PEDIATRIC ETHICS AND CHILDHOOD CANCER RESEARCH

1. PEDIATRIC ETHICSAND CHILDHOOD CANCER RESEARCH Eric Kodish, M.D. Rainbow Center for Pediatric Ethics Rainbow Babies and Childrens Hospital

2. American Academy of Pediatrics Vision Statement “We believe in the inherent worth of all children. The are our most enduring and vulnerable legacy.” -AAP 1999

3. PEDIATRIC ETHICS BENEFICENCE RESPECT FOR PERSONS JUSTICE

4. Principles of Medical Ethics • Respect for Persons is dominant principle for adult ethics (autonomy) • Beneficence is dominant principle for pediatric ethics (best interests of child)

5. The Geometry of Pediatric Ethics child parents clinician

6. Two Questions in Pediatric Ethics Should a particular therapy be given? BENEFICENCE Who should make a consent decision? AUTONOMY The answers may be incompatible

7. Informed Consent vs. Parental Permission • Autonomous authorization of adults on their own behalf is more robust than parental permission for children by proxy/surrogate • “…the pediatrician’s responsibilities to his or her patient exist independent of parental desires or proxy consent.” (American Academy of Pediatrics 1995 statement on informed consent, parental permission, and assent in pediatric practice)

8. Parental Permission • Is not the moral equivalent of informed consent. • Problems: surrogate decision necessarily less authentic • Use of best interests vs. substituted judgement standard

9. SUBSTITUTED JUDGMENT subjective respects autonomy BEST INTERESTS objective promotes beneficence PROXY CONSENT

10. Informed Consent in Pediatrics =Parental Permission + Assent of Child

11. Assent: A Clinical Definition • Awareness of the nature of his/her condition • What to expect with tests and treatment(s) • Assessment of understanding (including pressure to accept/assent) • Soliciting* an expression of willingness to accept the proposed test/treatment

12. Assent: A Clinical Definition *Regarding this final point, we note that no one should solicit a patient's views without intending to weigh them seriously. In situations in which the patient will have to receive medical care despite his or her objection, the patient should be told that fact and should not be deceived. -AAP COB ‘95

13. Assent: A Research Definition “A child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.” -CFR 46.402 (b)

14. Assent: Clinical vs. Research • Research is supererogatory • Assent/dissent determinative in research but not in clinical context • Veto power for all 3 moral actors? • For all studies, the older the child the more ethically justifiable (if assent is provided)

15. Informed Consent Data* • Direct Observation and audiotaping of consent process for children recruited to CCG leukemia RCTs, followed by extensive parent interviews and clinician reports. • Findings: The RCT is generally explained, but many parents do not understand their choice about the clinical trial (32%), and do not understand randomization (52%) • Minorities and those in lower social position are at greatest risk for non-understanding, and ask fewer questions. • This data may not be generalizable to the relapse context but is a potential concern for Phase II Window studies (*funded by RO1CA83267)

16. DECISION MAKING PREFERENCE: I prefer: 1. to leave all decisions regarding treatment to my child’s doctor. 2. that my child’s doctor makes the final decision about which treatment will be used, but seriously considers my opinion. 3. that my child’s doctor and I share responsibility for deciding which treatment is best. 4.to make the final selection of my child’s treatment after seriously considering my doctor’s opinion. 5.to make the final selection about which treatment my child will receive.

17. DECISION MAKING PREFERENCE: N = 108 parents

18. Parent Questions by Race and Social Class

19. Log of Parent Questions by Race and Social Position All cases ANOVA=.002

20. THE NUREMBERG CODE 1. The voluntary consent of the human subject is absolutely essential. (“This means that the person involved should have legal capacity to give consent;”)

21. Can we adhere to Nuremberg and do pediatric research? If the answer is no, children as a group will suffer. If the answer is yes, how can children be adequately protected?

22. How can we respect Nuremberg and do pediatric research? 1) Parents as surrogates: Permission 2) Involve Children: Assent 3) Societal Protection: IRB approval

23. Approvable Research: 4 categories: 46.405 2) Involving greater than minimal risk but presenting the prospect of direct benefit to the individual subject, if: • risk justified by anticipated benefit to subject • R:B ratio < alternatives • parental permission and assent obtained

24. RESEARCH ETHICS: RISK always means to the subject BENEFIT may include: benefits to the subject benefits to other patients benefits to society (i.e., knowledge) benefits to investigator/sponsor

25. PEDIATRIC RESEARCH ETHICS: Best interests of child-subject Science to benefit others

26. PHASE I ONCOLOGY RESEARCH IN CHILDREN • The controversy over “therapeutic intent” • Commensurate experience: (46.406 creep) --should not be a valid justification • Prospect of direct benefit is the ethical and regulatory key • Problems defining benefit: more than a tumor measurement • Considering the alternatives...

27. OPTIONSPHASE I ALTERNATIVE HOPSICE MEDICINE CARE

28. OPTIONS(pathways to hope??)PHASE I ALTERNATIVE HOPSICE MEDICINE CARE

29. PHASE I ONCOLOGY RESEARCH IN CHILDREN • Subject selection is not a controversy • Qualifies as “research with the prospect of direct benefit” • Potential for benefit mitigates but does not eliminate the need for protection from research risk

30. ALTERNATIVE MEDICINE Vulnerability concerns Incredibly prevalent Hard to define Pediatric differences Obligation to prevent harm Need to study Need to communicate

31. HOSPICE Not incompatible with Phase I study Underdeveloped in children, needs advocacy approach Reject the idea of a “right” way to die; each child and family is unique Must be part of the consent process for Phase I studies: a responsibility to the dying child

32. PHASE II WINDOW DESIGN • Subject selection controversial: How poor is “poor prognosis?” Context is everything. • Qualifies as “research with the prospect of direct benefit,” but may not be as good for the subject as alternatives (multi-agent) • New therapeutic paradigms may change ethical acceptability of these studies.

33. CONCLUSIONS • Good ethics starts with good science; but good science is not inherently ethical. • It follows that some research with tantalizing potential may need to be rejected on ethical grounds. • Accelerated drug development research in childhood cancer should proceed, but long-term follow up data must be collected and analyzed.

34. Children are both vulnerable subjects in need of protection from research risks and a neglected class that needs better access to the benefits of research.