[Federal Register Volume 65, Number 71 (Wednesday, April 12, 2000)]
[Notices]
[Pages 19777-19781]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-9064]



[[Page 19777]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00D-1223]


International Conference on Harmonisation; E11: Clinical 
Investigation of Medicinal Products in the Pediatric Population

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
guidance entitled ``E11: Clinical Investigation of Medicinal Products 
in the Pediatric Population.'' The draft guidance was prepared under 
the auspices of the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH). The draft guidance sets forth critical issues in pediatric 
drug development and approaches to the safe, efficient, and ethical 
study of medicinal products in the pediatric population. The draft 
guidance is intended to encourage and facilitate the timely development 
of pediatric medicinal products internationally.

DATES: Submit written comments by May 30, 2000.

ADDRESSES: Submit written comments on the draft guidance to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852. Copies of the draft guidance are 
available from the Drug Information Branch (HFD-210), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-827-4573. Single copies of the draft 
guidance may be obtained by mail from the Office of Communication, 
Training and Manufacturers Assistance (HFM-40), Center for Biologics 
Evaluation and Research (CBER), 1401 Rockville Pike, Rockville, MD 
20852, or by calling the CBER Voice Information System at 1-800-835-
4709 or 301-827-1800. Copies may be obtained from CBER's FAX 
Information System at 1-888-CBER-FAX or 301-827-3844.

FOR FURTHER INFORMATION CONTACT:
    Regarding the guidance: M. Dianne Murphy, Center for Drug 
Evaluation and Research (HFD-2), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857.
    Regarding the ICH: Janet J. Showalter, Office of Health Affairs 
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville, 
MD 20857, 301-827-0864.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote international harmonization of regulatory 
requirements. FDA has participated in many meetings designed to enhance 
harmonization and is committed to seeking scientifically based 
harmonized technical procedures for pharmaceutical development. One of 
the goals of harmonization is to identify and then reduce differences 
in technical requirements for drug development among regulatory 
agencies.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
consumer representatives and others. ICH is concerned with 
harmonization of technical requirements for the registration of 
pharmaceutical products among three regions: The European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission, the European Federation of Pharmaceutical Industries 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, the Centers for Drug 
Evaluation and Research and Biologics Evaluation and Research, FDA, and 
the Pharmaceutical Research and Manufacturers of America. The ICH 
Secretariat, which coordinates the preparation of documentation, is 
provided by the International Federation of Pharmaceutical 
Manufacturers Associations (IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization, the Canadian Health Protection Branch, and the 
European Free Trade Area.
    In October 1999, the ICH Steering Committee agreed that a draft 
guidance entitled ``E11: Clinical Investigation of Medicinal Products 
in the Pediatric Population'' should be made available for public 
comment. The draft guidance is the product of the Efficacy Expert 
Working Group of the ICH. Comments about this draft will be considered 
by FDA and the Efficacy Expert Working Group.
    In accordance with FDA's good guidance practices (62 FR 8961, 
February 27, 1997), this document is being called a guidance, rather 
than a guideline.
    The draft guidance sets forth critical issues in pediatric drug 
development and approaches to the safe, efficient, and ethical study of 
medicinal products in the pediatric population. The draft guidance 
addresses the following clinical study issues: (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, 
efficacy, safety); (4) age categories for studies; and (5) ethics of 
pediatric clinical investigation. The draft guidance is not 
comprehensive, but is intended to be used in conjunction with other ICH 
guidances and documents from regional regulatory authorities and 
pediatric societies. The draft guidance is intended to encourage and 
facilitate the timely development of pediatric medicinal products 
internationally.
    This draft guidance represents the agency's current thinking on 
clinical investigation of medicinal products in the pediatric 
population. 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 statute, regulations, or both.
    Interested persons may submit to the Dockets Management Branch 
(address above) written comments on the draft guidance on or before May 
30, 2000. Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. A copy 
of the draft guidance and received comments may be seen in the office 
above between 9 a.m. and 4 p.m., Monday through Friday. An electronic 
version of this guidance is available on the Internet at http://www.fda.gov/cder/guidance/index.htm or at http://www.fda.gov/cber/publications.htm.
    The text of the draft guidance follows:

