Ethical Considerations in Pediatric Trials

1
Ethical Considerations in Pediatric Trials
William K. Sietsema, PhD Vice President, Clinical
and Regulatory Strategic Planning,
Kendle and Adjunct Professor of Pharmaceutical
Sciences, University of Cincinnati, College of
Pharmacy
2
Topics to be Covered

• Concept that children deserve special protection
• Assent
• Parental permission
• Principles of the Belmont Report
• Concept of exploitation
• Beneficiaries of research adults versus children
• Sequencing adult and pediatric studies
• Use of placebo control groups
• IRB categories of risk
• Investigator payments in pediatric studies
• Improving IRB review of pediatric studies
• Minimizing distress

3
Children Deserve Special Protection
Social justice requires that distinction be
drawn between classes of subjects that ought, and
ought not, to participate in any particular kind
of research, based on the ability of members of
that class to bear burdens and on the
appropriateness of placing further burdens on
already burdened persons. Thus, it can be
considered a matter of social justice that there
is an order of preference in the selection of
classes of subjects (e.g., adults before
children)
The Belmont Report. Ethical Principles and
Guidelines for the Protection of Human Subjects
of Research. The National Commission for the
Protection Of Human Subjects of Biomedical and
Behavioral Research. April 18, 1979
4
But Children Deserve Research, too

• 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
• US Government agrees to need for research as
  evidenced by passing of
• PREA
• BPCA

Eric Kodish, MD, Rainbow Center for Pediatric
Ethics
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Assent

• a childs affirmative agreement to participate
  in a clinical investigation. Mere failure to
  object may not, absent affirmative agreement, be
  construed as assent 21 CFR 50.3(n)
• Only required when IRB judges that the children
  involved are capable of assenting
• IRB takes into account in making that
  determination
• Age
• Maturity
• Psychological state
• Determination can be made for all children in a
  trial or individually
• IRB determines whether and how assent is
  documented

21 CFR 50.55
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When Assent is Not Required

• Capability of the subjects to understand is
  limited
• Generally, below the age of 7
• Intervention holds out prospect of direct benefit
  and is only available in the clinical trial
• Parental permission is still required

21 CFR 50.55 and Guidelines for the Ethical
Conduct of Studies to Evaluate Drugs in Pediatric
Populations. Committee on Drugs. American
Academy of Pediatrics. Pediatrics 95286-294
(1995)
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When Assent May be Waived by IRB

• The investigation is considered minimal risk
• The waiver will not adversely affect the rights
  and welfare of the subjects
• The investigation could not be conducted without
  the waiver
• When appropriate, subjects will be provided with
  additional pertinent information after
  participation
• Consent is still required

21 CFR 50.55
8
Basis of Assent, Belmont Report
Special provision may need to be made when
comprehension is severely limited --- for
example, by conditions of immaturity or mental
disability. Each class of subjects that one might
consider as incompetent (e.g., infants and young
children) should be considered on its own terms.
Even for these persons, however, respect
requires giving them the opportunity to choose to
the extent they are able, whether or not to
participate in research. The objections of these
subjects to involvement should be honored, unless
the research entails providing them a therapy
unavailable elsewhere. Respect for persons also
requires seeking the permission of other parties
in order to protect the subjects from harm.
The Belmont Report. Ethical Principles and
Guidelines for the Protection of Human Subjects
of Research. The National Commission for the
Protection Of Human Subjects of Biomedical and
Behavioral Research. April 18, 1979
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Benefits of Assent to Child

• Assent reminds us that children should be treated
  with dignity and respect
• Permitting children a shared role in decision
  making benefits their development as autonomous
  individuals
• Requirement of assent serves to remind parents
  and investigators that children are persons with
  interests and not mere vessels for the purpose of
  research
• An assent requirement offers school-age children
  the opportunity to learn the meaning of respect
  for others

Diekema DK. Taking Children Seriously Whats so
Important about Assent? American Journal of
Bioethics 3(4)25-26 (2003)
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Parental Consent

• For research subjects under the age of 18 in the
  US
• In the US, permission must generally be obtained
  from both parents
• Exceptions for one parent if
• Other parent is deceased
• Other parent is unknown
• Other parent is incompetent
• Other parent not reasonably available
• Only one parent has legal custody
• IRB may allow permission from only one parent for
  investigations of minimal risk or where there is
  prospect for direct benefit

