28 March 2001 The Revised Declaration of Helsinki

Applying Ethical Principles to Applying Ethical Principles to Research in Pediatric Research in Pediatric

PopulationsPopulations

Robert M. Nelson, M.D., Ph.D.Chair, Committee on Bioethics

American Academy of Pediatrics

Chair, Committees for the Protection of Human Subjects

The Children’s Hospital of Philadelphia

Declaration of Helsinki §8

Ethical Standards of the Ethical Standards of the Declaration of HelsinkiDeclaration of Helsinki

Medical research subject to ethical standardsPromote respect for all human beingsProtect their health and rightsSpecial protection for the vulnerable

Research Involving Children (1977); The Belmont Report (1979)

Respect for ChildrenRespect 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 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

Declaration of Helsinki (2000) Paraphrased

BeneficenceBeneficence 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)

JusticeJustice 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)

Specifying an Ethical FrameworkSpecifying an Ethical FrameworkMinimal 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 childDisorder or condition (“justice”)

• Exposure to risk justified by potential direct benefit• If not, incremental risk limited to “minor increase”

only if child’s experience similar to actual situation

Additional SafeguardsAdditional SafeguardsSubpart 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

Research without direct benefitResearch without direct benefitRestrict 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 child’s own situation• Knowledge of vital importance for understanding or treatment

of child’s 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

Minimal RiskMinimal RiskDefinition (§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 parent’s perspective?

§46.405 Greater than Minimal Risk Research

Prospect of Direct BenefitProspect of Direct BenefitFor 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

45 CFR 46.407

National Review PanelNational 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

ControversiesControversies 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

QuestionQuestion 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?

§29, Adopted 52nd WMA General Assembly, October 2000

Declaration of HelsinkiDeclaration 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.”

ProtocolProtocolChildren 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/pseudoephedrineStudy Design: randomized, placebo-controlled,

six week duration (baseline, intervention, post-intervention baseline), single bedtime dose

AAP Committee on Drugs (1995)

Placebo/Observational ControlsPlacebo/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

Tri-Council Policy Statement - Canada (August 1998)

Placebos and equipoisePlacebos 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

ICH E-10 Section 2.1.3 Ethical Issues (July 2000)

ICH: Choice of Control GroupICH: 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

Edited Transcript FDA Pediatric Advisory Subcommittee (09-11-2000)

Applicability of E-10 to ChildrenApplicability 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.”

45 CFR 46.406

Application of §46.405 to Placebo Application of §46.405 to Placebo Controlled TrialControlled Trial

“Research equipoise” essentialProspect 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

Limiting Placebo ExposureLimiting Placebo ExposureActive control design

• Equivalence or superiority designThree arm trial (decrease subjects exposed)Add on trial (in addition to standard care)Trial of non-responders to standard careDecreased duration of placebo exposure

• Early escape, randomized withdrawal, short term trial with physiologic/surrogate endpoint, limited PK/PD trial if efficacy can be assumed

E-11 Clinical Investigation of Medicinal Products in the Pediatric Population

Sufficient Pediatric ExpertiseSufficient Pediatric ExpertiseSponsor

• 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 AEs