E11: Clinical Investigation of Medicinal Products in the Pediatric 
Population \1\

1. Introduction

1.1 Objectives of the Guidance 

    The number of medicinal products currently labeled for pediatric 
use is limited. It is the goal of this guidance to encourage and 
facilitate timely pediatric medicinal product development 
internationally. The

[[Page 19778]]

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.
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    \1\ This draft guidance represents the agency's current thinking 
on clinical investigation of medicinal products in the pediatric 
population. 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 statute, regulations, or both.
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1.2 Background

    Other ICH documents on the following topics include relevant 
information impacting on pediatric studies:
     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
     E8: General Considerations for Clinical Trials
     E9: Statistical Principles for Clinical Trials
     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

1.3 Scope of the Guidance

    Specific clinical study issues addressed 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 for studies; 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.

1.4 General Principles

    Pediatric patients should be given medicines that have been 
appropriately evaluated for their use. 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. Major advances in 
formulation chemistry and in pediatric study design ensure that this 
goal can be achieved.
    Drug development programs should include the pediatric patient 
population when a product is being developed for a disease/condition 
in adults and it is anticipated the product will be used in the 
pediatric population. The ethical imperative to obtain knowledge of 
the effects of medicinal products in pediatric patients has to be 
balanced against the ethical imperative to protect each pediatric 
patient in clinical studies. This responsibility is shared by 
companies, regulatory authorities, health professionals, and society 
as a whole.

2. Guidance

2.1 Issues When Initiating a Pediatric Medicinal Product 
Development Program

    Data on the appropriate use of medicinal products in the 
pediatric population should be available unless the use of a 
specific medicinal product in pediatric patients is clearly 
inappropriate. The 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 2.3. In 
general, pediatric studies should not delay completion of adult 
studies and availability of a medicinal product for adults. 
Justification for timing and the approach to the clinical program 
needs to be clearly addressed with regulatory authorities at an 
early stage.
    The decision to proceed with a pediatric development program, 
and the nature of the program, for a medicinal product involves 
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 age ranges of patients likely to be treated with 
the medicinal product
     Unique pediatric (developmental) safety concerns about 
the medicinal product, including any nonclinical safety issues
     Potential need for pediatric formulation development
    Of these factors, most important is the presence of a serious 
disease without good current 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, section 11. It 
should be noted that the most relevant safety data for pediatric 
studies come ordinarily from adult human exposure. Repeat-dose 
toxicology and reproductive toxicology/genotoxicology 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.

2.2 Pediatric Formulations

    There is a need for pediatric formulations that permit accurate 
dosing and enhance patient compliance. For oral administration, 
different types of formulations (suspensions, ``sprinkles,'' 
chewable tablets) and different 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 
concentrations of these various formulations may also be necessary. 
Consideration should be given to the development of alternative 
approaches for delivery of medicinal products such as patches or 
suppositories.
    For injectable formulations, the concentration of the medicinal 
product needs to be compatible with the doses to be administered, 
including doses for small premature infants if the drug is to be 
used in that population. This compatibility may require a more 
dilute solution to allow accurate administration of the dose using 
available syringes and administration pumps or a more concentrated 
solution where fluid restriction imposed for very small patients is 
a concern. For medicinal products supplied as single-use vials, 
consideration should be given to dose-appropriate single-dose 
packaging, conditions for safe multiple use of preservative-free 
vials, or addition of preservatives. Some excipients (e.g., benzyl 
alcohol) may be toxic, particularly 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 will help ensure 
that appropriate formulations are available for the pediatric 
population everywhere (see ICH guidances on topics Q1 through Q3).

2.3 Timing of Studies

    During clinical development, the timing of pediatric studies 
should be flexible and 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.

2.3.1 Medicinal Products for Diseases Predominantly or Exclusively 
Affecting Pediatric Patients

    In this case, the entire development program will be conducted 
in the pediatric population except for initial safety and 
tolerability data, which will usually be obtained from 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.

