E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

E11(R1) Addendum: Clinical
Investigation of Medicinal
Products in the Pediatric
Population
Guidance for Industry
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)
April 2018
ICH

E11(R1) Addendum: Clinical
Investigation of Medicinal
Products in the Pediatric
Population
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
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and/or
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Email: ocod@fda.hhs.gov
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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)
April 2018
ICH

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TABLE OF CONTENTS
I. INTRODUCTION (1)................................................................................................. 1
A. Scope and Objective of the ICH E11 Guidance Addendum (R1) (1.1)................................ 1
II. ETHICAL CONSIDERATIONS (2) .......................................................................... 2
III. COMMONALITY OF SCIENTIFIC APPROACH FOR PEDIATRIC DRUG
DEVELOPMENT PROGRAMS (3) .......................................................................... 3
IV. AGE CLASSIFICATION AND PEDIATRIC SUBGROUPS, INCLUDING
NEONATES (4).......................................................................................................... 4
V. APPROACHES TO OPTIMIZE PEDIATRIC DRUG DEVELOPMENT (5).......... 4
A. The Use of Existing Knowledge in Pediatric Drug Development (5.1) ................................ 5
B. The Use of Extrapolation in Pediatric Drug Development (5.2) ......................................... 5
C. The Use of Modelling and Simulation in Pediatric Drug Development (5.3) ....................... 6
VI. PRACTICALITIES IN THE DESIGN AND EXECUTION OF PEDIATRIC
CLINICAL TRIALS (6)............................................................................................. 7
A. Feasibility (6.1) ............................................................................................................. 7
B. Outcome Assessments (6.2) ............................................................................................ 8
C. Long-Term Clinical Aspects, Including Safety (6.3) ......................................................... 8
VII. PEDIATRIC FORMULATIONS (7) .......................................................................... 8
A. Dosage and Administration (7.1) .................................................................................... 9
B. Excipients (7.2) ............................................................................................................. 9
C. Palatability and Acceptability (7.3)................................................................................. 9
D. Neonates (7.4) ..............................................................................................................10
GLOSSARY......................................................................................................................... 11

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1
E11(R1) Addendum: Clinical Investigation of Medicinal Products
in the Pediatric Population
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency)
on this topic. It does not establish any rights for any person and is not binding on FDA or the public.
You can use an alternative approach if it satisfies the requirements of the applicable statutes and
regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance
as listed on the title page.
I. INTRODUCTION (1)2
A. Scope and Objective of the ICH E11 Guidance Addendum (R1) (1.1)
Pediatric drug development has evolved since the original guidance E11 Clinical
Investigation of Medicinal Products in the Pediatric Population (ICH E11 (2000))3
published, requiring consideration of regulatory and scientific advances relevant to pediatric
populations. This addendum does not alter the scope of the original guidance. ICH E11
(2000), including this addendum (R1); is not intended to be comprehensive; other ICH
guidances, as well as documents from regulatory authorities worldwide, the World Health
Organization (WHO), and pediatric societies, provide additional detail. The purpose of the
addendum is to complement and provide clarification and current regulatory perspective on
topics in pediatric drug development.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed
only as recommendations, unless specific regulatory or statutory requirements are cited. The
use of the word should in Agency guidances means that something is suggested or
1 This guidance was developed within the Expert Working Group (Multidisciplinary) of the International
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use), and has been subject to consultation by the regulatory parties, in accordance with the ICH process.
This document was endorsed by the ICH Steering Committee at Step 4 of the ICH process, August 2017. At
Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European
Union, Japan, and the United States.
2 This guidance finalizes the draft guidance E11(R1) Addendum: Clinical Investigation of Medicinal Products in
the Pediatric Population, issued November 22, 2016 (81 FR 83847). Arabic numbers reflect the organizational
breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, August
2017.
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the
FDA Drugs guidance web page at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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recommended, but not required, unless specific regulatory or statutory requirements are
specified as advised by regulatory authorities worldwide.
In this addendum, section II (2) on ETHICAL CONSIDERATIONS, section IV (4) on AGE
CLASSIFICATION AND PEDIATRIC SUBGROUPS INCLUDING NEONATES, and
section VII (7) on PEDIATRIC FORMULATIONS, supplement the content in ICH E11
(2000). Section III (3) on COMMONALITY OF SCIENTIFIC APPROACH FOR
PEDIATRIC DRUG DEVELOPMENT PROGRAMS addresses issues to aid scientific
discussions at various stages of pediatric drug development in different regions. Section V
(5) on APPROACHES TO OPTIMIZE PEDIATRIC DRUG DEVELOPMENT includes
enhancement to the topic of Extrapolation, and introduces Modelling and Simulation (M&S).
These sections describe essential considerations intended to provide high-level guidance on
the implementation of these important approaches in pediatric drug development, reflecting
the evolving nature of these topics. This harmonized addendum will help to define the
current recommendations and reduce the likelihood that substantial differences will exist
among regions for the acceptance of data generated in pediatric global drug development
programs and will ensure timely access to medicines for children.
II. ETHICAL CONSIDERATIONS (2)
ICH E11 (2000) section II.F (2.6) addresses relevant principles for the ethical conduct of
pediatric studies, including the roles and responsibilities of the Institutional Review
Board/Independent Ethics Committee (IRB/IEC), recruitment of study participants, parental
(legal guardian) consent/permission and child assent, and minimization of risk and distress.
These ethical principles are also defined in the current legal and regulatory framework of
health authorities worldwide responsible for ensuring safeguards for the protection of
children participating in research.
A fundamental principle in pediatric drug development requires that children should not be
enrolled in a clinical study unless necessary to achieve an important pediatric public health
need.4 When clinical studies are used to obtain information relevant to the use of a medicinal
product, such studies should be conducted in pediatric populations having the disease or
condition for which the investigational product is intended, unless an exception is justified.
Without a prospect of clinical benefit from an experimental intervention or procedure, the
foreseeable risks to which a pediatric participant would be exposed must be low.5 The
burden of a procedure or an intended intervention should also be minimized. Experimental
interventions or procedures that present greater than low risk should offer a sufficient
prospect of clinical benefit to justify exposure of a pediatric population to such risk.
Likewise, the balance of risk and anticipated clinical benefit should be at least comparable to
the available alternative treatments.6 There should be a reasonable expectation that a clinical
benefit resulting from the clinical study can be made available to this population in the future.
The general principles of ethical considerations for parental (legal guardian)
consent/permission and child assent are outlined in ICH E11 (2000) section II.F.3 (2.6.3) and
continue to apply. Information regarding the clinical study and the process of parental (legal
guardian) consent/permission and child assent should be provided to the parent (legal
4 See 21 CFR 56.111.
5 See 21 CFR 50.51 and 50.53.
6 See 21 CFR 50.52.

