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Special Ethical Protections for
Pediatric Research Participants:
Subpart D and Assent

Sara F. Goldkind, MD, MA
Bioethicist
Office of the Commissioner
Office of Pediatric Therapeutics

Disclaimer

The information contained in this handout does not represent FDA policy, but the Presenter's summation of the current state of the literature.

FDA Regulations
Protection of Human Subjects
21 CFR 50

• Subpart A: General Provisions
• Subpart B: Informed Consent
• Subpart C: [Reserved]
• Subpart D: Additional Safeguards for Children in Clinical Investigations

Definitions
FDA-------------------DHHS

Definitions
Same for FDA & DHHS

Children--persons who have not attained the legal age for consent to treatments or procedures involved in {clinical investigations/research}, under the applicable law of the jurisdiction in which the {clinical investigations/research} will be conducted

Minimal risk --the probability and magnitude of the harm or discomfort anticipated in the {clinical investigations/research} are not greater in and of themselves that those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests

Categories of Research Involving Children

• 50.51, 46.404: Not involving greater than minimal risk
• 50.52, 46.405: Involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects
• 50.53, 46.406: Involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition
• 50.54, 46.407: Not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

50.51, 46.404: Not involving greater than minimal risk

• IRB determines minimal risk
• IRB finds and documents that adequate provisions are made for soliciting assent from children and permission from of their parents or guardians

50.52, 46.405: Involving greater than minimal risk-prospect of direct benefit to individual subjects

• IRB justifies the risk by the anticipated benefit to the subjects
• The relation of the anticipated benefit to the risk is at least as favorable as that presented by available alternative approaches
• Adequate provisions for assent and permission

50.53, 46.406: Involving greater than minimal risk-no prospect of direct benefit to individual subjects-likely to yield generalizable knowledge about the subject's disorder or condition

• IRB determines the risk represents a minor increase over minimal risk
• The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or educational situations
• Likely to yield generalizable knowledge about the disorder or condition
• Adequate provisions for assent and permission

50.54, 46.407: Not otherwise approvable- opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

• IRB does not believe it can approve the research under the other categories
• Reasonable opportunity to further the understanding of serious problems affecting the health/welfare of children
• Referral to OHRP or FDA or both
  • Involves a panel of experts
  • Involves public review and comment

CONCEPTS CRITICAL TO CLASSIFICATION

• Minimal risk
• Minor increase over minimal risk
• Direct Benefit
• Disorder or condition

Minimal Risk

Regulations do not index it to a particular pediatric population

Minimal Risk

Current consensus-uniform standard rather than a relativistic standard

Institute of Medicine Recommendations -- Minimal Risk

• Normal experiences of average, healthy, normal children (absolute standard)
• Equivalence to the daily lives or experiences in routine physical or psychological examinations or tests
• Relation to the ages of the children to be studied
• Duration as well as the probability and magnitude of potential harms and discomfort

Minor Increase over Minimal Risk

Not Defined in Regulations

Institute of Medicine Recommendations -- Minor Increase Over Minimal Risk

• Slight increase in the potential for harms and discomfort
• Commensurability and comparability to experiences already familiar to the children being studies
• Relation to the ages of the children to be studied
• Duration as well as the probability and magnitude of potential harms and discomfort

Minimal Risk and Minimally
Greater Than Minimal Risk

• Cumulative
  • Types of interventions
  • Times repeated
• Special populations
• Magnitude
• Probability
• Duration
• Age-graded
• Commensurability/comparability

Direct Benefit

• Regulations
• Intervention or procedure that is likely to contribute to the subject's well-being

Institute of Medicine Recommendations -- Direct Benefit

• Analyze the anticipated direct benefits in relation to potential risks-ratio should be at least as favorable for the proposed research as for available alternatives
• Collateral or side-benefits (unrelated to the research) should not be assessed as a potential benefit in relation to potential harms
• Must assess research as a whole (cumulative risk) and each intervention or procedure independently (component risk)

Disorder or Condition

Not Defined in Regulations

Institute of Medicine Recommendations -- Disorder or Condition

• IOM
  • Specific characteristics that an established body of scientific evidence or clinical knowledge has shown to negatively affect children's health and well-being or to increase their risk of developing a health problem in the future

Disorder or Condition

Present and Future Aspects

Informed Consent: Basic Elements

• Study involves research
  • Purpose
  • Expected duration
  • Description of procedures/experimental components
• Reasonably foreseen risks or discomforts
• Reasonably foreseen benefits to the subject or to others
• Appropriate alternatives
• Confidentiality
• Compensation in general and for research-related injury
• Point of contact
• Participation is voluntary

