Ethical Considerations for Clinical Investigations

of Medical Products Involving Children

Draft Guidance for Industry, Sponsors, and IRBs

What is covered in this 

guidance?

This draft guidance describes 

the FDA’s current thinking 

regarding ethical considerations 

for clinical investigations of medical products in 

children and provides a detailed description of the 

additional human subject protection regulations 

that are included in 21 CFR 50, subpart D (Additional 

Safeguards for Children in Clinical Investigations).

Who are children? For the purposes of this 

draft guidance, children include neonates, 

infants, children, and adolescents who have 

not reached the legal age of consent in their 

local jurisdiction.

Why is this guidance 

important?

Clinical investigations in children 

are essential for obtaining data on 

the safety and effectiveness of drugs, 

biological products, and medical devices in children 

and to protect children from the risks associated with 

exposure to medical products that may be unsafe 

or ineffective. Children are a vulnerable population 

who cannot consent for themselves and therefore are 

afforded additional safeguards when participating in a 

clinical investigation. This draft guidance is intended 

to assist industry, sponsors, and institutional review 

boards (IRBs) when considering the enrollment of 

children in clinical investigations of medical products.

How is this snapshot helpful?

This snapshot provides an overview of the draft 

guidance to:

Summarize the steps for considering 

enrollment of children in a clinical 

investigation using the ethical framework 

in 21 CFR 50, subpart D

Present a high-level perspective of the 

draft guidance contents

Consolidate information in the draft 

guidance into a brief and easy-to-read 

resource

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about ethical considerations for clinical investigations of medical products involving 

children, read the guidance.

www.fda.gov 1
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about ethical considerations for clinical investigations of medical products involving 

children, read the guidance.

www.fda.gov 2

 STEP

01

 STEP

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Steps for Considering Enrollment of Children in a Clinical 

Investigation Using the Ethical Framework in 21 CFR Part 50, Subpart D

SCIENTIFIC NECESSITY

Consider the principle of scientific necessity (see draft guidance section III.A)

Children should not be enrolled into a clinical investigation unless their participation 

is necessary to answer an important scientific and/or public health question directly 

relevant to the health and welfare of children. 

 [ EXAMPLE ] Pediatric Extrapolation

For products that are being developed for use in adults and children, if effectiveness in 

adults can be extrapolated to children, then effectiveness studies in adults should be 

conducted to minimize the need to collect effectiveness data in children.

ETHICAL FRAMEWORK

Review the clinical investigation to determine whether it satisfies the criteria described 

in 21 CFR 50.51, 50.52, or 50.53 (see draft guidance section III)

