Guidance for Industry

E11 Clinical Investigation of

Medicinal Products

in the Pediatric Population

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

 ICH

December 2000
Guidance for Industry

E11 Clinical Investigation of

Medicinal Products

in the Pediatric Population

Additional copies are available from:

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or

 Office of Communication, Training and

Manufacturers Assistance, HFM-40

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 Food and Drug Administration

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Internet: http://www.fda.gov/cber/guidelines.htm.

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Mail: the Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

 ICH

December 2000
Table of Contents

I. INTRODUCTION (1.)...........................................................................................................................................................1

A. OBJECTIVES OF THE GUIDANCE (1.1)............................................................................................................................ 1

B. BACKGROUND (1.2).......................................................................................................................................................... 1

C. SCOPE OF THE GUIDANCE (1.3.).................................................................................................................................... 2

D. GENERAL PRINCIPLES (1.4)............................................................................................................................................. 2

II. GUIDANCE (2).......................................................................................................................................................................2

A. ISSUES WHEN INITIATING A PEDIATRIC MEDICINAL PRODUCT DEVELOPMENT PROGRAM (2.1)................... 2

B. PEDIATRIC FORMULATIONS (2.2).................................................................................................................................. 3

C. TIMING OF STUDIES (2.3)................................................................................................................................................ 4

D. TYPES OF STUDIES (2.4).................................................................................................................................................. 5

E. AGE CLASSIFICATION OF PEDIATRIC PATIENTS (2.5)............................................................................................... 9

F. ETHICAL ISSUES IN PEDIATRIC STUDIES (2.6)........................................................................................................... 12
1

Guidance for Industry1

E11 Clinical Investigation of Medicinal Products

in the Pediatric Population

I. INTRODUCTION (1.)

A. Objectives of the Guidance (1.1)

The number of medicinal products currently labeled for pediatric use is limited. This

guidance is intended to encourage and facilitate timely pediatric medicinal product

development internationally. The guidance provides an outline of critical issues in pediatric

drug development and approaches to the safe, efficient, and ethical study of medicinal

products in the pediatric population.

B. Background (1.2)

Other ICH documents with relevant information affecting pediatric studies include:

E2: Clinical Safety Data Management

E3: Structure and Content of Clinical Study Reports

E4: Dose-Response Information to Support Drug Registration

E5: Ethnic Factors in the Acceptability of Foreign Clinical

Data

E6: Good Clinical Practice: Consolidated Guideline

E8: General Considerations for Clinical Trials

E9: Statistical Principles for Clinical Trials

 

1

 This guidance was prepared under the auspices of the International Conference on Harmonisation of the

Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

This guidance represents the Food and Drug Administration'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.

An alternative approach may be used if such approach satisfies the requirements of the applicable

statutes and regulations.
2

E10: Choice of Control Group in Clinical Trials

M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for

Pharmaceuticals

Q1: Stability Testing

Q2: Validation of Analytical Procedures

Q3: Impurity Testing

C. Scope of the Guidance (1.3.)

Specific clinical study issues addressed in this guidance include:

1. Considerations when initiating a pediatric program for a medicinal product;

2. Timing of initiation of pediatric studies during medicinal product development;

3. Types of studies (pharmacokinetic, pharmacokinetic/pharmacodynamic (PK/PD),

efficacy, safety);

4. Age categories; and

5. Ethics of pediatric clinical investigation.

This guidance is not intended to be comprehensive; other ICH guidances, as well as

documents from regional regulatory authorities and pediatric societies, provide additional

detail.

D. General Principles (1.4)

Pediatric patients should be given medicines that have been appropriately evaluated for

their use in those populations. Safe and effective pharmacotherapy in pediatric patients

requires the timely development of information on the proper use of medicinal products in

pediatric patients of various ages and, often, the development of pediatric formulations of

those products. Advances in formulation chemistry and in pediatric study design will help

facilitate the development of medicinal products for pediatric use.

Drug development programs should usually include the pediatric patient population when a

product is being developed for a disease or condition in adults and it is anticipated the

product will be used in the pediatric population. Obtaining knowledge of the effects of

medicinal products in pediatric patients is an important goal. However, this should be done

without compromising the well-being of pediatric patients participating in clinical studies.

This responsibility is shared by companies, regulatory authorities, health professionals,

and society as a whole.

