Interests of Children, Slov. Pediatr 2000
  5 10-13.

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The 50th Anniversary of Randomised Controlled
Trials

• BMA/BMJ
• November 1998

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The Paediatricians (Physicians) Concern

• The duty of care
• The standard of care
• The bonus pater familias

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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 Paediatricians Approach to the
  Best Interests of Children, Slov. Pediatr 2000
  5 10-13.

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The Gold Standard

• . . . Properly controlled RCTs form the only
  scientifically valid tools.
• PP De Deyn, J.Pharm.Med. June 2000

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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

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Justification of Randomisation

• Scientific Equipoise
• Personal Equipoise

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Scientific Equipoise

• The medical community is genuinely uncertain as
  to which treatment is best.

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Personal Equipoise

• The patient is herself in a situation of
  uncertainty as to which treatment is best.

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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

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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

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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

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A Question
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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.

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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.

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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.