Guidance for Industry and FDA Staff 

Premarket Assessment of Pediatric 

Medical Devices 

 Document issued on: May 14, 2004

The draft of this document was issued on July 24, 2003

For questions regarding this document, contact Joy Samuels-Reid, M.D. at (301) 594-1287. 

For questions regarding products regulated by the Center for Biologics Evaluation and 

Research (CBER), contact Edward Tabor, M.D. at (301) 827-3518. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Devices and Radiological Health 

Center for Biologics Evaluation and Research 
Contains Nonbinding Recommendations 

Preface 

Public Comment

Written comments and suggestions may be submitted at any time for Agency consideration to 

the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, 

Room 1061, (HFA-305), Rockville, MD, 20852. Alternatively, electronic comments may be 

submitted to http://www.fda.gov/dockets/ecomments. When submitting comments, please 

refer to Docket No. 2003D-0319. Comments may not be acted upon by the Agency until the 

document is next revised or updated. 

Additional Copies 

Additional copies are available from the Internet at: 

http://www.fda.gov/cdrh/[specific address] or

http://www.fda.gov/cber/mdufma/mdufma.htm, or to receive this document via your 

fax machine, call the CDRH Facts-On-Demand system at 800-899-0381 or 301-827-

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Contains Nonbinding Recommendations 

Table of Contents 

I. Background................................................................................................................... 1

The Least Burdensome Approach............................................................................................. 2 

II. Stakeholder Input.......................................................................................................... 3 

III. Objectives ..................................................................................................................... 4 

IV. Pediatric Population and Use........................................................................................ 4 

A. Definition of Pediatric Population Subgroups.............................................................. 4 

B. Definition of Pediatric Use ........................................................................................... 5 

V. General Principles in Medical Device Evaluation........................................................ 5 

VI. Preclinical Studies......................................................................................................... 6

VII. Clinical Studies............................................................................................................. 6 

VIII. Unique Host Characteristics ........................................................................................... 9 

IX. Labeling ...................................................................................................................... 12 

A. Basic Elements of Labeling ........................................................................................ 12 

B. Pediatric Information .................................................................................................. 14

C. Special Considerations................................................................................................ 14

X. Protections for Pediatric Populations in Clinical Trials.................................................... 15 

A. Relevant Definitions................................................................................................... 15

B. Study Design Considerations...................................................................................... 17 

C. The Role of the Institutional Review Board (IRB)..................................................... 18 

D. Consent and Assent..................................................................................................... 18 

XI. Other Resources.......................................................................................................... 20
Contains Nonbinding Recommendations 

Guidance for Industry and FDA Staff 

Premarket Assessment of Pediatric 

Medical Devices 

This guidance represents the Food and Drug Administration's (FDA's) current thinking 

on this topic. It does not create or confer any rights for or on any person and does not 

operate to bind FDA or the public. You can use an alternative approach if the approach 

satisfies the requirements of the applicable statutes and regulations. If you want to discuss 

an alternative approach, contact the FDA staff responsible for implementing this 

guidance. If you cannot identify the appropriate FDA staff, call the appropriate number 

listed on the title page of this guidance. 

I. Background 

FDA reviews pediatric devices through all of its premarket pathways, including premarket 

notification (510(k)), premarket approval (PMA), biological license application (BLA), and 

humanitarian device exemption (HDE). A manufacturer may show substantial equivalence 

to a predicate device, or may seek marketing approval by demonstrating with reasonable 

assurance that the device is safe and effective for its intended use. Clinical evaluation may 

be needed to support marketing of a device indicated for pediatric use. If such studies are 

needed, they should be conducted in accordance with the investigational device exemptions 

(IDE) regulation (21 CFR 812). FDA has jurisdiction over significant risk studies, whereas 

Institutional Review Boards (IRBs) have oversight responsibility for non-significant risk 

studies. 

On October 26, 2002, the Medical Device User Fee and Modernization Act of 2002 

(MDUFMA) was signed into law. Among other things, MDUFMA amends the Federal, 

Food, Drug, and Cosmetic Act (the Act) by adding several new provisions intended to 

promote the development of safe and effective pediatric devices and to protect this 

vulnerable patient population during the course of clinical trials involving such products. 

This guidance, as well as a collateral guidance on procedures for ensuring that pediatric 

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expertise is available to FDA Advisory Panels when appropriate,1

 will help the agency 

achieve the intent of the pediatric provisions of MDUFMA. 

MDUFMA also requires FDA to request the Institute of Medicine (IOM) to conduct a study 

of whether the existing postmarket surveillance provisions of the Act provide "adequate 

safeguards regarding the use of devices in pediatric populations." Within four years of 

enactment of MDUFMA, FDA is to submit a report to Congress concerning IOM’s findings 

and any recommendations we have "for administrative or legislative changes to the system of 

postmarket surveillance" for pediatric devices. Representatives from FDA and IOM held 

several discussions to formulate the scope and objectives of the study, and IOM is currently 

engaged in planning activities related to its conduct. 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and 

should be viewed only as recommendations, unless specific regulatory or statutory 

requirements are cited. The use of the word should in Agency guidances means that 

something is suggested or recommended, but not required. 