II. GUIDANCE (2)

A. Issues When Initiating a Pediatric Medicinal Product Development

Program (2.1)
3

Data on the appropriate use of medicinal products in the pediatric population should be

generated unless the use of a specific medicinal product in pediatric patients is clearly

inappropriate. The timing of initiation of clinical studies in relation to studies conducted in

adults, which may be influenced by regional public health and medical needs, is discussed

in section II.C. Justification for the timing and the approach to the clinical program needs to

be clearly addressed with regulatory authorities at an early stage and then periodically

during the medicinal product development process. The pediatric development program

should not delay completion of adult studies and availability of a medicinal product for

adults.

The decision to proceed with a pediatric development program for a medicinal product,

and the nature of that program, involve consideration of many factors, including:

• The prevalence of the condition to be treated in the pediatric population

• The seriousness of the condition to be treated

• The availability and suitability of alternative treatments for the condition in the

pediatric population, including the efficacy and the adverse event profile (including

any unique pediatric safety issues) of those treatments

• Whether the medicinal product is novel or one of a class of compounds with known

properties

• Whether there are unique pediatric indications for the medicinal product

• The need for the development of pediatric-specific endpoints

• The age ranges of pediatric patients likely to be treated with the medicinal product

• Unique pediatric (developmental) safety concerns with the medicinal product,

including any nonclinical safety issues

• Potential need for pediatric formulation development

Of these factors, the most important is the presence of a serious or life-threatening disease

for which the medicinal product represents a potentially important advance in therapy. This

situation suggests relatively urgent and early initiation of pediatric studies.

Information from nonclinical safety studies to support a pediatric clinical program is

discussed in ICH M3. It should be noted that the most relevant safety data for pediatric

studies ordinarily come from adult human exposure. Repeated dose toxicity studies,

reproduction toxicity studies, and genotoxicity tests would generally be available. The need

for juvenile animal studies should be considered on a case-by-case basis and be based

on developmental toxicology concerns.

B. Pediatric Formulations (2.2)

There is a need for pediatric formulations that permit accurate dosing and enhance patient

compliance. For oral administration, different types of formulations, flavors, and colors may

be more acceptable in one region than another. Several formulations, such as liquids,

suspensions, and chewable tablets, may be needed or desirable for pediatric patients of

different ages. Different drug concentrations in these various formulations may also be
4

needed. Consideration should also be given to the development of alternative delivery

systems.

For injectable formulations, appropriate drug concentrations should be developed to allow

accurate and safe administration of the dose. For medicinal products supplied as singleuse vials, consideration should be given to dose-appropriate single-dose packaging.

The toxicity of some excipients may vary across pediatric age groups and between

pediatric and adult populations (e.g., benzyl alcohol is toxic in the preterm newborn).

Depending on the active substance and excipients, appropriate use of the medicinal

product in the newborn may require a new formulation or appropriate information about

dilution of an existing formulation. International harmonization on the acceptability of

formulation excipients and of validation procedures would help ensure that appropriate

formulations are available for the pediatric population everywhere.

C. Timing of Studies (2.3)

During clinical development, the timing of pediatric studies will depend on the medicinal

product, the type of disease being treated, safety considerations, and the efficacy and

safety of alternative treatments. Since development of pediatric formulations can be

difficult and time consuming, it is important to consider the development of these

formulations early in medicinal product development.

1. Medicinal Products for Diseases Predominantly or Exclusively

Affecting Pediatric Patients (2.3.1)

In such cases, the entire development program will be conducted in the pediatric

population except for initial safety and tolerability data, which will usually be obtained in

adults. Some products may reasonably be studied only in the pediatric population even in

the initial phases (e.g., when studies in adults would yield little useful information or expose

them to inappropriate risk). Examples include surfactant for respiratory distress syndrome

in preterm infants and therapies targeted at metabolic or genetic diseases unique to the

pediatric population.

2. Medicinal Products Intended to Treat Serious or Life-Threatening

Diseases, Occurring in Both Adults and Pediatric Patients, for

Which There Are Currently No or Limited Therapeutic Options

(2.3.2)

The presence of a serious or life-threatening disease for which the product represents a

potentially important advance in therapy suggests the need for relatively urgent and early

initiation of pediatric studies. In such cases, medicinal product development should begin

early in the pediatric population, following assessment of initial safety data and reasonable

evidence of potential benefit. Pediatric study results should be part of the marketing
5

application database. In circumstances where this has not been possible, lack of data

should be justified in detail.

