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Applying the Additional Safeguards for Children: 21 CFR 50, Subpart D. Robert M. Nelson, MD PhD Pediatric Ethicist, Office of Pediatric Therapeutics, Food and Drug Administration. Overview of Presentation. “Nested” Protections for Children (Subpart D)

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Applying the additional safeguards for children 21 cfr 50 subpart d

Applying the Additional Safeguards for Children:21 CFR 50, Subpart D

Robert M. Nelson, MD PhD

Pediatric Ethicist, Office of Pediatric Therapeutics, Food and Drug Administration

Pediatric Research: Challenges Facing IRBs - September 11, 2007

Overview of presentation
Overview of Presentation

  • “Nested” Protections for Children (Subpart D)

    • Scientific Necessity; Appropriate Balance of Risk/Benefit; Parental Permission; Child Assent

  • Case 1: Scientific Necessity; 21 CFR 50.52

  • Cases 2 and 3: Risk Level and Condition - 21 CFR 50.51 and 50.53

  • Case 4: Direct Benefit – 21 CFR 50.52

  • Case 5: EFIC - 21 CFR 50.24; Parental Permission and Child Assent

Clinical investigation
Clinical investigation…

  • means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.

21 CFR 312.3 - IND Application

Nested protections

Scientific Necessity



Appropriate Balance of Risk and Benefit

“Nested” Protections

Parental Permission

21 cfr 56 subpart c
21 CFR 56, Subpart C

  • Minimize Risks [21 CFR 56.111(a)(1)]

    • Eliminate any procedure (as unnecessary) that does not contribute to scientific objective

  • Equitable selection [21 CFR 56.111(b]

    • Subjects capable of informed consent (i.e., adults) should be enrolled prior to children

    • Do not enroll children unless essential (i.e., no other option, whether animal or adult human).

Principle of scientific necessity
Principle of Scientific Necessity

  • Children should not be enrolled in a clinical investigation unless absolutely necessary to answer an important scientific question about the health and welfare of children.

    • Study design capable of answering question

      (e.g., sample size, control group, blinding, etc.)

    • Practical application: “extrapolation”

    • Objective: “public health benefit” for children


  • “If the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the Secretary may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies.”

Pediatric Research Equity Act of 2003

Case 1 sle rct 1 of 3
Case 1: SLE RCT (1 of 3)

  • Unanswered Scientific Questions

    • Adequate Non-clinical animal studies (including juvenile animals) to justify pediatric use?

    • Inclusion Criteria:

      • Currently on steroids for 3 years; rapid taper and transition to investigational drug proven to be without adverse effects.

    • Initial ACE phase of investigation

      • Dose of investigational drug? Criteria for and duration of “stability” (6 months)? Why “unblinded” randomization?

    • Randomized withdrawal phase

      • Start of taper (steroid group: 3 ½ years?) Method and duration of taper? Criteria for failure?

    • Scientific necessity of pediatric trial?

      • Extrapolate efficacy from adults? Exposure-response in children? Availability of PD measures?

Appropriate balance of risk and benefit
Appropriate Balance of Risk and Benefit

Subpart A (adults)

  • Risks are reasonable in relation to anticipated benefits, if any, to subjects and importance of knowledge that may reasonably be expected to result

    21CFR§56.111; 45CFR§46.111

    Subpart D (children)

  • For research not offering the prospect of direct benefit, restricts allowable risk exposure (minimal risk, minor increase over minimal risk; ICH E6 GCP §4.8.14 “low”)

    21CFR§50.51 & §50.53; 45CFR§46.404 & §46.406

  • For research that offers prospect of direct benefit, restricts justification of risk exposure (comparable alternatives)

    21CFR§50.52; 45CFR§46.405

Component analysis
Component Analysis

  • Assess the potential harms and benefits of each intervention or procedure… When some procedures present the prospect of direct benefit and others do not, the potential benefits from one component of the research should not be held to offset or justify the risks presented by another.

    • IOM Recommendation 4.6

Ethical Conduct of Clinical Research Involving Children 2004

Subpart d additional protections for children1
Subpart D: Additional Protections for Children

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily lifeor during the performance of routine physical or psychological examinations or tests.