This guidance should be used in conjunction with other device-specific guidances to help 

ensure that medical devices intended for use in the pediatric population provide reasonable 

assurance of safety and effectiveness. 

The Least Burdensome Approach 

The issues identified in this guidance document represent those that we believe should be 

addressed before your device can be marketed. In developing the guidance, we carefully 

considered the relevant statutory criteria for Agency decision-making. We also considered 

the burden that may be incurred in your attempt to follow the guidance and address the issues 

we have identified. We believe that we have considered the least burdensome approach to 

resolving the issues presented in the guidance document. If, however, you believe that there 

is a less burdensome way to address the issues, you should follow the procedures outlined in 

the “A Suggested Approach to Resolving Least Burdensome Issues” document. It is 

available on our Center web page at http://www.fda.gov/cdrh/modact/leastburdensome.html. 

 

1

 “Pediatric Expertise for Advisory Panels; Guidance for Industry and FDA Staff” can be 

found at http://www.fda.gov/cdrh/ode/guidance/1208.html. 

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Contains Nonbinding Recommendations 

II. Stakeholder Input 

In developing the draft and final versions of this guidance, FDA considered comments from

its stakeholders. On February 4, 2003, FDA published a Federal Register notice entitled, 

“Medical Device User Fee and Modernization Act of 2003, Establishment of a Public 

Docket” (68 FR 5643)(hereinafter referred to as the MDUFMA Docket). In this FR notice, 

the agency identified several statutory provisions for which FDA was particularly interested 

in receiving stakeholder input, and this pediatric provision2

 was one of them. While no 

comments were submitted to the MDUFMA Docket on this topic, three comments were 

submitted in response to the draft of this guidance.3

 

One comment questioned why the guidance did not reference the least burdensome 

provisions of the act4

 or encourage the use of early collaboration meetings to help ensure that 

the least burdensome approach is followed in determining safety and effectiveness for 

pediatric devices. The agency acknowledges the omission. We have revised the guidance to 

refer to the least burdensome provisions and to encourage device sponsors to consult with the 

reviewing division either through the informal pre-IDE process or early collaboration 

meetings. 

Another comment asked how devices that are already legally marketed for pediatrics with an 

upper age limit of 18 would be affected by the guidance since this document extends the 

definition to age 21. As stated in the guidance, the agency recognizes that the age 

descriptions presented here are somewhat arbitrary and that other factors, such as the 

subject’s weight, body size, and physiological and neurological development may be more 

appropriate indicators than chronological age. The intent of this guidance is to identify those 

issues that should be considered by sponsors conducting clinical trials involving pediatrics to 

ensure that the studies are appropriately designed and that measures are taken to protect this 

vulnerable patient population. Similarly, the agency hopes this guidance will help 

manufacturers develop clear labeling for their products and take into account the above 

physiological and neurological factors, when appropriate. 

Finally, two comments sought clarification of how state and federal law pertaining to the age 

of consent relates to the clinical definition of the pediatric population put forth in the 

guidance. The agency has revised the guidance to clarify this distinction. 

 

2

 Section 213 of MDUFMA. 

3

 “Premarket Assessment of Pediatric Medical Devices; Draft Guidance for Industry and 

FDA Staff” was released for comment on July 24, 2003. 

4

 Sections 513(a)(1)(D) and 513(a)(30(D)(ii) of the act.

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III. Objectives 

1. To help define the pediatric population and pediatric use for medical devices. 

2. To help identify the types of information needed to provide reasonable assurance of 

the safety and effectiveness of medical devices intended for use in the pediatric 

population. 

3. To help define the guiding principles and protections sponsors should consider for 

pediatric subjects in device clinical trials. 

IV. Pediatric Population and Use 

A. Definition of Pediatric Population Subgroups 

For purposes of this guidance, we are proposing the following ranges of pediatric 

subpopulations to be used as a guide for manufacturers in developing medical devices: 

Table 1 Age Ranges of Pediatric Subgroups 

Pediatric Subgroup Approximate Age Range 

Newborn (neonate) from birth to 1 month of age 

Infant greater than 1 month to 2 years of age 

Child greater than 2 to 12 years of age 

Adolescent greater than 12 to 21 years of age 

Although the upper age limit used to define the pediatric population varies among 

experts, including adolescents up to the age of 21 is consistent with the definition found 

in several sources.5,6,7

 Given the scope of medical devices and the impact that a device 

could have on a growing adolescent, as well as the effect growth could have on the 

device, we believe that including the upper age limit identified above may be useful for 

some devices and device clinical trials. The agency recognizes, however, that the 

descriptions are somewhat arbitrary and that, in fact, the subject’s weight, body size, 

 

5

 Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th

Ed. Philadelphia: W.B. Saunders Company; 1996.

6

 Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill; 2002. 

7

 Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

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physiological development, neurological development, and neuromuscular coordination 

may often be more appropriate indicators than chronological age. 

Additional pediatric subpopulations include: 

- low birth weight describes newborns less than 2.5 Kg 

- very low birth weight describes newborns less than 1.5 Kg 

- preadolescent age group typically ranges from 11 to 13 years. 