3. Medicinal Products Intended to Treat Other Diseases and

Conditions (2.3.3)

In such cases, although the medicinal product will be used in pediatric patients, there is

less urgency than in previous cases, and studies would usually begin at later phases of

clinical development or, if a safety concern exists, even after substantial postmarketing

experience in adults. Companies should have a clear plan for pediatric studies and

reasons for their timing. Testing of these medicinal products in the pediatric population

would usually not begin until phase 2 or 3. In most cases, therefore, only limited pediatric

data would be available at the time of submission of the application, but more would be

expected after marketing. The development of many new chemical entities is discontinued

during or following phase 1 and 2 studies in adults for lack of efficacy or an unacceptable

side effect profile. Therefore, very early initiation of testing in pediatric patients might

needlessly expose these patients to a compound that will be of no benefit.

In cases of a nonserious disease where the medicinal product represents a major

therapeutic advance for the pediatric population, studies should begin early in

development, and pediatric data should be submitted in the application. Lack of data

should be justified in detail. Thus, it is important to carefully weigh benefit/risk and

therapeutic need in deciding when to start pediatric studies.

D. Types of Studies (2.4)

The principles outlined in ICH E4, E5, E6, and E10 apply to pediatric studies. Several

pediatric-specific issues are worth noting. When a medicinal product is studied in

pediatric patients in one region, the intrinsic (e.g., pharmacogenetic) and extrinsic (e.g.,

diet) factors2 that could affect the extrapolation of data to other regions should be

considered.

When a medicinal product is to be used in the pediatric population for the same

indication(s) as those studied and approved in adults, the disease process is similar in

adults and pediatric patients, and the outcome of therapy is likely to be comparable,

extrapolation from adult efficacy data may be appropriate. In such cases, pharmacokinetic

studies in all the age ranges of pediatric patients likely to receive the medicinal product,

together with safety studies, may provide adequate information for use by allowing

selection of pediatric doses that will produce blood levels similar to those observed in

 

2

 In the ICH E5 guideline on Ethnic Factors in the Acceptance of Foreign Data, factors that may result in

different drug responses to a drug in different populations are categorized as intrinsic ethnic factors or

extrinsic ethnic factors. In this document, these categories are referred to as intrinsic factors and extrinsic

factors, respectively.
6

adults. If this approach is taken, adult pharmacokinetic data should be available to plan the

pediatric studies.

When a medicinal product is to be used in younger pediatric patients for the same

indication(s) as those studied in older pediatric patients, the disease process is similar,

and the outcome of therapy is likely to be comparable, extrapolation of efficacy from older

to younger pediatric patients may be possible. In such cases, pharmacokinetic studies in

the relevant age groups of pediatric patients likely to receive the medicinal product,

together with safety studies, may be sufficient to provide adequate information for pediatric

use.

An approach based on pharmacokinetics is likely to be insufficient for medicinal products

where blood levels are known or expected not to correspond with efficacy or where there is

concern that the concentration-response relationship may differ between the adult and

pediatric populations. In such cases, studies of the clinical or the pharmacological effect of

the medicinal product would usually be expected.

Where the comparability of the disease course or outcome of therapy in pediatric patients

is expected to be similar to adults, but the appropriate blood levels are not clear, it may be

possible to use measurements of a pharmacodynamic effect related to clinical

effectiveness to confirm the expectations of effectiveness and to define the dose and

concentration needed to attain that pharmacodynamic effect. Such studies could provide

increased confidence that achieving a given exposure to the medicinal product in pediatric

patients would result in the desired therapeutic outcomes. Thus, a PK/PD approach

combined with safety and other relevant studies could avoid the need for clinical efficacy

studies.

In other situations where a pharmacokinetic approach is not applicable, such as for

topically active products, extrapolation of efficacy from one patient population to another

can be based on studies that include pharmacodynamic endpoints and/or appropriate

alternative assessments. Local tolerability studies may be appropriate. It may be

important to determine blood levels and systemic effects to assess safety.

When novel indications are being sought for the medicinal product in pediatric patients or

when the disease course and outcome of therapy are likely to be different in adults and

pediatric patients, clinical efficacy studies in the pediatric population are recommended.

1. Pharmacokinetics (2.4.1)

Pharmacokinetic studies generally should be performed to support formulation

development and determine pharmacokinetic parameters in different age groups to

support dosing recommendations. Relative bioavailability comparisons of pediatric

formulations with the adult oral formulation typically should be done in adults. Definitive

pharmacokinetic studies for dose selection across the age ranges of pediatric patients in
7

whom the medicinal product is likely to be used should be conducted in the pediatric

population.