2.3.2 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

    In this case, medicinal product development should begin early 
in the pediatric population, following initial safety data and 
reasonable evidence of potential benefit. Pediatric study results 
should be part of the marketing application data base. In 
circumstances where this has not been possible, lack of data should 
be justified in detail.

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2.3.3 Medicinal Products Intended to Treat Other Diseases and 
Conditions

    In this case, where the medicinal product will be used in 
pediatric patients but there is less urgency than in the previous 
cases, studies might begin at various phases of clinical development 
or, if a safety concern exists, even after substantial postmarket 
experience in adults. Companies should have a clear plan for 
pediatric studies and reasons for their choice of when to initiate 
them. Testing of these medicinal products in the pediatric 
population would usually not begin until Phase 2 or 3. In most 
cases, only limited pediatric data would be available at the time of 
application submission, but more would be expected after marketing. 
Even for a nonserious disease, if the medicinal product represents a 
major therapeutic advance for the pediatric population, studies 
should begin as early in development as possible, and the submission 
of pediatric data would be expected in the application. Lack of data 
should be justified in detail. As the development of many new 
chemical entities is discontinued in Phase 1 and 2 adult trials for 
lack of efficacy or an unacceptable side effect profile, very early 
initiation of testing in pediatric patients might needlessly expose 
these patients to a compound that will be of no benefit. Thus, it is 
important to carefully weigh risk/benefit and therapeutic need in 
deciding when to start studies.

2.4 Types of Studies

    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) factors that could impact the extrapolation of data to 
other regions should be considered.
    When the 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 or other studies, may provide adequate information for use by 
allowing selection of pediatric doses that will produce blood levels 
similar to those observed in 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. This 
approach may be necessary where assessment of outcome variables is 
particularly difficult in younger patients (e.g., forced expiratory 
volume (FEV1) below the age of 6 years). In such cases, 
pharmacokinetic studies in all 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.
    A pharmacokinetic approach may not be sufficient for medicinal 
products where blood levels are not known to correspond with 
efficacy or where there is concern that the concentration-response 
relationship may differ between the adult and pediatric populations. 
Where the comparability of the disease course or outcome of therapy 
in pediatric patients is expected to be similar, but the appropriate 
blood levels are not clear, it may be possible to use measurements 
of a pharmacodynamic effect to confirm the expectations of 
effectiveness and to define the dose and concentration needed to 
attain that pharmacodynamic effect. Such studies would provide 
increased confidence that achieving a given exposure to the 
medicinal product in pediatric patients will result in the desired 
therapeutic outcomes. A PK/PD approach could avoid the need for 
clinical efficacy studies.
    For certain products, it may be useful to determine blood levels 
for purposes of safety assessment (e.g., to determine relative 
systemic exposure for topically applied agents).
    When novel indications are being sought for the medicinal 
product in pediatric patients, or where the disease course and 
outcome of therapy are likely to be different in adults and 
pediatric patients, clinical efficacy studies in the pediatric 
population would need to be conducted. Similarly, in situations 
where a pharmacokinetic approach is not applicable, such as for 
topically active products, studies may need to include clinical 
endpoints or appropriate alternative assessments.

2.4.1 Pharmacokinetics

    Pharmacokinetic studies generally should be performed to support 
formulation development, determine pharmacokinetic parameters in 
different age groups to support dosing recommendations, and 
understand PK/PD relationships where these may differ from adults. 
Bioequivalence comparisons of pediatric formulations with the adult 
oral formulation typically should be done in adults. Definitive 
pharmacokinetic studies for dose selection across age ranges where 
the medicinal product is likely to be used should be conducted in 
the pediatric population.
    Pharmacokinetic studies in the pediatric population differ from 
most adult PK studies in that they are generally conducted in 
patients with the disease. This may lead to higher intersubject 
variability, but the data better reflect clinical use.
    For medicinal products that exhibit linear pharmacokinetics in 
adults, single-dose pharmacokinetic studies in the pediatric 
population may often be sufficient to ascertain correct dosing. This 
can be corroborated, if indicated, by sparse population sampling in 
multidose clinical studies. Any nonlinearity in absorption, 
distribution, and elimination in adults and any duration-of-effect-
related changes would suggest the need for steady state studies in 
the pediatric population. All these approaches are 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 will often 
be helpful in planning pediatric studies.
    Dosing recommendations for most medicinal products used in the 
pediatric population are usually based on milligrams (mg)/kilograms 
(kg) up to a maximum adult dose. While dosing on a mg/square meter 
basis might be preferred, clinical experience indicates that errors 
in measuring height or length (particularly in smaller children and 
infants) and calculation errors of 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 with extra care to ensure 
proper dose calculation.