Although these pediatric subpopulations are not included in Table 1, device labeling and 

clinical studies should address, as applicable, any issues that pertain to these or other 

pediatric subpopulations, such as low birth weight newborns. 

It is important to note the distinction between the clinical age limit of 21 described in this 

guidance and the legal age for consent. For the purposes of informed consent, 

manufacturers must comply with all federal and state regulations governing age and 

mental capacity.9

 A detailed discussion of informed consent issues as they pertain to the 

pediatric population is presented in Section X. 

B. Definition of Pediatric Use 

For purposes of this guidance, FDA will consider a pediatric use to be any use of a 

medical device in a pediatric population, as defined above, in which there is a primary 

pediatric indication. General indications, where considerable pediatric application is 

anticipated, are also included in this definition. 

V. General Principles in Medical Device Evaluation 

In general, FDA assesses safety and effectiveness of devices in the pediatric population using 

the same regulatory bases, scientific approaches, and processes we use to assess all devices. 

Device considerations that are also germane to pediatric devices include, but are not limited 

to, the following preclinical and clinical testing as well as other regulatory controls: 

- biocompatibility, including toxicity and carcinogenicity 

- sterility and infection control 

 

9 See 21 CFR § 50.55 Requirements for permission by parents or guardians and for assent by 

children. 

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- environmental factors related to location of use, such as electromagnetic fields and 

radiation 

- design controls and good manufacturing practices (GMP) 

Because the pediatric population represents a particularly vulnerable group, specific 

measures are needed to protect the safety of pediatric study subjects. Adult devices may be 

inappropriate for use in pediatric subjects for a variety of reasons, or may require specific 

design changes and/or specific labeling to accommodate their use in pediatric subjects. We

recommend that you consider the following when you develop devices or plan a clinical trial 

for devices intended for pediatric subjects: 

- height 

- weight 

- growth and development 

- disease or condition 

- hormonal influences 

- anatomical and physiological differences from the adult population 

- activity and maturity level 

- immune status. 

VI. Preclinical Studies 

Given the wide spectrum of devices, the necessary preclinical testing may vary considerably. 

FDA may request bench or animal data depending on the type of device, the target 

population, and the extent of existing knowledge about the device. In many cases, FDA has 

developed device-specific guidance documents that will provide information on the types of

pre-clinical testing that should be completed either to support marketing or to support 

initiation of a clinical trial. We recommend that you contact the reviewing division or visit 

the CDRH or CBER websites for a complete listing of relevant guidances. 

VII. Clinical Studies 

As is true for medical devices in general, FDA does not believe that clinical data will be 

necessary to demonstrate safety and effectiveness for all devices intended for pediatric 

populations. The agency recognizes that the amount and type of evidence required will 

depend on a number of factors, including the nature of the device, what is already known 

about the product in the adult population (if relevant), what is known or can be extrapolated 

about the device to the pediatric population, and the underlying disease or condition being 

treated. In some cases, well-designed bench and animal testing will be sufficient to evaluate 

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the device. In others, clinical data may be needed to evaluate the safety and effectiveness of 

the device. 

FDA is committed to following the least burdensome principles as described in the guidance 

document entitled, “The Least Burdensome Provisions of the FDA Modernization Act of

1997: Concept and Principles.”10 This commitment applies equally to pediatric devices. We

recommend that sponsors of pediatric device clinical trials take advantage of the informal 

pre-IDE process11 and/or the more formal early collaboration meetings12 to obtain feedback 

on their investigational protocol before initiating the trial and to discuss the least burdensome 

regulatory path. 

If it is determined that clinical data are needed, it may be that the course of the disease and 

the device's effects are similar in adult and pediatric patients. In such a situation, the 

pediatric indication may be supported by the adult data with limited additional safety data in 

the pediatric population. In other cases, the prognosis, severity, or symptoms of the disease 

in the adult population may be significantly different than in the pediatric population, the 

device's effects may not be well understood, or there may be risks specific to the pediatric 

population necessitating clinical data in this population. 

In some situations, devices that are already approved and indicated for adult populations are 

modified for pediatric uses. To support the modifications, the manufacturer should conduct a 

risk analysis of the changes and develop methods to adequately address or mitigate the 

identified risks. This may require verification testing alone, or validation testing may be 

needed in the intended pediatric population. 

Finally, because weight, body size, and physiological and neurological development all vary 

among pediatric subpopulations and change as the child grows, clinical data may be needed 

to assess safety and effectiveness in the various subgroups. In other cases, it may be possible 

to extrapolate from one group to another, thus limiting or obviating the need for clinical data. 

When clinical trials in a pediatric population are necessary to support a marketing 

application, these trials should follow existing scientific approaches and methods to ensure 

the safety of subjects. 

 

10 This guidance is available at: www.fda.gov/cdrh/ode/guidance/1332.html. 11 For information on the pre-IDE Program, see the documents at: 

www.fda.gov/cdrh/d951.html and www.fda.gov/cdrh/ode/d99-1.html. 12 For information on the early collaboration meetings, see the guidance at: 

www.fda.gov/cdrh/ode-p98-3.html

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In summary, FDA believes clinical data are appropriate when any of the following 

circumstances apply: 

- supporting information from sources, such as pre-clinical bench or animal testing, 

literature, or adult clinical trials, are inadequate to establish safety and effectiveness 

for the pediatric indication 

- adult data are inadequate to predict pediatric risks and adverse events 

- pediatric data are needed for validation of design modifications 

- pediatric data are needed to develop an age-appropriate treatment regimen. 

