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
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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 Industry
E11 Clinical Investigation of Medicinal Products
in the Pediatric Population
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.
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).
1 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)
2 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
3 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 single-
use 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
4 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.
5 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
6 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
7   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)
8 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 product-
specific 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
9 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 body-
surface-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.
10 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 childs
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
11 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.
12 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
participants 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
13 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 participants right to refuse further
investigational procedures should always be respected except as noted in section II.F.3.
14