21 CFR §56.102(i)

Case 1 sle rct 2 of 3
Case 1: SLE RCT (2 of 3)

  • Minimal Risk (21 CFR 50.51)

    • Even with indexing minimal risk to a “healthy” child (as recommended by The National Commission, IOM, NBAC and SACHRP), the assessments included in the protocol description are no more than minimal risk.

    • Note that safety and/or outcome assessments that are necessary due to the administration of an investigational drug may be evaluated as “risks” under 21 CFR 50.52.

Subpart d additional protections for children3
Subpart D: Additional Protections for Children

  • Criteria for Approval:

  • Risk justified by anticipated benefit to subjects (within each arm of study)

  • Relation of anticipated benefit to risk at least as favorable as available alternative approaches (both inside and outside research)

Choice of control group
Choice of Control Group

  • As a general rule, research subjects in the control group of a trial… should receive an established effective intervention. In some circumstances it may be ethically acceptable to use an alternative comparator, such as placebo or "no treatment".

  • Placebo may be used:

    • when there is no established effective intervention

    • when withholding an established effective intervention would expose subjects to, at most, temporary discomfort or delay in relief of symptoms (i.e., only a minor increase over minimal risk)

    • when use of an established effective intervention as comparator would not yield scientifically reliable results and use of placebo would not add any risk of serious or irreversible harm to the subjects

CIOMS Guideline 11; see also ICH E-10 and Clarification to Para. 29 Declaration of Helsinki

Subpart d additional protections for children5
Subpart D: Additional Protections for Children

  • Criteria for approval:

  • only a minor (or slight) increase over minimal risk

  • experiences reasonably commensurate with actual or expected situation

  • yield generalizable knowledge of vital importance for understanding or amelioration of disorder or condition

Case 1 sle rct 3 of 3
Case 1: SLE RCT (3 of 3)

  • The Risks of the Placebo Taper

    • If the steroid taper is conducted according to an established standard of clinical care, it may be considered to offer the “prospect of direct benefit” in reducing steroid exposure

    • If the taper is started earlier (i.e., before three years of stability) and/or occurs more rapidly, the risks should be limited to a minor increase over minimal risk. The availability of a “validated disease surrogate” would support this risk assessment.

    • How this reasoning would be applied to the taper of the investigational drug is unclear in the absence of additional scientific information (such as from adult tapering studies).

Enrolling healthy children
Enrolling “Healthy” Children?

  • Absent “condition,” children cannot be enrolled in more than “minimal risk” research

    • Exception: referral under 21 CFR §50.54 (4th category)

    • “reasonable opportunity” to understand, prevent, or alleviate “serious problem” affecting health or welfare of children; in accord with “sound ethical principles”

  • “Condition” must pertinent to research question

    • Exposure to risk requires scientific justification; not simply baseline exposure to a comparable level of risk

Definition of condition
Definition of Condition

  • a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) 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.

    • IOM Recommendation 4.3

IOM Report on Research Involving Children 2004

Ich e6 good clinical practice 1996
ICH E6 Good Clinical Practice 1996

  • Nontherapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:

    • objectives of trial cannot be met by means of a trial in subjects who can give informed consent personally

    • foreseeable risks to subjects are low

    • negative impact on subject’s well-being is minimized and low

    • trial is not prohibited by law

    • approval/favorable opinion of IRB/IEC is expressly sought on inclusion of such subjects, and written approval/favorable opinion covers this aspect

  • Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended.

Section 4.8.14; also 2001 EU Clinical Trial Directive

Case 2 insulin clamp bmi
Case 2: Insulin Clamp, BMI

  • The risks associated with the performance of the (presumably euglycemic) insulin clamp procedure present a minor increase over minimal risk.

    • Assuming adequate PI/research team expertise

  • Thus the children to be enrolled in this study must have a condition or disorder (i.e., be at risk for type 2 diabetes) under 21 CFR 50.53.

  • Children with a “normal” BMI do not have such a condition. This population could only be included after 21 CFR 50.54 review.