When the above circumstances exist, clinical data from pediatric subjects help ensure that 

manufacturers: 

- design the device properly for the intended population 

- perform accurate risk assessments 

- provide clear instructions for use. 

Compared to drugs, devices present additional challenges due to the range of technology they 

incorporate and their varying applications. It is difficult to outline a prescriptive approach 

that would be appropriate for evaluating all devices. For example, some devices are 

relatively simple in terms of design and use, such as blood pressure cuffs and 

bilirubinometers. FDA generally recommends only pre-clinical testing to support adult and 

pediatric use of these types of products. Other devices may present additional risks, e.g., 

intraosseous access devices. For devices of this kind, the supporting information included 

performance studies in animals and cadavers, clinical experience in the adult population, and 

a clinical trial in a pediatric population. The study design addressed issues relating to 

differences in bone density and depth of penetration requirements in children of various ages 

and between children and adults. The study also addressed issues related to the growth plate 

and epiphyseal closure in children. 

If clinical data are needed, other sources of data, such as published studies and reports and 

actual use information, may help reduce the burden. FDA advises sponsors to consider these 

alternative sources of information when designing their clinical trial. Sponsors should also 

consider if adequate data may be gathered by including pediatric patients as well as adults in 

the original studies conducted on the device. Finally, the type and extent of the studies 

needed, especially in different age groups, is often best decided on a case-by-case basis. 

FDA encourages you to discuss your clinical trial plan with the reviewing division. 

FDA recommends that when developing medical devices for pediatric use, you consider the 

following: 

Risk Assessment and Mitigation 

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Because the risk posed by the device may vary depending on the particular pediatric 

subgroup, you should determine the types of risk for each targeted pediatric subgroup by 

conducting a risk assessment. When assessing risk, you should consider the following 

critical factors: 

• age and degree of physiological maturity of the child 

• nature and natural history of the clinical condition to be treated 

• presence of complicating clinical conditions 

• safety and effectiveness of the device that may have been demonstrated in older 

patients, or that is expected on the basis of other clinical or preclinical 

investigations 

• likely duration of device use and its impact on the growth and development of the 

child. 

Using the results of the risk analysis, you should develop methods to address or mitigate 

the identified risks. In many cases, well-designed bench and animal studies may 

accomplish this. In others, clinical data will be necessary. 

Pediatric Subgroups 

If clinical data are needed to support a pediatric indication, you should make every effort 

to gather data that adequately addresses each targeted pediatric subgroup. In some cases, 

the expected benefit and safety can be determined without separate studies in each 

subgroup. That is, it may be extrapolated from one age group to another. In other cases, 

such as with neonates, clinical data gathered specifically in that subgroup will likely be 

needed. You should be prepared to provide data for each targeted subpopulation or a 

justification as to why it is either not needed or can be extrapolated. 

VIII. Unique Host Characteristics 

We recommend that you specify relevant subsets of the pediatric population in your intended 

use and indications rather than pooling them all into a single pediatric population. You 

should address the factors discussed below with respect to your device design, clinical study 

design, and labeling for each population. We recommend that you address these factors in 

devices specific to pediatrics and in general use devices with pediatric indications, where 

there may be unique issues when used in the pediatric population. 

Age

As discussed in Section IV, the identification of specific age limits for pediatric 

subpopulations is somewhat arbitrary. Characteristics such as the subject’s weight, body 

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size, physiological and neurological development, and neuromuscular coordination may 

be more appropriate when deciding upon the appropriate subpopulation for a device. For 

example, the use of cochlear implants in certain pediatric subgroups may not be advisable 

due to the size of the implant or may be inappropriate due to the stage of the neurological 

development of the child. Therefore, when designing the clinical trial or the device 

labeling, age may be used as a preliminary approximator, but other factors should be 

considered to further define the appropriate population. 

Size

We recommend that you determine if design modifications are necessary based on 

subject size (e.g., weight, height, body mass, or surface area). 

Growth and Development 

We recommend that you consider the following: 

- impact of growth on the device and vice versa 

- if the child will outgrow the device, and if so, at what rate 

- if adjustments to the device will be necessary 

- if further intervention may be needed 

- impact of technological advances in the device (e.g., will the device be easily 

upgraded?)

Body Habitus 

We recommend that you consider the following: 

- normal as well as abnormal variations in the targeted pediatric group 

- normal anatomic landmarks for each subgroup and anticipated deviations based 

on the targeted population 

- impact of anomalies, particularly congenital anomalies. 

Developmental Milestones 

We recommend that you consider the following: 

- impact of the device on the child 

- activity level of the child 

- ambulatory status of the child 

- maturity level of the child 

- stage of puberty (for example, in the pre-adolescent and adolescent, breast bud 

development may influence device placement). 