Practical Considerations to Facilitate Pharmacokinetic Studies

    The volume of blood withdrawn should be minimized in pediatric 
studies; institutional review boards/independent ethics committees 
(IRB's/IEC's) generally establish the maximum amount of blood 
(usually on a milliliters (mL)/kg or percentage of total blood 
volume basis) that may be taken for experimental purposes. Several 
approaches can be used to minimize the amount of blood drawn:
     Use of sensitive assays (gas chromatography/mass 
spectroscopy, tandem mass spectroscopy) for parent drugs and 
metabolites to decrease the volume of blood required per sample
     Use of 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
     Use of population pharmacokinetic approaches to 
minimize the number of samples obtained from each patient. 
Techniques include:
    -- 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''
    -- Population pharmacokinetic analysis using the most useful 
sampling time points derived from modeling of adult data
    -- The use of indwelling catheters, etc., to minimize distress 
as discussed in section 2.6.5.

2.4.2 Efficacy

    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 
unique features 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 2.4. Where efficacy studies are needed, it may be necessary 
to develop, validate, and employ different endpoints for specific 
age and developmental subgroups. Measurement of subjective symptoms 
such as pain requires different assessment instruments for patients

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of different ages. Responses of chronic diseases may vary in 
patients with early stages of disease and in patients with years of 
disability and organ dysfunction. Many diseases in the preterm and 
term newborn infant are unique or have unique manifestations 
precluding extrapolation of efficacy from older pediatric patients 
and calling for novel methods for outcome assessment.

2.4.3 Safety

    Reporting requirements for adverse events, as described in ICH 
guidances on E2 topics and ICH E6, apply to pediatric studies. Age-
appropriate, normal laboratory values and clinical measurements 
should be used in adverse event reporting. Unexpected exposures to 
medicinal products (accidental ingestions, etc.) 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 than 
matured adult organs, some adverse events 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, either while patients are on chronic therapy or 
during the post-therapy period, may be needed to determine possible 
effects on skeletal, behavioral, cognitive, sexual, and immune 
maturation and development.

2.4.4 Postmarketing Experience

    Normally the pediatric data base is limited at the time of 
approval. Therefore, postmarketing and long-term followup studies 
and surveillance are particularly important. They may provide safety 
and/or efficacy information for subgroups within the pediatric 
population or additional information for the entire pediatric 
population.

2.5 Age Classification of Pediatric Patients

    Any classification of the pediatric population into age 
categories is arbitrary, but classification provides an initial 
basis for thinking about study design in pediatric patients. As 
discussed below, decisions about how to stratify studies and data by 
age need to consider developmental biology and pharmacology. Thus, a 
flexible approach is necessary to ensure that studies reflect 
current knowledge of pediatric pharmacology.
    If the clearance pathways of a medicinal product are well 
established and the ontogeny of the pathways understood, age 
categories for pharmacokinetic evaluation might be chosen based on 
any ``break point'' where clearance is likely to change 
dramatically. 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 too many small 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 suggested as a possible categorization. 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 to 18 years (dependent on 
region))

2.5.1 Preterm Newborn Infants

    The study of medicinal products in preterm newborn infants 
presents specific challenges because of the unique pathophysiology 
and responses to therapy in this population. The complexity and 
ethical considerations of studying preterm infants suggest the need 
for careful protocol development with expert input from 
neonatologists 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 infant.
    The category of preterm 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. Essential features to 
be considered in this age range 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/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 
assessing outcomes.

