Protecting Children in Cancer Research: What Really Matters

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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

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The Belmont Report

• BENEFICENCE
• RESPECT FOR PERSONS
• JUSTICE

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PRINCIPLESPRACTICE

REGS AND THEIR INTERPRETATION
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The Geometry of Pediatric Research Ethics
child
parents
investigator
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PEDIATRIC ETHICS

• BENEFICENCE
• RESPECT FOR PERSONS
• JUSTICE

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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)

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The Belmont Report

• BENEFICENCE
• An obligation with 2 general rules
• Do not harm
• Maximize possible benefits and minimize possible
  harms

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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

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What Really Matters

• Before a clinical trial begins
• During the conduct of the trial
• After a trial has closed

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What Really Matters Before a clinical trial
begins

• Significant science The potential to help
  children with cancer.
• RiskBenefit 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.

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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
• RB ratio
• parental permission and assent obtained

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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

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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...

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OPTIONSPHASE I ALTERNATIVE HOPSICE
MEDICINE CARE

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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

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ALTERNATIVE MEDICINE

• Vulnerability concerns
• Incredibly prevalent
• Hard to define
• Pediatric differences
• Obligation to prevent harm
• Need to study
• Need to communicate

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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

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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)

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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)

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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?

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How can we respect Nuremberg and do pediatric
research?

• 1) Parents as surrogates Permission
• 2) Involve Children Assent
• 3) Societal Protection IRB approval

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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 pediatricians 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)

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Parental Permission

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

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PROXY CONSENT

• SUBSTITUTED JUDGMENT
• subjective
• respects autonomy

• BEST INTERESTS
• objective
• promotes beneficence

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Informed Consent in Pediatrics Parental
Permission Assent of Child
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Assent A Research Definition

• A childs affirmative agreement to participate
  in research. Mere failure to object should not,
  absent affirmative agreement, be construed as
  assent.
• -CFR 46.402 (b)

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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)

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DECISION MAKING PREFERENCE

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

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DECISION MAKING PREFERENCE

N 108 parents
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The over-interpretation of regulatory concerns
can prevent the ethically meaningful
participation of children in research. (Heathers
story)
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Heather K.

• Vaginal RMS diagnosed with large tumor causing
  intestinal compression
• Informed consent for non-randomized
• Phase III IRS study signed 605 PM
• Bowel obstruction at 11PM, chemotherapy
  emergently started
• RDE enrollment impossible next AM

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Well-intended regulatory protections can
paradoxically prevent the ethical participation
of children in cancer research.
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A Synergistic Approach
EDUCATION
PROTECTION OF HUMAN SUBJECTS
REGULATION
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What Really MattersAfter a trial has closed

• Monitoring for late effects of therapy
• Publication of results/dissemination of findings
• Return of results to subjects

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PEDIATRIC RESEARCH ETHICS
Best interests of child-subject
Science to benefit others
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CONCLUSIONS

• Beneficence, as described in the Belmont report,
  is the key ethical principle that should guide
  monitoring pediatric oncology patients in studies
• Riskbenefit assessment is more important than
  informed consent

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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

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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.