Pathophysiology 

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We recommend that you determine the impact of the disease/condition on the pediatric 

patient and take into account the following: 

- maturity or immaturity of various organ systems, including the immune system

- impact of materials, chemicals, electromagnetic radiation, electrical stimulation, 

and other agents 

- hormonal influences, for example, effects of puberty in the preadolescent and 

adolescent population 

- short-term and long-term effects of device use. 

Behavioral factors 

We recommend that you consider the behavior expected in the targeted pediatric 

subgroup and anticipate the potential impact of the device. For example, an adolescent 

with a learning disorder may not be able to interface very well with certain devices and 

may require additional help or an alternative therapy. 

Psychosocial factors 

We recommend that you consider the psychosocial factors of the pediatric subgroups. 

For some pediatric devices or device trials, the family structure and environment, 

including how supportive the various family members are and who the primary caregiver 

will be, are important factors to consider. 

Human Factors 

Each pediatric subgroup will have different needs; therefore, you should consider these in 

the design and use of the device. We recommend that you consider the following for 

each targeted subgroup: 

- invasiveness of the device 

- optimal size of the device 

- manual dexterity and strength required 

- resistance to damage from wear and tear 

- portability 

- clarity of the labeling 

- ease of use 

- level of interaction required for the proper functioning and use of the device 

- age-appropriate usability of the user interface 

- age and maturity level needed to safely and effectively operate the device, 

particularly in adolescents and especially with regard to placement, compliance, 

and use of the device. 

Surgical Factors for Implantable Devices 

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For each targeted pediatric subgroup, we recommend that you assess: 

- the surgical site and anatomical landmarks 

- surgical technique and level of expertise needed 

- short-term and long-term effects of the surgery and the device 

- immune status and update immunizations, if indicated 

- special issues pertaining to combination products, such as the possibility of 

drug/device interactions 

- the need for antibiotic prophylaxis. 

IX. Labeling 

Labeling requirements for medical devices are defined by regulation.13 In general, the goal 

of medical device labeling is to provide the user with the following information: 

- What the device is 

- What the device does 

- When the device should and should not be used 

- How the device should be used to achieve maximum benefit and minimal risk. 

To this end, we recommend that labeling for devices intended for use in pediatric subgroups 

incorporate the information discussed below. 

A. Basic Elements of Labeling 

The following list identifies some of the basic elements of labeling and discusses ways to 

address these elements for pediatric populations. 

Device Description 

Many devices and device accessories come in different models, sizes, shapes, and 

materials, as well as different modes of operation and different levels of 

sophistication requiring varying degrees of user interface. The labeling should 

describe various options recommended for use in pediatric subgroups and, when 

feasible, present these options in tabular form by age, weight, or other appropriate 

criteria. 

Indications for Use 

If your device is intended for use in a pediatric population, you should clearly define 

the indication(s) as well as the target population in the labeling. The indication may 

 

13 For premarket notification submissions, see 21 CFR 807.87(e). For PMAs and HDEs, see 

21 CFR 814.20(b)(10) and 21 CFR 814.104(b)(4)(ii).

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be general (e.g., cut, coagulate, ablate), or specific (e.g., treatment of vesicoureteral 

reflux). The target population may be broad (e.g., children and adults of all ages) or 

narrow (e.g., infants between the ages of 6-9 months). You should be prepared to 

explain and, when necessary, support the indication and targeted population(s) with 

appropriate data. 

Contraindications, Warnings, and Precautions 

Contraindications, warnings, and precautions, respectively, alert the potential user to 

situations where the device should absolutely not be used; data suggest that there is 

increased risk associated with use of the device; or data are lacking to define 

risk/benefit for a particular aspect of use or in a particular subgroup. Given the 

vulnerability of the pediatric population and specific host concerns described above, 

it is especially important that the contraindications, warnings, and precautions in 

labeling provide clear descriptions and well-defined actions and consequences. 

Contraindications, warnings, and precautions for devices intended for pediatric use 

should clearly address the risks associated with age, size, and maturity of the 

pediatric subject and alert the user to specific hazards associated with the use of the 

device in the target population. 

Adverse Events 

Another key element of labeling is a discussion of device-related adverse events that 

have been reported from clinical investigations or literature pertaining to the use of

medical devices. Device-related adverse events could be captured in many different 

ways: by severity, frequency, indication, gender, etc. If your device is intended for 

use in pediatrics, you should make a concerted effort to obtain and report the 

frequency of device-related adverse events according to the various pediatric 

subgroups in which the device will be used. This information will assist health care 

providers in assessing age-specific risk profiles and may be useful in mitigating the 

risks. 

Clinical Studies 

As discussed above, gathering clinical information directly on the targeted pediatric 

subgroup may be necessary. The importance of summarizing that information in 

labeling warrants special attention. Your labeling should present information in a 

way that is clear, objective, and meaningful. You should report study results in a 

format that allows the user to recognize easily substantive differences in performance 

between children and adults and between various pediatric subgroups. Labeling 

should summarize these data using appropriate qualitative or quantitative analyses, 

recognizing that subgroups may be too small to show statistical significance using 

standard tests. 