Pharmacokinetic studies in the pediatric population should generally be conducted in

patients with the disease. This may lead to higher intersubject variability than studies in

normal volunteers, but the data will better reflect clinical use.

For medicinal products that exhibit linear pharmacokinetics in adults, single-dose

pharmacokinetic studies in the pediatric population may provide sufficient information for

dosage selection. This can be corroborated, if indicated, by sparse sampling in multidose

clinical studies. Any nonlinearity in absorption, distribution, and elimination in adults and

any difference in duration of effect between single and repeated dosing in adults would

suggest the need for steady state studies in the pediatric population. All these approaches

can be facilitated by knowledge of adult pharmacokinetic parameters. Knowing the

pathways of clearance (renal and metabolic) of the medicinal product and understanding

the age-related changes of those processes can often be helpful in planning pediatric

studies.

Dosing recommendations for most medicinal products used in the pediatric population are

usually based on milligram (mg)/kilogram (kg) body weight up to a maximum adult dose.

While dosing based on mg/square meter body surface area might be preferred, clinical

experience indicates that errors in measuring height or length (particularly in smaller

children and infants) and calculation errors of body surface area from weight and height are

common. For some medications (e.g., medications with a narrow therapeutic index, such

as those used in oncology), surface-area-guided dosing may be necessary, but extra care

should be taken to ensure proper dose calculation.

Practical considerations to facilitate pharmacokinetic studies

The volume of blood withdrawn should be minimized in pediatric studies. Blood volumes

should be justified in protocols. Institutional review boards/independent ethics committees

(IRBs/IECs) review and may define the maximum amount of blood (usually on a milliliters

(mL)/kg or percentage of total blood volume basis) that may be taken for investigational

purposes. Several approaches can be used to minimize the amount of blood drawn and/or

the number of venipunctures.

• Sensitive assays for parent drugs and metabolites to decrease the volume of blood

required per sample

• Laboratories experienced in handling small volumes of blood for pharmacokinetic

analyses and for laboratory safety studies (blood counts, clinical chemistry)

• Collection of routine, clinical blood samples wherever possible at the same time as

samples are obtained for pharmacokinetic analysis
8

• The use of indwelling catheters, to minimize distress as discussed in section II.E.5.

• Use of population pharmacokinetics and sparse sampling based on optimal sampling

theory to minimize the number of samples obtained from each patient. Techniques

include (1) sparse sampling approaches where each patient contributes as few as 2 to

4 observations at predetermined times to an overall population area-under-the-curve

and (2) population pharmacokinetic analysis using the most useful sampling time points

derived from modeling of adult data.

2. Efficacy (2.4.2)

The principles in study design, statistical considerations, and choice of control groups

detailed in ICH E6, E9, and E10 generally apply to pediatric efficacy studies. There are,

however, certain features unique to pediatric studies. The potential for extrapolation of

efficacy from studies in adults to pediatric patients or from older to younger pediatric

patients is discussed in section II.D. Where efficacy studies are going to be conducted,

companies may want to develop, validate, and employ different endpoints for specific age

and developmental subgroups. Measurement of subjective symptoms, such as pain, calls

for different assessment instruments for patients of different ages. In pediatric patients with

chronic diseases, the response to a medicinal product may vary among patients not only

because of the duration of the disease and its chronic effects but also because of the

developmental stage of the patient. Many diseases in the preterm and term newborn infant

are unique or have unique manifestations precluding extrapolation of efficacy from older

pediatric patients and call for novel methods of outcome assessment.

3. Safety (2.4.3)

ICH guidances on E2 topics and ICH E6, which describe adverse event reporting, apply to

pediatric studies. Age-appropriate, normal laboratory values and clinical measurements

should be used in adverse event reporting. Unintended exposures to medicinal products

(accidental ingestions) may provide the opportunity to obtain safety and pharmacokinetic

information and to maximize understanding of dose-related side effects.

Medicinal products may affect physical and cognitive growth and development, and the

adverse event profile may differ in pediatric patients. Because developing systems may

respond differently from matured adult organs, some adverse events and drug interactions

that occur in pediatric patients may not be identified in adult studies. In addition, the

dynamic processes of growth and development may not manifest an adverse event acutely,

but at a later stage of growth and maturation. Long-term studies or surveillance data, either

while patients are on chronic therapy or during the posttherapy period, may be needed to

determine possible effects on skeletal, behavioral, cognitive, sexual, and immune

maturation and development.