21 CFR 50.55 also see Diekema DS. Conducting
Ethical Research in Pediatric Emergency Medicine.
Clinical Pediatric Emergency Medicine 4273-284
(2003)
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Basis of Parental Consent,Belmont Report
not every human being is capable of
self-determination. The capacity for
self-determination matures during an individual's
life Respect for the immature and the
incapacitated may require protecting them as they
mature or while they are incapacitated.
The Belmont Report. Ethical Principles and
Guidelines for the Protection of Human Subjects
of Research. The National Commission for the
Protection Of Human Subjects of Biomedical and
Behavioral Research. April 18, 1979
12
Basis of Parental Consent,25 Years After Belmont
Report
Dr. Schwetz As another vulnerable group, do you
think it is appropriate for us today to be
encouraging that research will be done in
children so that we have drugs that have data
that would allow their safe use in children? Dr.
Height I certainly do, but I also think this is
all the more reason why we need to be conscious
of the importance of having surrogates who are
responsible, people who help make responsible
decisions for children. I think this is where we
lie with children, a need to make sure of those
who are speaking for them are responsibly
informed.
From an interview of Dr. Dorothy I. Height,
Belmont Oral History Project, June 30, 2004
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Waiver of Parental Consent

• IRBs should consider waiving parental permission
  for adolescent research participation when
  research
• Is important to adolescent health and well-being
  and cannot reasonably or practically be carried
  out without waiver, or
• Involves treatments that state laws permit
  adolescents to receive without parental
  permission and evidence exists that adolescents
  capable of understanding, and
• Appropriate safeguards included to protect
  interests of adolescent consistent with risk
  presented by research
• Special considerations needed for emancipated
  minors, mature minors, and parents under the
  age of 18 and vary by state

Ethical Conduct of Clinical Research Involving
Children, Recommendation 5.4 (IOM 2004) and
Guidelines for the Ethical Conduct of Studies to
Evaluate Drugs in Pediatric Populations.
American Academy of Pediatrics. Pediatrics
95286-294 (1995)
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Concept of Exploitation

• Are children being exploited in some
  international settings?
• When trials are being conducted in one location
  because they could not be conducted elsewhere?
• When there is no intention to make the therapy
  available to the population in which the test is
  being conducted?
• When trial might be considered unethical in
  another country?

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Example of Proposed SurfaxinTM Trial

• Treatment of Respiratory Distress Syndrome in
  premature infants
• Cost of treatment in US is 2000
• Probable death if untreated
• Company wanted to conduct placebo-controlled
  trial in 325 infants
• Could not conduct in US because treatment is
  generally available and parents would not consent
  to placebo controlled trial
• Trial planned in Latin America, where treatment
  unaffordable
• Following public debate, company agreed not to
  conduct trial
• However, Temple of US FDA defended design on
  basis that without trial, none of the infants
  would be treated and even placebo-treated infants
  would receive better care

London AJ. Justice and the Human Development
Approach to International Research. Hastings
Center Report. January-February 2005
16
Beneficiaries of Research,Adult versus Pediatric

• Primarily children, for a drug intended for
  treating pediatric diseases (e.g. otitis media)
• Primarily adults, for a drug intended for
  treating adult diseases (e.g. hypertension)
• Both adults and children, for a drug generally
  useful for adult and pediatric diseases (e.g.
  dysmenorrhea)

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Sequence of Adult and Pediatric Studies in
Clinical Development

• Where intervention may benefit primarily adults
  or both adults and children, conduct pivotal
  studies in adults first
• Subsequent studies in children only need to
  establish optimal dose level so placebo may be
  avoided
• This approach not an option if intervention
  primarily benefits children or if pediatric
  studies must be first

ICH Guidance E11 Clinical Investigation of
Medicinal Products in the Paediatric Population
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Use of Least Vulnerable Population

• Dont use institutionalized children to study
  intervention in a disease prevalent in
  non-institutionalized subjects
• But use of institutionalized children may be
  appropriate if disease primarily affects those
  children and the intervention cannot be studied
  any other way

ICH Guidance E11 Clinical Investigation of
Medicinal Products in the Paediatric Population
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Need for Placebo Controls

• Placebo should be avoided in pediatric studies
  wherever possible
• Not at the expense of good science
• Poorly controlled study risks not learning from a
  study and undermines potential benefits
• Easier to avoid placebo if adults used to prove
  efficacy
• Placebo controls absolutely unacceptable where
  risk to the subjects may be mortality or
  irreversible morbidity
• Alternative designs may substitute for placebo
  control in some circumstances
• Add-on design with SOC as background
• Randomized withdrawal designs to minimize time on
  placebo

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More on Placebo Controls

• Under federal regulations, for an IRB to approve
  research involving children and an untreated
  placebo control, requires either
• (1) Balance of potential harms and benefits in
  placebo arm must be as favorable as those for
  active treatment, or
• (2) Potential harms in placebo arm are no more
  than minimal or involve only a minor increase
  over minimal risk