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Instructions for use 

Understanding how to use a medical device correctly can be as important as the 

design, manufacturing, and testing of the device. Instructions may be provided for 

the health care practitioner, as is the case with prescription products, or the patient, as 

is the case with over-the-counter products, or both. Labeling provided for the 

healthcare practitioner or caregiver should be written to provide the user with 

instructions for safe and effective use. This includes addressing anatomic, 

developmental, educational, and other age-related factors in this section of the 

labeling to help ensure proper use of the device and prevent avoidable device-related 

adverse events. Any instructions provided specifically for the pediatric patient should 

be age-appropriate with respect to written language and other visual and auditory 

tools. 

B. Pediatric Information 

You should submit appropriate information and summarize it adequately to ensure that 

labeling is satisfactory for all pediatric subgroups or specific pediatric subgroups (e.g., 

all pediatric subgroups except neonates) targeted in your intended use. 

If you did not include a particular subgroup, or did not include sufficient numbers in that 

subgroup in your clinical trials, and there is reason to expect that there may be 

differences in safety and effectiveness among subgroups, your labeling should indicate 

that the device was not tested in the particular subgroup or that there is insufficient 

information to establish safety and effectiveness for that subgroup. 

We recommend that you describe the specific age ranges rather than using “pediatric” in 

a broad sense. Please see Table 1 Age Ranges of Pediatric Subgroups.

C. Special Considerations 

We recommend that you ensure the instructions for use are clear, take into consideration 

different pediatric subgroups, and address any special issues, where appropriate. For 

example, including a precaution to consider future breast bud development in female 

pediatric subjects when selecting a site on the chest for placement of a port or catheter 

may be appropriate. Another example may be including a precaution that provides 

advice on the appropriate activity level for the child, especially with respect to 

participation in certain sports. 

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X. Protections for Pediatric Populations in Clinical Trials 

The pediatric population represents a vulnerable subgroup of research subjects. Therefore, it 

is important that special measures be taken to protect the rights, safety, and welfare of the 

pediatric study participant. Every effort should be made to ensure that adequate protections 

are provided to these subjects during the conduct of clinical trials. The roles and 

responsibilities of the clinical investigator, sponsor, and the Institutional Review Board are 

crucial in protecting the rights and welfare of the pediatric subject. 

FDA regulations governing IRBs identify children as subjects who may be vulnerable and 

subject to coercion. In such cases, IRBs must determine that additional safeguards are in 

place to protect their rights and welfare (21 CFR Part 56.111(b)). FDA’s guidance document 

entitled, Guidance for Institutional Review Boards and Clinical Investigators,

http://www.fda.gov/oc/ohrt/irbs/default.htm addresses issues regarding informed consent and 

the assent of children. The basic requirements of 21 CFR §50.20 regarding informed consent 

apply to the pediatric population. See also the guidance entitled, E11 Clinical Investigation 

of Medicinal Products in the Pediatric Population, 

http://www.fda.gov/cber/gdlns/ichclinped.pdf. 

We recommend that you consult 21 CFR Part 50 - Subpart D Additional Safeguards for 

Children in Clinical Investigations (discussed below) and other referenced resources dealing 

with informed consent, assent, permission, financial remuneration, direct benefit, and 

minimal risk. 

A. Relevant Definitions 

The following terms are defined in FDA’s and the Department of Health and Human 

Services’ human subject protection regulations and guidance: 

Assent means a child’s affirmative agreement to participate in a clinical investigation. 

Mere failure to object may not be construed as assent. 21 CFR 50.3(n). 

Children means persons who have not attained the legal age for consent to treatments or 

procedures involved in the clinical investigations, under the applicable law of the 

jurisdiction in which the clinical investigation will be conducted. 21 CFR 50.3(o). 

Emancipated Minor: A legal status conferred upon persons who have not yet attained the 

age of legal competency as defined by state law, but who are entitled to treatment as if

15
Contains Nonbinding Recommendations 

they had by virtue of assuming adult responsibilities, such as self-support, marriage, or 

procreation.14

Family member means any one of the following legally competent persons: Spouse; 

parents; children (including adopted children); brothers, sisters, and spouses of brothers 

and sisters; and any individual related by blood or affinity whose close association with 

the subject is the equivalent of a family relationship. 21 CFR 50.3(m). 

Guardian means an individual who is authorized under applicable state or local law to 

consent on behalf of a child to general medical care when general medical care includes 

participation in research. For purposes of subpart D of 21 CFR Part 50, a guardian also 

means an individual who is authorized to consent on behalf of a child to participate in 

research. 21 CFR 50.3(s). 

Legally authorized representative means an individual or judicial or other body 

authorized under applicable law to consent on behalf of a prospective subject to the 

subject’s participation in the procedure(s) involved in the research. 21 CFR 50.3(l). 

Mature Minor: Persons who have not reached adulthood (as defined by state law) but 

who may be treated as an adult for certain purposes (e.g., consenting to medical care). 

Note that a mature minor is not necessarily an emancipated minor. 15

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. 21 CFR 50.3(k). 

Parent means a child’s biological or adoptive parent. 21 CFR 50.3(p). 

Permission means the agreement of parent(s) or guardian to the participation of their 

child or ward in a clinical investigation. Permission must be obtained in compliance with 

subpart B of 21 CFR Part 50 and must include the elements of informed consent 

described in Sec. 50.25. 21 CFR 50.3(r). 