4. Postmarketing Information (2.4.4)
9

Normally the pediatric database is limited at the time of approval. Therefore,

postmarketing surveillance is particularly important. In some cases, long-term follow-up

studies may be important to determine effects of certain medications on growth and

development of pediatric patients. Postmarketing surveillance and/or long-term follow-up

studies may provide safety and/or efficacy information for subgroups within the pediatric

population or additional information for the entire pediatric population.

E. Age Classification of Pediatric Patients (2.5)

Any classification of the pediatric population into age categories is to some extent

arbitrary, but a classification such as the one below provides a basis for thinking about

study design in pediatric patients. Decisions on how to stratify studies and data by age

should take into consideration developmental biology and pharmacology. Thus, a flexible

approach is necessary to ensure that studies reflect current knowledge of pediatric

pharmacology. The identification of which ages to study should be medicinal productspecific and justified.

If the clearance pathways of a medicinal product are well established and the ontogeny of

the pathways is understood, age categories for pharmacokinetic evaluation might be

chosen based on any break point where clearance is likely to change significantly.

Sometimes, it may be more appropriate to collect data over broad age ranges and

examine the effect of age as a continuous covariant. For efficacy, different endpoints may

be established for pediatric patients of different ages, and the age groups might not

correspond to the categories presented below. Dividing the pediatric population into many

age groups might needlessly increase the number of patients required. In longer term

studies, pediatric patients may move from one age category to another; the study design

and statistical plans should prospectively take into account changing numbers of patients

within a given age category.

The following is one possible categorization. There is, however, considerable overlap in

developmental (e.g., physical, cognitive, and psychosocial) issues across the age

categories. Ages are defined in completed days, months, or years.

• Preterm newborn infants

• Term newborn infants (0 to 27 days)

• Infants and toddlers (28 days to 23 months)

• Children (2 to 11 years)

• Adolescents (12 to 16-18 years (dependent on region))

1. Preterm Newborn Infants (2.5.1)

The study of medicinal products in preterm newborn infants presents special challenges

because of the unique pathophysiology and responses to therapy in this population. The

complexity of and ethical considerations involved in studying preterm newborn infants

suggest the need for careful protocol development with expert input from neonatologists
10

and neonatal pharmacologists. Only rarely will it be possible to extrapolate efficacy from

studies in adults or even in older pediatric patients to the preterm newborn infant.

The category of preterm newborn infants is not a homogeneous group of patients. A 25-

week gestation, 500-gram (g) newborn is very different from a 30-week gestation newborn

weighing 1,500 g. A distinction should also be made for low-birth-weight babies as to

whether they are immature or growth retarded. Important features that should be

considered for these patients include:

1. gestational age at birth and age after birth (adjusted age);

2. immaturity of renal and hepatic clearance mechanisms;

3. protein binding and displacement issues (particularly bilirubin);

4. penetration of medicinal products into the central nervous system (CNS);

5. unique neonatal disease states (e.g., respiratory distress syndrome of the newborn,

patent ductus arteriosus, primary pulmonary hypertension);

6. unique susceptibilities of the preterm newborn (e.g., necrotizing enterocolitis,

intraventricular hemorrhage, retinopathy of prematurity);

7. rapid and variable maturation of all physiologic and pharmacologic processes

leading to different dosing regimens with chronic exposure; and

8. transdermal absorption of medicinal products and other chemicals.

Study design issues that should be considered include:

1. weight and age (gestational and postnatal) stratification;

2. small blood volumes (a 500-g infant has 40 mL of blood);

3. small numbers of patients at a given center and differences in care among centers;

and

4. difficulties in assessing outcomes.

