4. Benjamin Waterhouse -
prominent early American
pediatrician, widely credited
for the introduction of
vaccination in the United
States. Tested initial
shipment of smallpox
vaccine from London on his
seven children, then exposed
three to patients with
5. Carl Janson 1891
• "When I began my experiments with black smallpox
pus, I should, perhaps, have chosen animals for the
purpose, but the most fit subjects, calves, were
obtainable only at considerable cost.”
• experiments conducted on 14 children provided
through the “kind permission” of the head physician
of a nearby foundlings’ home.
6. Study Site: Willowbrook State School
Subjects: Severely mentally retarded children
Purpose: Study the natural history of hepatitis
Intervention: Subjects were fed viral laden extracts of
stool (gg+v and v only).
Potential Risk: Chronic liver disease (v only)
Potential Benefit: Immunity via a sub clinical infection
Parental Consent: Coerced by admittance restriction
7. Is it ever ethical to conduct research with
• Research WITH the prospect of benefit:
– “Children are not small adults”
– Essential for safety and efficacy of pediatric interventions
• Research WITHOUT the prospect of benefit:
– 1970’s: McCormick-Ramsey debate
• Ramsey- Children need to be protected;
• McCormick- Research on children is morally acceptable and
8. Justification for “Non-therapeutic”
Research with Children?
• Benefits to child of learning altruism;
• Assumption that children would volunteer
if they could (substituted judgment);
• Obligation of children to contribute to the
• Utility -- the benefits outweigh the risks.
9. History Causes Us to Question
• Is non-therapeutic research on children ever
• Who should decide about children's
participation in research – the child, the
parent, or both?
• On what basis should this decision be made --
benefit to the child or benefit to others?
11. Slide 11
Ethical Principles-Belmont Report
– Do no harm.
– Maximize possible benefits, minimize possible harms.
• Respect for Persons
– Recognize the autonomy of persons.
– Protect those with diminished capacity.
– Informed Consent Process.
– Burdens and benefits of research distributed fairly.
– Fair and just subject selection.
12. Conflict in Ethical Principles?
Respect for Persons
Protect Those with
(Equal Moral Force)
13. The Pendulum Swings
14. Slide 14
Respect for Children
The National Commission (1977, 1979)
Parental Permission (but within limits):
Protect child’s health and safety (i.e., beneficence).
Child Assent (not as a right, but a benefit):
Nurture child’s moral growth and developing autonomy.
ICH GCP E11
When a potential research subject who is deemed
incompetent is able to give assent to decisions about
participation in research, the physician must seek that assent
in addition to the consent of the legally authorized
representative. The potential subject's dissent should be
15. Slide 15
• Declaration of Helsinki (2008)
– For a potential research subject who is incompetent, the physician must seek
informed consent from the legally authorized representative. These individuals
must not be included in a research study that has no likelihood of benefit for them
unless it is intended to promote the health of the population represented by the
potential subject, the research cannot instead be performed with competent
persons, and the research entails only minimal risk and minimal burden. (27)
• ICH GCP E11 Guidelines
Tobe of benefit to those participating in a clinical study, as well as to the
rest of the pediatric population, a clinical study must be properly designed to
ensure the quality and interpretability of the data obtained. In addition, participantsin
study except under the
clinical studies are expected to benefit from the clinical
The Belmont Report (1979)
• Fair sharing of burden and benefit of research
Declaration of Helsinki (2008)
Medical research involving a disadvantaged or vulnerable population or
community is only justified if the research is responsive to the health needs
and priorities of this population or community and if there is a reasonable
likelihood that this population or community stands to benefit from the
results of the research (§17).
ICH GCP E11 ( 2000)
Data on the appropriate use of medicinal products in the pediatric population
should be generated unless the use of a specific medicinal product in
pediatric patients is clearly inappropriate. The timing of initiation of clinical
studies in relation to studies conducted in adults, which may be influenced by
regional public health and medicalneeds.
17. Slide 17
American Academy of Pediatrics 2010
• Have scientific uncertainty with regard to the research question being asked;
• Understand the pathophysiologic features of pediatric illnesses and how they evolve with
• Understand the adverse effects of drugs, drug interactions, and pediatric
• Strive to prevent bias from affecting the design, conduct, or reporting of
the results of the research study;
• Ensure adequate disclosure of all conflicts of interest (COI) related to the research to the
subjects and their families;
• Be an effective communicator and present a balanced view of the risks
and benefits of the research when seeking participation in the study;
• Vigorously guard against scientific misconduct;
• Maintain complete records and;
• Comply with all regulatory, legal, and ethical standards for research in children.
19. Slide 19
Principles for Guidance Risk/Benefit
• Competent adults can agree to place themselves at risk for
benefit of society or others. Need to be careful with children.
• Sliding scale for research involving children:
– classified into one of four categories according to the risk
and the direct benefit to the child.
– as risk-benefit relationship of the research becomes less
favorable, additional requirements must be satisfied.
20. Slide 20
Regulations: Children (United States)
Risk justified by benefit
Risk/benefit is as
favorable as alternative
Parental permission, child
21. Slide 21
Regulations: Children (United States)
potential for direct
subject disorder or
Minor increase over minimal
Intervention presents experiences
commensurate with those inherent
in actual or expected situations
procedure likely to yield
knowledge of vital importance to
understanding or alleviating a
both parents permission, child
22. Slide 22
Regulations:Children (United States)
problem of children
HHS/ FDA panel of experts
23. Minimal Risk
• Establishes proper scope of parental authority in
exposing child to non-beneficial research risk.
• How do we define minimal risk?