 

14 IRB Guidebook: Chapter VI Special Classes of Subjects, 

http://ohrp.osophs.dhhs.gov/irb/irb_chapter6.htm#g4 

15 IRB Guidebook: Chapter VI Special Classes of Subjects, 

http://ohrp.osophs.dhhs.gov/irb/irb_chapter6.htm#g4

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B. Study Design Considerations 

As discussed above, FDA recommends that sponsors identify the subgroup(s) in which to 

evaluate the device, unless the device is intended for the entire pediatric population. 

When deciding whether a clinical trial is needed for a particular pediatric population, the 

following points are important to consider: 

• Does the research have an identifiable prospect of direct benefit to the individual 

child participant? Can that benefit be achieved through alternative means?

• Does the research have an identifiable prospect of risk to the individual child 

participant? What safeguards are proposed to minimize these risks? When 

procedures involving greater than minimal risk to children are anticipated, are 

convincing scientific and ethical justifications given?

It is important when designing the study that every attempt is made to anticipate and 

reduce possible study hazards. Investigators should be knowledgeable of all relevant preclinical data and be properly trained and experienced in the pediatric population and 

medical procedures used for this population. 

We recommend that you ensure appropriate pediatric expertise is reasonably available 

during the entire trial. We also recommend all clinical sites have staff and equipment 

appropriate for pediatric care. Your clinical sites should also have pediatric-specific 

emergency measures, such as properly sized oxygen, suction, and resuscitation devices as 

well as medications to treat severe anaphylaxis and adverse reactions (see also 

http://www.ems-c.org.) 

Because many procedures used during clinical trials are often new to the child, every 

effort should be made to ensure the participants’ experiences in the study are positive and 

to minimize discomfort and distress. Additionally, before studies are undertaken, an 

evaluation should be made to determine if the needed information can be obtained from

less vulnerable populations. When studies are conducted in the pediatric population, 

every attempt should be made to include individuals representing the demographics of 

the region and the disease being studied. Studies in handicapped or institutionalized 

pediatric subjects should be limited to diseases or conditions found principally in these 

populations. 

To be of benefit to those participating in a clinical study, the study must be properly 

designed and conducted to ensure that quality data are obtained. Following Good 

Clinical Practice (GCP) is crucial to obtaining quality and reliable data from the study. 

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Contains Nonbinding Recommendations 

C. The Role of the Institutional Review Board (IRB) 

The principal role of the IRB is to protect the rights and welfare of human research 

subjects; this is especially true when studies involve children as subjects. To safeguard 

the child’s interests and to protect children from harm, special ethical and regulatory 

considerations are in place for reviewing research involving children. The regulations at 

21 CFR 50 Subpart D Additional Protections for Children Involved as Subjects of 

Research describe these considerations. 

IRBs reviewing research involving children as subjects must consider the benefits, risks 

and discomforts inherent in the proposed research and assess their justification in light of 

the expected benefits to the child subject or to society as a whole. The IRB should weigh 

the circumstance of the subject under study, the magnitude of risks that may accrue for 

the research procedures, and the potential benefits the research may provide to the 

subjects. 

The regulations require IRBs to classify research involving children into one of four 

categories and to document their discussions of the risks and benefits of the research 

study. The four categories are: 

• Clinical investigations not involving greater than minimal risk (21 CFR 50.51) 

• Clinical investigations involving greater than minimal risk but presenting the 

prospect of direct benefit to individual subjects. (21 CFR 50.52) 

• Clinical investigations involving greater than 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 50.53) 

• Clinical investigations not otherwise approvable that present an opportunity to 

understand, prevent, or alleviate a serious problem affecting the health or welfare 

of children. (21 CFR 50.54) 

In all cases, IRBs must determine that adequate provisions have been made for soliciting 

the assent of children and the permission of their parents or guardians. (21 CFR 50.55) 

D. Consent and Assent 

We recommend that you ensure that the informed consent document is clearly written 

and that the risks and benefits are thoroughly explained. FDA recognizes that consent 

depends on a number of factors, including: 

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- age 

- maturity level 

- legal status of the subject (emancipated or mature minor) 

- applicable law of the jurisdiction in which the research is conducted and which in 

turn determines legal age of consent 

- comprehension level of the pediatric research participant, parents, guardians, and 

legally authorized representative. 

We also recommend that you consider: 

- prognosis and life expectancy of patients with certain diseases or disorders 

- mental capacity, intellectual quotient, and level of functioning 

- differing ages and maturity level 

- direct benefits and risks of the pediatric participant’s research involvement 

(research versus therapeutic treatment) 

- ethical issues 

- proper monitoring (data and safety monitoring). 

When children or minors are involved in research, the regulations require the assent of 

the child or minor and the permission of the parent(s) in place of the consent of the 

subjects. 21 CFR 50.55. While children may be legally incapable of giving informed 

consent, they may possess the ability to assent to or dissent from participation. The 

regulations do not require that assent be sought from children starting at a specific age, 

but that their assent should be sought when the children are capable of providing their 

assent. Therefore, children should be asked whether or not they wish to participate in the 

research particularly if the research: (1) does not involve interventions likely to be of 

benefit to the subjects and (2) the children can comprehend and appreciate what it means 

to be a volunteer for the benefit of others. 