From Ethical Conduct of Clinical Research
Involving Children (IOM 2004)
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IRB Categories of Risk

• Minimal risk (21 CFR 50.51)
• Greater than minimal risk with prospect of direct
  benefit to subjects (21 CFR 50.52)
• Greater than minimal risk without prospect of
  direct benefit to subjects (21 CFR 50.53)
• Not otherwise approvable but present opportunity
  to understand, prevent, or alleviate a serious
  health problem affecting children (21 CFR 50.54)

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Minimal Risk Category

• Assent required
• Permission (consent) of parents or guardians
  required

23
Greater than Minimal Risk with Prospect of Direct
Benefit

• IRB must find
• Risks are justified by anticipated benefits to
  the subjects
• Relation of anticipated benefit to risk is at
  least as favorable as that from available
  alternative approaches
• Adequate provisions are made for assent and
  consent

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Greater than Minimal Risk with No Prospect of
Direct Benefit

• IRB must find
• Risk represents a minor increase over minimal
  risk
• Intervention or procedure presents experiences
  reasonably commensurate with those inherent in
  their actual or expected medical, dental,
  psychological, social, or educational situations
• Intervention or procedure likely to yield
  generalizable knowledge about condition that is
  of vital importance to understanding or
  ameliorating condition
• Adequate provisions are made for assent and
  consent (both parents)

25
Not Otherwise Approvable but May Address Serious
Health Problem

• May proceed only if
• IRB finds that the research will address a
  serious health problem affecting children
• FDA commissioner, after consultation with experts
  and following public review
• Agrees with IRB that the research will address a
  serious health problem affecting children
• The investigation will be conducted according to
  sound ethical principles
• That adequate provisions are made for assent and
  consent (both parents)

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Ethics of Investigator Payments

• Investigators and their staffs appropriately
  reimbursed for costs of conducting research
• Finder's fees or bonuses for enrolling a specific
  number of children are unethical and should not
  be permitted.

From Ethical Conduct of Clinical Research
Involving Children, Recommendation 6.4 (IOM 2004)
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Improving Pediatric Expertise of IRBs

• IRBs reviewing pediatric studies should have
  expertise in child health care and research
• At least 3 members with pediatric expertise
  should be present (and voting) when a pediatric
  research protocol is reviewed and should have
  expertise in
• Pediatric clinical care and research
• Psychosocial aspects of child and adolescent
  health care and research
• Ethics of research involving children
• When appropriate, IRBs should consult child
  health experts, parents, children, adolescents,
  and community members who can provide relevant
  perspectives
• IRBs should include at least one nonscientist,
  unaffiliated member who can represent explicitly
  the perspectives of parents and children

From Ethical Conduct of Clinical Research
Involving Children, Recommendation 8.3 (IOM 2004)
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Minimizing Distress

• Studies designed by personnel experienced with
  children
• Use of appropriate formulations and routes of
  administration
• Studies designed for pediatric populations, dont
  copy adult
• Use personnel skilled in pediatric procedures
• Physical setting - furniture, activities, toys,
  food appropriate for age
• Use familiar environment where participants
  normally receive care
• Topical anesthesia for placing catheters
• Catheters instead of repeated venipunctures
• Piggybacking sample collections
• If child becomes upset by procedure, researchers
  should accept this as a valid refusal

ICH Guidance E11 Clinical Investigation of
Medicinal Products in the Paediatric Population
and MRC Ethics Guide. Medical Research Involving
Children. 2004. Medical Research Council.
London, UK.
29
Summary From ICH E11

• Vulnerable, requiring special measures to shield
  from undue risk
• Studies properly designed to insure quality and
  interpretability
• Participants expected to benefit except under
  special circumstances
• IRBs approving pediatric research have members
  knowledgeable in pediatric ethical, clinical, and
  psychosocial issues
• Recruitment free from inducements to parents or
  children
• Compensation to parents/children limited to
  subsistence and must be approved by IRB
• Assent from participant if capable and permission
  from parents
• Use of least vulnerable population in which
  research can be conducted
• Minimize distress by actions and environment

ICH Guidance E11 Clinical Investigation of
Medicinal Products in the Paediatric Population
30
Acknowledgements

• I am grateful for contributions from and
  discussions with the following
• Albert R. Jonsen, PhD, Professor Emeritus of
  Ethics in Medicine, School of Medicine,
  University of Washington, Consultant and Lecturer
  in Bioethics
• Douglas S. Diekema, MD, MPH, Department of
  Pediatrics, Childrens Hospital and Medical
  Center, Seattle