2. Term Newborn Infants (0 to 27 days) (2.5.2)

Although term newborn infants are developmentally more mature than preterm newborn

infants, many of the physiologic and pharmacologic principles discussed above also apply

to term infants. Volumes of distribution of medicinal products may be different from those

in older pediatric patients because of different body water and fat content and high bodysurface-area-to-weight ratio. The blood-brain barrier is still not fully mature and medicinal

products and endogenous substances (e.g., bilirubin) may gain access to the CNS with

resultant toxicity. Oral absorption of medicinal products may be less predictable than in

older pediatric patients. Hepatic and renal clearance mechanisms are immature and

rapidly changing; doses may need to be adjusted over the first weeks of life. Many

examples of increased susceptibility to toxic effects of medicinal products result from

limited clearance in these patients (e.g., chloramphenicol grey baby syndrome). On the

other hand, term newborn infants may be less susceptible to some types of adverse effects

(e.g., aminoglycoside nephrotoxicity) than are patients in older age groups.
11

3. Infants and Toddlers (28 days to 23 months) (2.5.3)

This is a period of rapid CNS maturation, immune system development, and total body

growth. Oral absorption becomes more reliable. Hepatic and renal clearance pathways

continue to mature rapidly. By 1 to 2 years of age, clearance of many drugs on a mg/kg

basis may exceed adult values. The developmental pattern of maturation is dependent on

specific pathways of clearance. There is often considerable inter-individual variability in

maturation.

4. Children (2 to 11 years) (2.5.4)

Most pathways of drug clearance (hepatic and renal) are mature, with clearance often

exceeding adult values. Changes in clearance of a drug may be dependent on maturation

of specific metabolic pathways.

Specific strategies should be addressed in protocols to ascertain any effects of the

medicinal product on growth and development. Children achieve several important

milestones of psychomotor development that could be adversely affected by CNS-active

drugs. Entry into school and increased cognitive and motor skills may affect a child’s

ability to participate in some types of efficacy studies. Factors useful in measuring the

effects of a medicinal product on children include skeletal growth, weight gain, school

attendance, and school performance. Recruitment of patients should ensure adequate

representation across the age range in this category, as it is important to ensure a

sufficient number of younger patients for evaluation. Stratification by age within this

category is often unnecessary, but it may be appropriate to stratify patients based on

pharmacokinetic and/or efficacy endpoint considerations.

The onset of puberty is highly variable and occurs earlier in girls, in whom normal onset of

puberty may occur as early as 9 years of age. Puberty can affect the apparent activity of

enzymes that metabolize drugs, and dose requirements for some medicinal products on a

mg/kg basis may decrease dramatically (e.g., theophylline). In some cases, it may be

appropriate to specifically assess the effect of puberty on a medicinal product by studying

pre- and postpubertal pediatric patients. In other cases, it may be appropriate to record

Tanner stages of pubertal development or obtain biological markers of puberty and

examine data for any potential influence of pubertal changes.

5. Adolescents (12 to 16-18 years (dependent on region)) (2.5.5)

This is a period of sexual maturation; medicinal products may interfere with the actions of

sex hormones and impede development. In certain studies, pregnancy testing and review

of sexual activity and contraceptive use may be appropriate.

This is also a period of rapid growth and continued neurocognitive development.

Medicinal products and illnesses that delay or accelerate the onset of puberty can have a

profound effect on the pubertal growth spurt and, by changing the pattern of growth, may
12

affect final height. Evolving cognitive and emotional changes could potentially influence the

outcome of clinical studies.

Many diseases are also influenced by the hormonal changes around puberty (e.g.,

increases in insulin resistance in diabetes mellitus, recurrence of seizures around

menarche, changes in the frequency and severity of migraine attacks and asthma

exacerbations). Hormonal changes may thus influence the results of clinical studies.

Within this age group, adolescents are assuming responsibility for their own health and

medication. Noncompliance is a special problem, particularly when medicinal products

(for example, steroids) affect appearance. In clinical studies compliance checks are

important. Recreational use of unprescribed drugs, alcohol, and tobacco should be

specifically considered.

The upper age limit varies among regions. It may be possible to include older adolescents

in adult studies, although issues of compliance may present problems. Given some of the

unique challenges of adolescence, it may be appropriate to consider studying adolescent

patients (whether they are to be included in adult or separate protocols) in centers

knowledgeable and skilled in the care of this special population.

F. Ethical Issues in Pediatric Studies (2.6)

The pediatric population represents a vulnerable subgroup. Therefore, special measures

are needed to protect the rights of pediatric study participants and to shield them from

undue risk. The purpose of this section is to provide a framework to ensure that pediatric

studies are conducted ethically.

To be of benefit to those participating in a clinical study, as well as to the rest of the

pediatric population, a clinical study must be properly designed to ensure the quality and

interpretability of the data obtained. In addition, participants in clinical studies should

benefit from the clinical study except under the special circumstances discussed in ICH E6.