2.5.2 Term Newborn Infants (0 to 27 days)

    While 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., digoxin-induced arrhythmias, aminoglycoside nephrotoxicity).

2.5.3 Infants and Toddlers (28 days to 23 months)

    This is a period of CNS maturation associated with completion of 
myelination. During this time, the immune system is rapidly 
developing, and both total body growth and brain growth are rapid. 
Oral absorption becomes more reliable. Hepatic and renal clearance 
pathways continue to mature rapidly. Clearance of many drugs on a 
mg/kg basis may exceed adult values by 1 to 2 years of age. The 
developmental pattern of maturation is dependent on specific 
pathways of clearance. There is often considerable interindividual 
variability in maturation.

2.5.4 Children (2 to 11 years)

    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. Similarly, entry into school and increased cognitive 
and motor skills may affect a child's ability to participate in some 
types of efficacy studies (e.g., FEV1, pain assessment scales). 
Among factors useful in determining the effects of a medicinal 
product on children are skeletal growth, weight gain, school 
attendance, and school performance. Recruitment of patients should 
ensure adequate representation across the age range in this 
category. This is important to ensure a sufficient number of younger 
patients for evaluation. Stratification by age within this category 
often is 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

[[Page 19781]]

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.

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

    This is a period of sexual maturation; medicinal products may 
interfere with the actions of sex hormones and impede development. 
Pregnancy testing and, in relevant studies, review of sexual 
activity and contraceptive use become necessary.
    This is also a period of rapid growth. 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 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., insulin resistance increases in diabetes mellitus, 
seizures may recur around menarche, frequency and severity of 
migraine and asthma change). 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 should be 
specifically considered and monitored.
    The upper age limit was arbitrarily set and may vary 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 skillful in the care of this special population.

2.6 Ethical Issues in Pediatric Studies

    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 
are expected to obtain some direct or indirect benefit from the 
clinical study except under the special circumstances discussed in 
ICH E6 (``Good Clinical Practice,'' section 4.8.14).

2.6.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC)

    The roles and responsibilities of IRB's/IEC's 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.

2.6.2 Recruitment

    Recruitment of study participants should occur in a noncoercive 
manner. While reimbursement and subsistence costs may be covered in 
the context of a pediatric clinical study, coercive inducements 
(financial or other), either to the parents or to the child, are not 
appropriate.
    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.

2.6.3 Consent

    Pediatric study participants are dependent on their parents or 
guardians who take legal responsibility for the participants' 
welfare and safety; fully informed consent should be obtained from 
the legal guardian in accordance with regional laws or regulations. 
All participants should be fully informed about the study in 
language and terms they are able to understand. Participants should 
assent to enroll in a study (age of assent to be determined by 
IRB's/IEC's). 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. A 
participant's wish to withdraw from a study must be respected. There 
may be circumstances in therapeutic studies where, in the opinion of 
the investigator, parents, and IRB/IEC, the welfare of a pediatric 
patient would be jeopardized by his or her failing to participate in 
the study; the patient's agreement or assent may be waived under 
such circumstances. Emancipated or mature minors (as 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 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 where the disease or condition in these 
pediatric patients would be expected to alter the disposition or 
pharmacodynamic effects of a medicinal product.

2.6.4 Minimizing Risk

    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 the 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 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 noted.

2.6.5 Minimizing Distress

    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 a competent and experienced IRB/IEC.
    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, andfood appropriate for age
     Conducting studies in a familiar environment such as 
the hospital or clinic where participants normally receive their 
care
     Using approaches to minimize discomfort of procedures, 
such as:
    -- Topical anesthesia to place IV catheters
    -- Indwelling catheters rather than repeated venipunctures for 
blood sampling
    -- Collection of some protocol-specified blood samples when 
routine clinical samples are obtained
    IRB's/IEC's 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 must be respected.

    Dated: April 5, 2000.
William K. Hubbard,
Senior Associate Commissioner for Policy, Planning, and Legislation.
[FR Doc. 00-9064 Filed 4-11-00; 8:45 am]
BILLING CODE 4160-01-F