• probability and magnitude of harm or discomfort
anticipated in the research are not greater than those
ordinarily encountered in daily life or during routine
physical or psychological examinations or tests;
• Whose ordinary life, that of a normal or sick child?
• Absolute standard (e.g., the healthy child) or;
• Relative standard (e.g., the type of risks to which a particular
child or population involved in experimentation are
24. Daily Life: Rationale
Children whose lives ordinarily involve greater risk (e.g., children
already taking toxic drugs to treat cancer; children who live in
violence- prone neighborhoods) should not be subjected to
greater research risk than other children under the umbrella of
the “minimal risk” definition.
Children living in unsafe environments may be exposed routinely
to risks (i.e. exposure to unhealthy levels of lead), but such risks
are neither socially desirable nor ethical when introduced through
experimental procedures defined as minimal risk.
25. Suggestions for what may be considered routine
physical examinations or tests
• Physical: Well child care is one reasonable basis for comparison
• Routine history taking
• Urine collection via bag
• Chest x-ray
• Bone density test
• Wrist x-ray for bone age
• Vision and hearing testing
• Neurological test
• Oral glucose challenge
• Minor diet changes
26. Suggestions for what may be considered
routine psychological examinations or tests
• Intelligence testing
• Mental and motor scales
• Standard educational tests
• Tests of social development
• Evaluation of
– Family and peer relations
– Emotional regulation
– Feelings of sadness or
• Class room observation
• Consider potential for benefit to the child
• Consider benefits to children as a class in the
future/scientific knowledge (indirect).
28. Slide 28
What is the Risk/Benefit Category ?
• Extra 1 cc of blood for investigational assay;
• Extra biopsy tissue obtained during clinically indicated
kidney biopsy procedure:
– Investigational assay;
– Additional clinical testing to monitor rejection.
• Clinical trial of interferon-alfa and ribavirin for chronic
hepatitis C (requires 2 additional CT scans):
– Open label;
– Placebo versus interferon-alfa & ribavirin.
• Testing new questionnaire to use to ask children about
30. Slide 30
How Do We Get Consent In Pediatric Research?
• Parents cannot give true "consent" – legally only an
autonomous person can do that for themselves. But
parents can and should be respected in their role as
responsible for the child’s welfare (Parental
• Children cannot give true "consent" – they may not
have the legal or cognitive ability to make this
decision. But this does not mean they should have
no say regarding participation (Child assent).
• Even when Assent is not possible, investigators can
and should recognize dissent.
• Affirmative agreement
• Consider active engagement of child in decision
• Need to consider maturity and, psychological,
emotional, developmental state
• Assent not required when
– child not capable; age, maturity, psychological
– research presents direct benefit, important to
child’s well being, available only in context of
– May be cultural differences in different countries
32. Slide 32
Consent and Assent Tips
• Should child/adolescent sign a separate assent form?
Should it be verbal?
• Should one or both parents provide permission?
• Should parents be present or absent when speaking
with child (age dependent)?
• Consider visual methods: pictures, videos, visits to
research location, comic books, work books.
• Appropriate level of language for child.
• Need to recognize developing autonomy of adolescent.
34. Minimizing Risk
Sufficient Pediatric Expertise
• Appropriate protocol design to minimize risk.
Institutional Review/Ethics Board
• Knowledge of pediatric ethical, clinical, psychosocial
• Consider risks from child’s perspective;
• Familiar with research designs that minimize risk.
• Trained and experienced in studying children, including
evaluation and management of adverse events.
E11 Clinical investigational of medicinal products in pediatric population
35. Slide 35
Further Minimization of Risk / Distress
• Utilize all pre-clinical data and clinical safety data
from adults, older children when possible;
• Design study to minimize number of participants
and procedures, consistent with good study design;
• Perform studies at pediatric centers/locations
experienced in research and management of
• Consider implication of research on family as a unit;
• Data safety monitoring plans essential.
36. Slide 36
Further Minimization of Risk / Distress
• Design protocols taking into account medical and
psychological needs of child/family;
• Consider school schedules, follow-up,
• Topical anesthesia prior to blood draws and IV
• Indwelling lines vs. venipunctures;
• Collect samples/perform assessments at time of
38. Slide 38
Payments In Pediatrics
• Balance avoiding “undue influence” against
• Avoid paying parents for use of children;
• Consider 4 components:
– Reimburse (parking, transportation, meals);
– Compensate (time);
– Tokens of Appreciation (gifts, savings bonds, gift
certificates, baby needs (formula, thank you note);
– Incentives (above and beyond those mentioned, used
to influence decision).
39. Slide 39
– Parents requesting access to research information;
– Use of illicit drugs as exclusion criteria;
– When is it necessary to breach confidentiality?
• Immediate harm to self (suicide, some drug dependencies);
• Immediate threat to others (intended homicide).
– What happens with results?
• Respecting developing autonomy
– Large range for emotional and psychological development.
40. Slide 40
• Contraception/Pregnancy Testing
– Confidentiality of adolescent’s sexual activity:
• Determining whether sexually active;
• Contraceptive requirements.
– Pregnancy Testing: Reporting of results:
• Screening to determine eligibility;
• During trial; if positive, need to remove from trial;
• Informed consent considerations.
41. Other Controversial Issues
• Use of normal children (i.e. metabolic studies);
• Pharmacokinetic and toxicity testing;
• Research genetic testing;
• Biobanking of pediatric samples;
• Consent when children turn adults.
42. Slide 42
• Children must be included in research.
• We need to involve children in more research, can’t
• IRB/REC assume an additional responsibility of
considering best interests of child and protection.
• Pediatric expertise at all levels is most important
• Be creative in solutions to allow research to go
• Some research we just cannot do in children.