Applying Ethical Principles to Research in Pediatric Populations

1
Applying Ethical Principles to Research in
Pediatric Populations

• Robert M. Nelson, M.D., Ph.D.
• Chair, Committee on Bioethics
• American Academy of Pediatrics
• Chair, Committees for the Protection of Human
  Subjects
• The Childrens Hospital of Philadelphia

2
Ethical Standards of the Declaration of Helsinki

• Medical research subject to ethical standards
• Promote respect for all human beings
• Protect their health and rights
• Special protection for the vulnerable

3
Respect for Children

• Declaration of Helsinki (2000)
• Obtain informed consent from parent (24)
• If child capable, obtain assent (25)
• The National Commission (1977, 1979)
• Parental Permission (but within limits)
• Protect childs health and safety (i.e.,
  beneficence)
• Child Assent (not as a right, but a benefit)
• Nurture childs moral growth and developing
  autonomy

4
Beneficence

• Well-being of the child subject takes precedence
  over interests of science and society (5)
• ICH GCP Guidelines 2.3 The rights, safety, and
  well-being of the trial subjects are the most
  important considerations and should prevail over
  interests of science and society.
• The physician in medical research must protect
  life, health, privacy, and dignity of the child
  subject (10)
• Responsibility for the child subject always rests
  with medically qualified person and never with
  the parent, even though parent has given
  permission (15)

5
Justice

• The Belmont Report (1979)
• Fair sharing of burden and benefit of research
• Declaration of Helsinki (2000)
• Medical research only justified if reasonable
  likelihood that population in which research
  carried out may benefit from results (19)
• A child should not be included in research
  unless necessary to promote health of similar
  children and cannot be performed on adults (24)

6
Specifying an Ethical Framework

• Minimal risk (beneficence)
• Establishes proper scope of parental authority in
  exposing child to non-beneficial research risk
• Waive child assent if research beneficial (25?)
• Assent (respect)
• Research presents similar experiences to child
• Disorder or condition (justice)
• Exposure to risk justified by potential direct
  benefit
• If not, incremental risk limited to minor
  increase only if childs experience similar to
  actual situation

7
Additional Safeguards

• Subpart D of 45 CFR 46
• Restricts allowable risk exposure for research
  that does not offer prospect of direct benefit
  (46.404 or 46.406)
• Restricts justification of risk exposure for
  research that offers prospect of direct benefit
  (46.405)
• 21 CFR 50, 56 (FDA Regulations)
• Required to adopt Subpart D by 17 April 2001

8
Research without direct benefit

• Restrict to minimal risk research (404), or
• not greater than ordinarily encountered in daily
  life
• Minor increase over minimal risk (406) if
• Research experience similar to childs own
  situation
• Knowledge of vital importance for understanding
  or treatment of childs disorder or condition
• ICH Good Clinical Practice Guidelines (4.8.14)
• Foreseeable risks are low (same as minimal risk?)
• Negative impact on well-being minimized and low
• Unless exception justified, should be conducted
  in patients having disease or condition for which
  product is intended

9
Minimal Risk

• Definition (46.102(i))
• 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
• Interpretation? (balance respect and justice)
• Daily life of healthy child or sick child?
• Absolute or relative standard of minimal risk?
• Statistical versus normative interpretations?
• A child is or should be exposed to routine
  risks?
• Evaluate from a parents perspective?

10
Prospect of Direct Benefit

• For more than minimal risk research, require
• prospect of direct benefit for individual child
• risk justified by anticipated benefit to child
• risk not justified by resulting knowledge
• relation of anticipated benefit to risk similar
  to available alternatives (i.e., research
  equipoise)
• adequate provisions for child assent and parental
  permission

11
National Review Panel

• Process (advisory to Secretary of DHHS)
• Consultation with a panel of experts
• Opportunity for public review and comment
• Required findings
• reasonable opportunity to understand, prevent, or
  alleviate serious problem affecting children
• conducted according to sound ethical principles
• adequate provisions for assent and permission

12
Controversies

• Exposing healthy children to more than minimal
  risk
• Controls single dose PK studies
• Prevention trials with more than minimal risk
• Disorder or condition? (obesity, schizophrenia)
• Use of placebo controls
• Declaration of Helsinki versus ICH Choice of
  Control Group
• Threshold death or irreversible morbidity?
• Alternative designs to minimize placebo exposure

13
Question

• Fact A medication is approved as safe and
  effective treatment for a condition.
• Principle Genuine uncertainty on the part of the
  expert medical community about the comparative
  therapeutic merits of each arm of a clinical
  trial is required.
• Question Can one ethically perform a
  placebo-controlled trial even though safe and
  effective treatment for that condition exists?