Informed Consent: Additional Elements

• The particular procedure may involve risk to the subject (embryo or fetus)
• Circumstances of termination
• Costs to the subject
• Consequences of withdrawal
• Significant new findings may be communicated
• Approximate number of subjects

Assent

• Respect for persons
• Provides information
• Offers shared decision-making
• Honors dissent
• Allows independent decision-making as appropriate

In Summation: Children's Understanding

• Most studies reported differences between children & adolescents
• Children could understand practical aspects of the research (e.g., what would be done to them) but had a lesser ability to understand more abstract features (alternative treatments, their right-to-withdraw)

In Summation: Younger Adolescents' Understanding

• Variable results in the literature
• Consistent with a continuing maturation of cognitive capacities, most research shows differences between younger and older adolescents' comprehension in general and research rights specifically
• Experience with grave illnesses are more predictive of their understanding (this does not hold true across all studies)

In Summation: Older Adolescents' Understanding

• Variable results in the literature
  • Some studies equate older adolescents with adults and some do not

Some Legal Aspects of Assent

• Some states allow children to assent to minor risk research without parental permission but most states do not have explicit provisions
• Creation of exceptional categories-for most states:
  • Mature minor: is near the age of majority, displays sufficient understanding of medical procedures, and can be medically emancipated in the treatment of certain conditions including STD, pregnancy, drug abuse, contraceptive interventions (not sterilization)
  • Emancipated minor: may be eligible to give consent due to a variety of circumstances-judicial decree, marriage, parenthood, living independently, self-supporting, service in the armed forces

When should assent be solicited?
21 CFR 50.55, 406.408 (a)

• The IRB must determine that adequate provisions are made for soliciting the assent of children when in the judgment of the IRB the children are capable of providing it:
  • Age
  • Maturity
  • Psychological state

When is assent unnecessary?
21 CFR 50.55(c), 46.408 (a)

• The assent of the children is not a necessary condition for proceeding with the clinical investigation if:
  • The capability of some or all of the children is so limited that they cannot be reasonably be consulted
  • The intervention or procedure holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the clinical investigation

When can assent be waived?
21 CFR 50.55 (d) (e), 45 CFR 46.116 (d)

• Even when the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement if it finds and documents that:
  • Involves no more than minimal risk to the subjects
  • Will not adversely affect the rights of the subjects
  • Could not practicably be carried out without the waiver
  • Whenever appropriate the subjects will be provided with pertinent information after participation
  • Parental permission is granted-cannot be waived under FDA regulations except under 21 CFR 50.23 and 21 CFR 50.24

When can assent be waived?
45 CFR 46

• Under certain circumstances 45 CFR 46.116 (c) allows for the waiving of consent (e.g., public health programs)
• 45 CFR 46.116 (d) also allows for the alteration on some or all elements of consent
• 45 CFR 46.408 (c) allows for the waiving of parental permission under certain circumstances when "it is not a reasonable requirement" (neglected or abused children, research related to sexual activity, contraceptives/pregnancy, drug and alcohol abuse may also be considered such circumstances)

How should Informed Consent be documented?
21 CFR 50.27, 21 CFR 56.109

• Informed consent shall be documented in written form except if it finds that the research presents:
  • No more than minimal risk
  • Involves no procedures for which written consent is normally required
• Provisions for reading and informed consent to someone/short form presented orally with written summary and witness
• The consent document would represent a potential harm resulting in breach of confidentiality as the principal risk to the subject (45 CFR 46.117)

Some Nuances

• Federal regulations do not trump local or state laws
• Important case precedents exist regarding assent
• Regulations state IRB's determine documentation of assent 21 CFR 50.55 (f)
• 21 CFR 50.51 (45 CFR 46.404) , 21 CFR 50.52 (45 CFR 46.405) require permission of only one parent
• 21 CFR 50.53 (45 CFR46.406), 21 CFR 50.54 (45 CFR 46.407) require permission of two parents unless . . .

Some Nuances

• Additional exceptions to informed consent under FDA regulations (Narrow and stipulated):
  • 50.23 Exception from general requirements
    • Life-threatening situation requiring use of test article
    • 50.23 the President may waive the prior consent requirement for the administration of an investigational new drug in connection with the member's participation in a particular military operation
  • 50.24 Exception from informed consent requirements for emergency research
    • Life-threatening situation, available treatments are unproven or unsatisfactory

Presentations

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