1. Institutional Review Board/Independent Ethics Committee (IRB/IEC)

(2.6.1)

The roles and responsibilities of IRBs and IECs, as detailed in ICH E6, are critical to the

protection of study participants. When protocols involving the pediatric population are

reviewed, there should be IRB/IEC members or experts consulted by the IRB/IEC who are

knowledgeable in pediatric ethical, clinical, and psychosocial issues.

2. Recruitment (2.6.2)

Recruitment of study participants should occur in a manner free from inappropriate

inducements either to the parent(s)or legal guardian or the study participant.
13

Reimbursement and subsistence costs may be covered in the context of a pediatric clinical

study. Any compensation should be reviewed by the IRB/IEC.

When studies are conducted in the pediatric population, an attempt should be made to

include individuals representing the demographics of the region and the disease being

studied, unless there is a valid reason for restricting enrollment.

3. Consent and Assent (2.6.3)

As a rule, a pediatric subject is legally unable to provide informed consent. Therefore

pediatric study participants are dependent on their parent(s) or legal guardian to assume

responsibility for their participation in clinical studies. Fully informed consent should be

obtained from the legal guardian in accordance with regional laws or regulations. All

participants should be informed to the fullest extent possible about the study in language

and terms they are able to understand. Where appropriate, participants should assent to

enroll in a study (age of assent may be determined by IRBs and IECs or be consistent with

local legal requirements). Participants of appropriate intellectual maturity should personally

sign and date either a separately designed, written assent form, or the written informed

consent. In all cases, participants should be made aware of their rights to decline to

participate or to withdraw from the study at any time. Attention should be paid to signs of

undue distress in patients who are unable to clearly articulate their distress. Although a

participant’s wish to withdraw from a study must be respected, there may be

circumstances in therapeutic studies for serious or life-threatening diseases in which, in the

opinion of the investigator and parent(s) or legal guardian, the welfare of a pediatric patient

would be jeopardized by his or her failing to participate in the study. In such a situation,

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

the study. Emancipated or mature minors (defined by local laws) may be capable of giving

autonomous consent.

Information that can be obtained in a less vulnerable, consenting population should not be

obtained in a more vulnerable population or one in which the patients are unable to provide

individual consent. Studies in handicapped or institutionalized pediatric populations

should be limited to diseases or conditions found principally or exclusively in these

populations, or situations in which the disease or condition in these pediatric patients

would be expected to alter the disposition or pharmacodynamic effects of a medicinal

product.

4. Minimizing Risk (2.6.4)

However important a study may be to prove or disprove the value of a treatment,

participants may suffer injury as a result of inclusion in a study, even if the whole community

benefits. Every effort should be made to anticipate and reduce known hazards.

Investigators should be fully aware before the start of a clinical study of all relevant

preclinical and clinical toxicity of the medicinal product. To minimize risk in pediatric

clinical studies, those conducting the study should be properly trained and experienced in
14

studying the pediatric population, including the evaluation and management of potential

pediatric adverse events.

In designing studies, every attempt should be made to minimize the number of participants

and of procedures, consistent with good study design. Mechanisms should be in place to

ensure that a study can be rapidly terminated should an unexpected hazard be identified.

5. Minimizing Distress (2.6.5)

Repeated invasive procedures may be painful or frightening. Discomfort can be minimized

if studies are designed and conducted by investigators experienced in the treatment of

pediatric patients.

Protocols and investigations should be designed specifically for the pediatric population

(not simply re-worked from adult protocols) and approved by an IRB or IEC as described in

section II.F.1.

Practical considerations to ensure that participants’ experiences in clinical studies are

positive and to minimize discomfort and distress include the following:

• Personnel knowledgeable and skilled in dealing with the pediatric population and its

age-appropriate needs, including skill in performing pediatric procedures

• A physical setting with furniture, play equipment, activities, and food appropriate for

age

• The conduct of studies in a familiar environment such as the hospital or clinic where

participants normally receive their care

• Approaches to minimize discomfort of procedures, such as (1) topical anesthesia to

place IV catheters, (2) indwelling catheters rather than repeated venipunctures for

blood sampling, and (3) collection of some protocol-specified blood samples when

routine clinical samples are obtained.

IRBs and IECs should consider how many venipunctures are acceptable in an attempt to

obtain blood samples for a protocol and ensure a clear understanding of procedures if an

indwelling catheter fails to function over time. The participant’s right to refuse further

investigational procedures should always be respected except as noted in section II.F.3.