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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 The Belmont Report BENEFICENCE RESPECT FOR PERSONS JUSTICE PRINCIPLES PRACTICE REGS AND THEIR INTERPRETATION

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protecting children in cancer research what really matters

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

the belmont report

The Belmont Report

BENEFICENCE

RESPECT FOR PERSONS

JUSTICE

principles practice

PRINCIPLESPRACTICE

REGS AND THEIR

INTERPRETATION

pediatric ethics

PEDIATRIC ETHICS

BENEFICENCE

RESPECT FOR PERSONS

JUSTICE

principles of medical ethics
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)
the belmont report7

The Belmont Report

BENEFICENCE:

An obligation with 2 general rules:

Do not harm

Maximize possible benefits and minimize possible harms

the belmont report8

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”

what really matters
What Really Matters:
  • Before a clinical trial begins
  • During the conduct of the trial
  • After a trial has closed
what really matters before a clinical trial begins
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.
approvable research 4 categories
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
research ethics

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

phase i oncology research in children
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...
phase i oncology research in children15
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
alternative medicine

ALTERNATIVE MEDICINE

Vulnerability concerns

Incredibly prevalent

Hard to define

Pediatric differences

Obligation to prevent harm

Need to study

Need to communicate

hospice

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

what really matters during the conduct of the trial
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)
the nuremberg code
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;”)

can we adhere to nuremberg and do pediatric research
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?

how can we respect nuremberg and do pediatric research
How can we respect Nuremberg and do pediatric research?

1) Parents as surrogates: Permission

2) Involve Children: Assent

3) Societal Protection: IRB approval

informed consent vs parental permission
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)
parental permission
Parental Permission
  • Is not the moral equivalent of informed consent.
  • Problems: surrogate decision necessarily less authentic
  • Use of best interests vs. substituted judgement standard
proxy consent
SUBSTITUTED JUDGMENT

subjective

respects autonomy

BEST INTERESTS

objective

promotes beneficence

PROXY CONSENT
assent a research definition
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)

assent clinical vs research
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)
decision making preference
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.

slide30

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

heather k
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
slide32

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

a synergistic approach
A Synergistic Approach

EDUCATION

PROTECTION OF

HUMAN SUBJECTS

REGULATION

what really matters after a trial has closed
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
pediatric research ethics
PEDIATRIC RESEARCH ETHICS:

Best interests

of child-subject

Science to

benefit others

conclusions
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
conclusions37
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
slide38

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.