1. Research Involving
Children & Adolescents
Susan Kornetsky, MPH, CIP
Director, Clinical Research Compliance
Children’s Hospital, Boston
Slide 1

2. Slide 2
• History
• Ethical principles and vulnerability
• Risk/ benefit assessment
• Parental permission and assent
• Minimizing risks and distress in pediatrics
• Other issues
– Payments
– Adolescents
– Other Issues

3. Edward Jenner
18th century
Children used for
medical immunization
experiments
Slide 3

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
smallpox.
Slide 4

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
children?
• 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
morally obligatory.

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
community;
• Utility -- the benefits outweigh the risks.

9. History Causes Us to Question
• Is non-therapeutic research on children ever
justified?
• 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?

10. “Therapeutic Orphans”
From 1973-1997, the
percentage of FDA
approved drugs which
contained no pediatric
labeling was 71-81%.

11. Slide 11
Ethical Principles-Belmont Report
• Beneficence
– 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.
• Justice
– Burdens and benefits of research distributed fairly.
– Fair and just subject selection.

12. Conflict in Ethical Principles?
Respect for Persons
Protect Those with
Limited Autonomy
Limit Research
with Children
(Conflict)
(Equal Moral Force)
Fair Share
Research Benefits
Promote Research
in Children
Slide 12

13. The Pendulum Swings
• Protect/Restrict
Therapeutic orphans
Liability
High Cost
Small Market
Promote/Provide Incentives
Slide 13
Inclusion
Patent Extensions

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
respected. (28)

15. Slide 15
Beneficence
• 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
special circumstances.

16. Justice
 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
Investigators must:
• Have scientific uncertainty with regard to the research question being asked;
• Understand the pathophysiologic features of pediatric illnesses and how they evolve with
age;
• Understand the adverse effects of drugs, drug interactions, and pediatric
drug formulations;
• 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.

18. Risk /Benefit

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)
Category
Minimal risk
Greater than
minimal risk;
potential for
direct benefit
Requirements
Parental Permission
Child’s assent
Risk justified by benefit
Risk/benefit is as
favorable as alternative
Parental permission, child
assent

21. Slide 21
Regulations: Children (United States)
Category
Greater than
minimal: no
potential for direct
benefit;yield
generalizable
knowledge about
subject disorder or
condition
Requirements
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
condition
both parents permission, child
assent

22. Slide 22
Regulations:Children (United States)
Category Requirements
Not otherwise
approvable but
opportunity to
understand, prevent,
alleviate serious
problem of children
HHS/ FDA panel of experts
to review
Public Comment
Parental permission/assent

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
typically exposed).

24. Daily Life: Rationale
Slide 24
 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
• Venipuncture/fingerstick/heelstick
• 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
hopelessness
• Class room observation

27. Benefits
• Consider potential for benefit to the child
subject (direct);
• 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
abusive situations.

29. Slide 29
Parental Permission/Assent

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
permission).
• 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.

31. Assent
• Affirmative agreement
• Consider active engagement of child in decision
process
• Need to consider maturity and, psychological,
emotional, developmental state
• Assent not required when
– child not capable; age, maturity, psychological
state, coma
– research presents direct benefit, important to
child’s well being, available only in context of
research
– May be cultural differences in different countries
Slide 31

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.

33. Slide 33
Minimizing Risk and Distress in
Pediatric Research

34. Minimizing Risk
Sufficient Pediatric Expertise
 Sponsor
• Appropriate protocol design to minimize risk.
 Institutional Review/Ethics Board
• Knowledge of pediatric ethical, clinical, psychosocial
issues;
• Consider risks from child’s perspective;
• Familiar with research designs that minimize risk.
 Investigator
• 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
pediatric subjects;
• 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,
convenience;
• Topical anesthesia prior to blood draws and IV
catheters;
• Indwelling lines vs. venipunctures;
• Collect samples/perform assessments at time of
clinical procedures

37. Slide 37
Other Issues

38. Slide 38
Payments In Pediatrics
• Balance avoiding “undue influence” against
“reducing barriers”;
• 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
Adolescent Research
• Confidentiality
– 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).
• Privacy
– What happens with results?
• Respecting developing autonomy
– Large range for emotional and psychological development.

40. Slide 40
Adolescent Research
• 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.
Slide 41

42. Slide 42
Conclusion
• Children must be included in research.
• We need to involve children in more research, can’t
“over protect”.
• IRB/REC assume an additional responsibility of
considering best interests of child and protection.
• Pediatric expertise at all levels is most important
protection.
• Be creative in solutions to allow research to go
forward.
• Some research we just cannot do in children.