Pediatric advisory committee reviews under 21 cfr 50 54
Pediatric Advisory Committee Reviews under 21 CFR 50.54

  • All three referrals due to lack of condition for research presenting a minor increase over minimal risk.

    • Effects of a Single Dose of Dextroamphetamine in ADHD: A Functional MRI Study (Sept. 2004)

    • Precursor Preferences in Surfactant Synthesis of Newborns (June 2005)

    • Gonadotropin Releasing Hormone (GnRH) Agonist Test in Disorders of Puberty (Nov 2005)

  • Guidance for Clinical Investigators, Institutional Review Boards and Sponsors Process for Handling Referrals to FDA under 21 CFR 50.54


Case 3 autism screening
Case 3: Autism Screening

  • The risks associated with the procedural sedation for the MRI scan may present a minor increase over minimal risk, depending on the anesthetic approach and agents used.

    • Assuming adequate PI/research team expertise

  • Thus the infants to be enrolled in this study must have a condition or disorder under 21 CFR 50.53.

  • Absent criteria that establish such a condition (i.e., at risk for autism spectrum disorder), the MRI scan could only be performed without procedural sedation.

    • Consider using an older age group with behavioral techniques to eliminate the need for procedural sedation.

Case 4 gene therapy for gbm
Case 4: Gene Therapy for GBM

  • A sequential approach (i.e., non-clinical animal models and adult human studies) may be necessary to obtain sufficient data to support either (a) an acceptably low risk of the experimental intervention [50.51 or 50.53] or (b) a sufficient prospect of direct benefit to justify those risks [50.52].

  • A major challenge for new pediatric product development is bridging “gap” between (a) research involving procedures and/or interventions that present only a minor increase over minimal risk [50.53] given absence of sufficient data to establish prospect of direct benefit; and (b) conduct of “proof of concept” or pivotal trials for dosing, safety and/or efficacy that offer a sufficient prospect of direct benefit to the enrolled children to justify exposure to greater than a minor increase over minimal risk [50.52].

21 cfr 312 80 drugs intended to treat life threatening and severely debilitating illnesses
21 CFR 312.80Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

  • The purpose of this section is to establish procedures… to expedite the development… of new therapies intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists. …While the statutory standards of safety and effectiveness apply to all drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those drugs, demand flexibility in applying the standards.

  • FDA has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses. These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated.

Case 5 selected efic requirements
Case 5: Selected EFIC Requirements

  • Life-threatening situation, available treatments unproven or unsatisfactory, need valid evidence for safety and efficacy

  • Obtaining informed consent (IC) not feasible because

    • Subjects unable to give IC as result of medical condition

    • Must intervene before consent from LAR feasible

    • No reasonable way to identify subjects prospectively

  • Research holds prospect of direct benefit because

    • Life-threatening situation that necessitates intervention

    • Preclinical studies support potential for direct benefit

  • Additional protections, including…

    • Community consultation

    • Public disclosure

    • Opportunity, if feasible, to object to participation

21 CFR §50.24

Parental permission
Parental Permission

  • Agreement… to participation of child… in clinical investigation. Permission must be obtained in compliance with 21 CFR §50.20-27 (IC regulation)

    • 21 CFR §50.3(r)

  • Waiver? Only EFIC for emergency research

    • 21 CFR §50.24

  • Children = persons who have not attained legal age for consent to treatments or procedures involved in clinical investigations, under applicable law of jurisdiction [i.e., local study site].

    • 21 CFR §50.3(o)

Case 5 emergent treatment
Case 5 – Emergent Treatment

  • Study Objective: Wound healing

    • Does this study require adolescent population?

  • EFIC? Is injury life-threatening? Is informed consent not feasible within therapeutic window?

  • Although adolescents with self-inflicted injuries may be depressed, have STD or be victim of abuse (with rights to confidential treatment), the intervention does not address (i.e., treat) any of these conditions. Absent EFIC, parental consent would be required as adolescent likely would not have the legal right to consent to the intervention.

FDA Web Page

Link to Peds page