Protecting Children in Cancer Research: What Really Matters

1. Protecting Children in Cancer Research: What Really Matters Eric Kodish, M.D. Rainbow Center for Pediatric Ethics Rainbow Babies and Childrens Hospital Case Medical School

2. The Belmont Report BENEFICENCE RESPECT FOR PERSONS JUSTICE

3. PRINCIPLESPRACTICE REGS AND THEIR INTERPRETATION

4. The Geometry of Pediatric Research Ethics child parents investigator

5. PEDIATRIC ETHICS BENEFICENCE RESPECT FOR PERSONS JUSTICE

6. 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)

7. The Belmont Report BENEFICENCE: An obligation with 2 general rules: Do not harm Maximize possible benefits and minimize possible harms

8. The Belmont Report BENEFICENCE: “not always so unambiguous” i.e., prohibiting “research that presents more than minimal risk without immediate prospect of direct benefit to children involved….limits potential for great benefit to children in the future”

9. What Really Matters: • Before a clinical trial begins • During the conduct of the trial • After a trial has closed

10. What Really Matters: Before a clinical trial begins • Significant science: The potential to help children with cancer. • Risk:Benefit assessment • Study design that will 1)answer the question and 2) does not subjugate the interests of any single subject to the needs of the research.

11. 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

12. 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

13. 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...

14. OPTIONSPHASE I ALTERNATIVE HOPSICE MEDICINE CARE

15. 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

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

17. 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

18. What Really Matters: During the conduct of the trial • Informed Consent • Ongoing monitoring (DSMB) • Ethical action to suspend/stop a study at the right time: (not too soon but not too late)

19. 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;”)

20. 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?

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

22. 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)

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

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

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

26. 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)

27. 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)

28. 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.

29. DECISION MAKING PREFERENCE: N = 108 parents

30. The over-interpretation of regulatory concerns can prevent the ethically meaningful participation of children in research. (Heather’s story)

31. Heather K. • Vaginal RMS diagnosed with large tumor causing intestinal compression • Informed consent for non-randomized Phase III IRS study signed 6:05 PM • Bowel obstruction at 11PM, chemotherapy emergently started • RDE enrollment impossible next AM

32. Well-intended regulatory protections can paradoxically prevent the ethical participation of children in cancer research.

33. A Synergistic Approach EDUCATION PROTECTION OF HUMAN SUBJECTS REGULATION

34. What Really Matters:After a trial has closed • Monitoring for late effects of therapy • Publication of results/dissemination of findings • Return of results to subjects

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

36. CONCLUSIONS • Beneficence, as described in the Belmont report, is the key ethical principle that should guide monitoring pediatric oncology patients in studies • Risk:benefit assessment is more important than informed consent

37. CONCLUSIONS • The protection of children from research risk and the imperative to improve the treatment of childhood cancer are both ethically important • Regulatory fervor intended to protect children currently threatens the ethical conduct of pediatric cancer research

38. 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.