14
Declaration of Helsinki

• The benefits, risks, burdens and effectiveness
  of a new method should be tested against those of
  the best current prophylactic, diagnostic, and
  therapeutic methods. This does not exclude the
  use of placebo, or no treatment, in studies where
  no proven prophylactic, diagnostic or therapeutic
  method exists.

15
Protocol

• Children ages 6 to 11 years with primary
  nocturnal enuresis (bedwetting)
• Approved best current proven treatments
• Imipramine and Desmopressin (DDAVP)
• Only 25 to 50 effective, serious adverse
  reactions
• Study Medication Ibuprofen/pseudoephedrine
• Study Design randomized, placebo-controlled, six
  week duration (baseline, intervention,
  post-intervention baseline), single bedtime dose

16
Placebo/Observational Controls

• No commonly accepted therapy study agent first
  one that may modify course of disease
• Commonly used therapy
• questionable efficacy
• high frequency of undesirable side effects
• risks significantly greater than benefits
• Identify undesirable side effects produced by
  adding new treatment to established regimen
• Disease with frequent, spontaneous exacerbations
  and remissions efficacy of therapy not
  demonstrated

17
Placebos and equipoise

• Substantial doubt regarding net therapeutic
  advantage of standard therapy
• Informed refusal for minor condition no undue
  suffering or irreversible harm of any magnitude
  from withholding therapy
• Effective treatment not available to patients due
  to cost constraints or short supply
• Conditions of justice prevail in health care
  system

18
ICH Choice of Control Group

• Placebo controls may be used if
• No serious harm of withholding effective
  treatment (or)
• Serious harm death or irreversible morbidity
• Effective treatment has severe toxicity
• Voluntary and informed consent required
• Noncoercive setting and patients fully informed

19
Applicability of E-10 to Children

• QUESTION Dr. Temple, the threshold for a
  placebo to be considered is when withholding the
  effective treatment would not result in either
  death or irreversible morbidity. Do you believe
  E-10 discussed that issue in the context of
  pediatrics, and if not, would be appropriate to
  tackle it in E-11?
• DR. TEMPLE I don't think E-10 considered it.
  Informed consent was an important part of its
  consideration. Informed consent is clearly
  different in children. So, I think E-11 probably
  does need to discuss it, but E-10, I don't
  believe did.

20
Application of 46.405 to Placebo Controlled Trial

• Research equipoise essential
• Prospect of direct benefit
• Do not assume safety and efficacy of study
  intervention in analyzing risks and benefits
• Risk justified by anticipated benefit (each arm)
• Equipoise between arms internal to the trial
• Anticipated benefit and risk as favorable as
  available (non-research) alternatives
• Equipoise among trial arms and non-trial
  alternatives

21
Limiting Placebo Exposure

• Active control design
• Equivalence or superiority design
• Three arm trial (decrease subjects exposed)
• Add on trial (in addition to standard care)
• Trial of non-responders to standard care
• Decreased duration of placebo exposure
• Early escape, randomized withdrawal, short term
  trial with physiologic/surrogate endpoint,
  limited PK/PD trial if efficacy can be assumed

22
Sufficient Pediatric Expertise

• Sponsor
• Appropriate protocol design to minimize risk
• Institutional Review/Ethics Board
• Knowledge of pediatric ethical, clinical,
  psychosocial issues
• Consider risks from childs perspective
• Familiar with research designs that minimize risk
• Investigator
• Trained and experienced in studying children,
  including evaluation and management of AEs