Clinical investigations not involving greater than 

minimal risk 50.51

50.52

50.53

Clinical investigations involving greater than minimal 

risk but presenting the prospect of direct benefit to 

individual subjects

Clinical investigations involving greater than minimal 

risk (but no more than a minor increase over minimal 

risk) and no prospect of direct benefit to individual 

subjects, but likely to yield generalizable knowledge 

about the subjects’ disorder or condition

21 CFR
www.fda.gov 3 21 CFR

50.51 50.52 50.53

Definitions

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 

life or during the performance of 

routine physical or psychological 

examinations or tests

Prospect of direct benefit refers to 

the potential benefit to the individual child from exposure to the 

research intervention or procedure 

being studied (e.g., the investigational drug or medical device) in the 

clinical investigation

Minor increase over minimal 

risk should be understood to 

mean a slight increase over 

minimal risk that poses no 

significant threat to the child’s 

overall health or well-being

Interpretation

• The standard of minimal risk

should be interpreted as those

risks encountered in the daily

life of normal, average, healthy,

children living in safe environments and indexed to the

experiences of children of the

same age and developmental

stage as the subject population

• Given that investigational drugs

generally are considered to

have the potential to cause

harm, an investigational drug

utilized in a clinical investigation that includes children is not

considered minimal risk

• Prospect of direct benefit refers

to potential clinical benefit

directly from the research intervention or procedure, not from

ancillary interventions or procedures done as part of the trial

• An IRB must find not only that the

risk is justified by the anticipated

benefit to the child, but also the

relation of the anticipated benefit

to the risk is at least as favorable

as any available alternatives

• Assessment of risk is predicated

on adequate safety data. All

available relevant clinical and/or

nonclinical safety data should be

included in the risk analysis

• Any potential harms with the

intervention or procedure

should be expected to be

transient and reversible and

the probability for severe

pain, discomfort, or harm

should be extremely small or

nonexistent

• The intervention or procedure must be likely to yield

generalizable knowledge

about the subjects’ disorder

or condition that is of vital

importance for the understanding or amelioration

of the subjects’ disorder or

condition

Examples

Procedures considered “minimal 

risk” may include single blood 

draw, physical exam, chest x-ray, 

surveys

Data are required to establish proof 

of concept and support that the 

proposed dose (or device characteristics) and duration of exposure 

to the intervention or procedure are 

adequate to offer potential clinical 

benefit 

(see Assessment of Prospect 

of Direct Benefit)

Procedures that might be 

considered a “minor increase 

over minimal risk” may include 

urine collection via a catheter, 

bone marrow aspirate with 

topical pain relief, a single 

lumbar puncture, a single dose 

of an investigational drug with 

adequate safety information

Take Home Points

• Healthy children may be

enrolled

• Not appropriate for trials of

investigational medical products

• The child must have the prospect of benefiting from the

intervention and the anticipated

benefit must justify the risks

• Common basis for IRB approval

of trials of investigational medical products

• The child must have the

disorder or be at risk for the

disorder, the knowledge to

be gained about the disorder

must be vital, and the risk

must not pose a significant

threat to the child’s health

21 CFR Section Comparison Table STEP

02
www.fda.gov 4

The necessary evidence to determine prospect of direct benefit for a pediatric clinical investigation may 

be based on one or more sources of information. When adult data are available in conditions that exist both 

in adults and children, evidence of clinical benefit from the drug or device in adults can provide support 

for prospect of direct benefit before clinical investigations are initiated in children. For conditions whose 

manifestations occur primarily or exclusively in children, collection of adult data evaluating the drug or 

device may not be available or feasible. In those cases, nonclinical data obtained in a relevant animal or in 

vitro model for the condition of interest may often be the only source of information to support prospect of 

direct benefit. Relevant animal or device modeling and simulation data may provide evidence of prospect of 

direct benefit and may preclude or mitigate the need to preliminarily collect relevant adult data. (See draft 

guidance sections III.C and IV.A.)

 ASSESSMENT OF PROSPECT OF DIRECT BENEFIT

 STEP

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COMPONENT ANALYSIS

Conduct a component analysis of the clinical investigation to determine whether each 

intervention or procedure satisfies the regulatory requirements under 21 CFR 50, 

subpart D (see draft guidance section III.E)

A research protocol may include multiple research-related interventions or procedures, 

some that offer prospect of direct benefit and some that do not. Any intervention or 

procedure conducted solely for research purposes (not needed for clinical management 

or routine clinical care) should be evaluated separately to determine whether it offers 

prospect of direct benefit to the enrolled child (known as a “component analysis” of 

risk). If a specific intervention or procedure does not offer prospect of direct benefit, the 

risk of the intervention or procedure should be limited to a minor increase over minimal 

risk, and meet the other conditions outlined under 21 CFR 50.53. 

 [ EXAMPLE ] Placebo

The risks associated with the administration of a placebo in a clinical investigation 

should be part of the component analysis of risk. For children enrolled in the 

active study arm of a placebo-controlled clinical investigation, there is prospect of 

direct benefit that is offered by the investigational medical product; for children in 

the placebo arm, however, there is no prospect of direct benefit from the placebo 

intervention or procedure. See the draft guidance for a discussion of factors to 

consider when assessing risks to children in the placebo arm of a trial.

