The Ethical Conduct of Clinical Research Involving Children

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• The Ethical Conduct of Clinical Research
  Involving Children
• Institute of Medicine
• National Academy of Sciences
• 2004

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IOM/Academies Reports

• Ethical Conduct of Clinical Research Involving
  Children (2004)
• Responsible Research (2003)
• Protecting Participants and Facilitating Social
  and Behavioral Sciences Research (2003)
• View or purchase at www.nap.edu

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CONTEXT FOR IOM STUDY

• Incentives for pediatric research
• 1997 FDA pediatric exclusivity
• 1998 NIH inclusion of children policy
• 2002 Best Pharmaceuticals for Children
• 2003 Pediatric Research Equity Act
• 1997 to 2001 Estimated tripling of children
  participating in clinical trials
• Underscores importance of research protections
  for children

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CHARGE TO IOM COMMITTEE

• Consider definition of minimal risk for purposes
  of approving research involving children
• Assess appropriateness of regulations for
  children of different ages
• Evaluate regulatory compliance
• Consider IRB roles, responsibilities

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CHARGE (contd)

• Examine comprehension of parents and children of
  childs research participation
• Examine process for obtaining parental permission
  and child assent to research participation
• Examine appropriateness of payments to parents or
  children

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REGULATORY FRAMEWORK

• Common Rule (Subpart A) basic regulations to
  protect human research participants developed by
  DHHS now applies to 17 agencies
• Subpart D protections for children also adopted
  by Dept of Education, CIA, and SSA but not, e.g.,
  HUD, EPA, etc.
• FDA similar but separate regulations

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REGULATORY FRAMEWORK

• Some research that can be approved for adults
  cannot be approved for children
• If research with children involves more than
  minimal risk, it must (in brief summary)
• involve only slightly more risk AND children with
  disorder/condition AND vitally important have
  potential for direct benefit OR
• knowledge about the disorder/condition OR
• be approved by DHHS or FDA (rarely)

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DEFINITION Minimal Risk

• Definition in Subpart A
• probability and magnitude of harm or discomfort
  anticipated in research are not greater . . .
  than those ordinarily encountered in daily life
  or . . . in routine physical or psychological
  examinations or tests.

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DEFINITION Minimal Risk

• Interpretation What is minimal risk is same for
  healthy and ill children
• It is not acceptable to approve higher risk in
  research because children to be studied research
  face higher risk in their daily lives (e.g.,
  unsafe homes) or in their medical care (e.g.,
  painful tests or treatments)

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APPROPRIATENESS OF REGULATIONS Recommendations

• All research with children should occur under
  umbrella of formal human research participants
  program that incorporates the protections of
  Subpart D.
• FDA rules should be consistent with other DHHS
  rules allowing waiver of parental permission when
• Permission not in childs best interests
• Other safeguards in place

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COMPLIANCE WITH REGULATIONS Findings

• Lack of dataespecially on research involving
  childrenmake systematic evaluation impossible.
• Considerable evidence of inconsistency in
  interpretation.
• Some evidence of inattention to certain aspects
  of regulations.

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COMPLIANCE WITH REGULATIONS Recommendations

• Need for more explicit federal guidance to
  investigators and IRBs to encourage consistency
  and compliance with Subpart D
• Guidance should be easily located on federal
  IRB web sites
• OHRP, FDA should collect more data to guide
  education, QI, enforcement

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COMPREHENSION OF RESEARCHFindings

• Adultsas parents and in their own rightoften
  misunderstand research
• Therapeutic misconception believing purpose of
  clinical research is to treat rather than gain
  knowledge
• Written information is too complex
• Focus is too often on forms not communication

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COMPREHENSION OF RESEARCH Findings

• Even young children can understand basic
  information about what will happen in research.
• Older adolescents similar to adults in many
  aspects of understanding.
• Education and discussion usually increase
  understanding.

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PERMISSION AND ASSENTBasics

• Instead of informed consent
• Parents provide permission and
• Children, when appropriate, provide their assent
  (or dissent)

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Assent is not informed consent

• Seeking assent is respectful.
• My daughter will be nine years old and she needs
  some kind of input in whats going on. Shes
  presently in a study and I need for her to be
  able to understand what shes getting herself
  into . . . Shes at the point where she asks a
  lot of questions.
• Andrell Vaughn, parent, 2003

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PERMISSION AND ASSENT Recommendations

• Focus on process not forms
• It has to be very interactive process. After I
  was asked this entire list of questions, I began
  to question my own first response. Just giving a
  kid a piece of paper--no matter how
  comprehensible--is not effective. I think the kid
  needs to be prompted with questions.
• Sarah, research participant at age 13

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PERMISSION AND ASSENT Recommendations

• Provide details in protocol on how permission and
  assent will be sought.
• Try to provide written information at 6th grade
  reading level.
• Devise ongoing process for families facing
  serious, acute illness.

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Permission as ongoing process

• There is never enough time in those situations
  to make an informed decision. We signed the
  form because thats what you do.
• Its always at the worst time to be reading this
  type of material . . . Parents arent in control
  nor is the child.
• Joseph Lilly, parent, 2003

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PAYMENTS TO PARENTS OR CHILDREN

• Concern some payments may distort parents or
  childs decisions and lead to choices that are
  not in the childs best interests.
• Findings limited data but evidence of
  considerable variability in practices
• Findings lack of explicit IRB policies and
  guidance for investigators

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PAYMENTS TO PARENTS OR CHILDREN Recommendations

• IRBs should adopt explicit policies on acceptable
  payment practices.
• To equalize access to research participation,
  IRBs, agencies, sponsors should encourage
  investigators to accommodate parental work and
  family commitments.

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PAYMENTS TO PARENTS OR CHILDREN Recommendations

• Okay reasonable reimbursement for expenses of
  being in research
• Okay tokens of appreciation
• Scrutinize carefully payments for childs time
  and inconvenience for research w/o prospect of
  benefit
• Never okay payments to parent or child for
  increased research risk