 

Researchers may seek assent of children of various ages. Older children may be well 

acquainted with signing documents through prior experience with testing, licensing, and 

other procedures normally encountered in their lives. Signing a form to give their assent 

for research would not be perceived as unusual and would be reasonable. Younger 

children, however, may never have had the experience of signing a document. For these 

children, requiring a signature may not be appropriate, and some other technique to 

verify assent could be used. For example, a third party may verify, by signature, that the 

assent of the child was obtained. 

Although there is no requirement that the informed consent document contain a space for 

assent by children, many investigators and IRBs consider it standard practice to obtain 

the agreement of older children who can understand the circumstances before enrolling 

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Contains Nonbinding Recommendations 

them in research. The basic requirement of 21 CFR 50.20 applies, i.e., the legally 

effective informed consent of the subject or the subject's legally authorized representative 

must be obtained before enrollment. Parents, legal guardians and/or others may have the 

ability to give permission to enroll children in research, depending on applicable state 

and local law of the jurisdiction in which the research is conducted. (Note: permission to 

enroll in research is not the same as permission to provide medical treatment.) IRBs 

generally require investigators to obtain the permission of one or both of the parents or 

guardian (as appropriate) and the assent of children who possess the intellectual and 

emotional ability to comprehend the concepts involved. Some IRBs require two 

documents, a fully detailed explanation for parents and older children to read and sign, 

and a shorter, simpler one for younger children. 

 

For some research activities, IRBs may require that either an IRB member or an advocate 

for the child be present during the assent and permission procedures to verify the child 

understands and to support the child’s preferences. The IRB may also require that the 

parent(s) or a close family member be present during the research, especially if a young 

child will be exposed to significant discomfort or inconvenience, or if the child will be 

required to spend time in an unfamiliar place (i.e., study site). 

In all cases where assent is required, the proposed research should be explained to the 

child in language that is appropriate to the child’s age, experience, maturity, and 

condition. This explanation should include a discussion of any discomfort and 

inconveniences the child may expect to experience if he or she agrees to participate. The 

subject should also be made aware of his or her rights to decline to participate or to 

withdraw from the study at any time. Additionally, the safety of the subject is always an 

overriding factor in the continuation of a subject in any study. If a subject wishes to 

withdraw from a study and, in the opinion of the investigator and the IRB, the safety and 

welfare of the pediatric subject would be jeopardized by his/her removal from the study, 

continued parental or legal guardian consent should be sufficient to allow participation in 

the study. 

 

A useful reference on informed consent for children participating in research can be 

found in the guidance entitled, “A Pediatric Research- Assent Decision Matrix” 

(http://ohrp.osophs.dhhs.gov/panels/407-01pnl/riskcat.htm). This matrix is based on the 

relationship between benefit and risk ratio and the age of the subject. The matrix is 

arranged in descending order of ratio of benefits to risk as defined in Subpart D and the 

age potential for assent by child subjects. 

XI. Other Resources 

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21

FDA Regulations 

Protection of Human Subjects 21 CFR Part 50 (see especially Subpart D Additional 

Safeguards for Children in Clinical Investigations) 

Institutional Review Boards 21 CFR Part 56 

Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products; 

Interim Rule 66 FR 20589, April 24, 2001. 

Guidance 

Guidance on Medical Device Patient Labeling; Final Guidance for Industry and FDA 

Reviewers http://www.fda.gov/cdrh/ohip/guidance/1128.html

Medical Device Use –Safety: Incorporating Human Factors Engineering into Risk 

Management http://www.fda.gov/cdrh/humfac/1497.html

Recognition and Use of Consensus Standards; Final Guidance for Industry and FDA,

06/20/2001 http://www.fda.gov/cdrh/ost/guidance/321.html and CDRH standards database 

FDA Recognized Consensus Standards.

International Conference on Harmonisation (ICH) Guidance for Industry: E11 Clinical 

Investigation of Medicinal Products in the Pediatric Population 

http://www.fda.gov/cber/gdlns/ichclinped.pdf

Guidance for Institutional Review Boards and Clinical Investigators, 1998 Update 

http://www.fda.gov/oc/ohrt/irbs/default.htm

Additional References 

IRB Guidebook: Chapter VI Special Classes of Subjects, 

http://ohrp.osophs.dhhs.gov/irb/irb_chapter6.htm. 

Age Limits of Pediatrics (RE8116). Pediatrics 1988;81(5):736 American Academy of 

Pediatrics, http://www.aap.org/policy/02031.html

A Pediatric Research “Assent” Decision Matrix, http://ohrp.osophs.dhhs.gov/panels/407-

01pnl/riskcat.htm. 

International Organization for Standardization (ISO) 10993-6: 1994 – Biological Testing of 

Medical Devices. 
Contains Nonbinding Recommendations 

22

CDRH Standards Program webpage http://www.fda.gov/cdrh/stdsprog.html

American National Standards Institute (ANSI) - Association for the Advancement of Medical 

Instrumentation (AAMI) Electrosurgical Devices (ANSI/AAMI) HF18-1993, 4.1 and 4.2.