 [ EXAMPLE ] Nontherapeutic Procedural Sedation

Procedures in children in a clinical trial may require sedation and the risks of sedation 

needed for nonbeneficial “research only” (nontherapeutic) procedures should be 

considered. See the draft guidance to review the considerations for the use of sedation 

for nontherapeutic procedures agreed upon by the Pediatric Ethics Subcommittee of 

the FDA’s Pediatric Advisory Committee in March 2015.

STEP

02
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about ethical considerations for clinical investigations of medical products involving 

children, read the guidance.

www.fda.gov 5

 STEP

04

STOP

PARENTAL/GUARDIAN PERMISSION AND CHILD ASSENT

Evaluate the trial’s requirements and processes for permission and assent (see draft 

guidance section III.G)

A clinical investigator must obtain permission from the parent(s) or guardian when 

a child is enrolled in a clinical investigation (21 CFR 50.55(e)). The parental/guardian 

permission form must address the required elements and appropriate additional 

elements of consent (see 21 CFR 50.25) to allow the parent(s) or guardian to make an 

informed decision. Unless the IRB waives the requirement, adequate provisions must be 

made for soliciting assent from the child if the IRB determines that the child is capable 

of providing assent (21 CFR 50.55(a)).

Informed consent is a process; parents, guardians, and assenting children should 

be given the opportunity to ask questions when considering study participation and 

continue to be provided information as the study progresses and the situation requires.

POTENTIAL FOR REVIEW PER 21 CFR 50.54

If the protocol does not meet the criteria under 50.51, 50.52, or 50.53, IRBs may 

consider the potential for review per 21 CFR 50.54.

For example, if an intervention or a procedure in a pediatric protocol exceeds a minor 

increase over minimal risk and does not offer prospect of direct benefit, the protocol is 

not approvable by an IRB under 21 CFR 50.51, 50.52, or 50.53. 

If an IRB finds that the research presents a reasonable opportunity to further the 

understanding, prevention, or alleviation of a problem affecting the health or welfare 

of children, the IRB can refer the protocol to the FDA for review and consultation with a 

panel of experts and for public review and comment in accordance with the provisions 

under 21 CFR 50.54 (see draft guidance section III.F).

 [ EXAMPLE ]

Children 7 years of age and older are often considered capable of assent; however, the 

age, maturity, and psychological state (mental capacity and developmental stage) of 

the child involved in the research must be considered.
www.fda.gov 6

Guidance Snapshots are a communication tool and are not a substitute for the guidance document.

To learn more about ethical considerations for clinical investigations of medical products involving 

children, read the guidance. 

To see additional Guidance Snapshots, check out the pilot program.

 CODE OF FEDERAL REGULATIONS (CFR)

for the protection of human subjects involved in FDA-regulated research

21 CFR Part 50 Protection of Human Subjects 

21 CFR 50, Subpart A General Provisions 

21 CFR 50, Subpart B Informed Consent of Human Subjects 

21 CFR 50, Subpart D Additional Safeguards for Children in Clinical Investigations 

21 CFR Part 56 Institutional Review Boards 

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guidance

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Drug Development Timeline

* When to Apply the Draft Guidance

Recommendations

BASIC 

RESEARCH

PROTOTYPE 

DESIGN OR 

DISCOVERY

FDA 

FILING & 

APPROVAL

PRECLINICAL 

DEVELOPMENT*

Consider pediatric 

trials early in product 

development. 

Consider initiating 

any nonclinical 

studies needed to 

provide safety and/or 

effectiveness data to 

support the prospect 

of direct benefit and 

risk assessment in 

children.

POSTMARKET OR 

POSTAPPROVAL 

STUDIES*

Apply the draft guidance 

recommendations to all 

pediatric post-marketing 

clinical investigations.

CLINICAL DEVELOPMENT*

Apply the draft guidance recommendations 

during protocol development and regulatory 

review. Consider:

• Data needed to provide evidence for the 

prospect of direct benefit and to conduct a

risk assessment 

• Scientific necessity (and the potential use of 

pediatric extrapolation): Identify knowledge 

gaps and only collect pediatric data needed 

to answer important scientific and/or public

health questions directly relevant to the 

health and welfare of children

• Pediatric trial designs that maximize benefit

and minimize risk

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