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guardian) and/or child participant, as appropriate, at the time of enrollment, especially
relating to long-term studies or studies that may call for sample retention. When obtaining
child assent, relevant elements of informed consent should be provided appropriate to the
child’s capability to understand. Lack or absence of expression of dissent or objection must
not be interpreted as assent.7 Over the course of a clinical study, it may be necessary to
reassess the assent of a child in recognition of the child’s evolving maturity and competency.
During clinical studies, there may be a requirement for obtaining adequate informed consent
from pediatric participants once a child reaches the age of legal consent. Local regulations
related to confidentiality and privacy of pediatric participants should be followed.
Policies that promote clinical research transparency are also relevant in pediatric clinical
research. A fundamental principle of drug development is the public availability of objective
and unbiased clinical study results to enhance clinical research, to avoid unnecessary clinical
trials especially in children, and to inform clinical decisions in pediatric practice.
III. COMMONALITY OF SCIENTIFIC APPROACH FOR PEDIATRIC DRUG
DEVELOPMENT PROGRAMS (3)
General principles outlined in ICH E11 (2000) section I.D. (1.4) continue to apply. Pediatric
drug development programs are increasingly multiregional. Multiregional pediatric drug
development programs face specific challenges due to regional differences in pediatric
regulatory requirements, operational practicalities, and cultural expectations. These regional
differences in some instances limit the ability of health authorities to align regulatory
processes. Thus, timely and efficient drug development calls for a common scientific
approach for which the following key questions should be addressed:
(1) What is the medical need in one or more pediatric populations that the drug could
address?
(2) Who are the appropriate pediatric populations or subgroups that could be
considered?
(3) What objectives(s) for the pediatric development program could be considered?
(4) Based on the existing knowledge, including developmental physiology, disease
pathophysiology, nonclinical data, data in adult or pediatric populations or
subgroups, or data from related compounds, what are the knowledge gaps?
(5) Are there specific juvenile animal studies that should be conducted?
(6) What clinical studies and/or methodological approaches could be considered?
(7) What pediatric-specific clinical study design elements could be considered?
(8) Are there different formulations/dosage forms that should be used for specific
pediatric subgroups, both to facilitate an optimal dose-finding strategy, and for
treatment of pediatric patients in different subgroups?
A common scientific approach should consider input from stakeholders (e.g., clinicians,
patients, experts from academia) and should be based on scientific advances and up-to-date
knowledge.
Early consideration of pediatric populations during drug development planning, along with
early interactions between drug developers and regulatory authorities worldwide, can
7 See 21 CFR 50.3(n)

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facilitate agreement on a common scientific approach. When differences are identified,
established regulatory pathways to minimize the impact of these differences can be used.
Therefore, a common scientific approach, not common regional requirements, is at the
cornerstone of efficient pediatric drug development and timely delivery of safe and effective
medicines for children.
IV. AGE CLASSIFICATION AND PEDIATRIC SUBGROUPS, INCLUDING
NEONATES (4)
A rationale for the selection of the pediatric population to be included in clinical studies
should be provided. Chronologic age alone may not serve as an adequate categorical
determinant to define developmental subgroups in pediatric studies. Physiological
development and maturity of organs, pathophysiology of disease or condition, and the
pharmacology of the investigational product are factors to be considered in determining the
subgroups in pediatric studies. Furthermore, the arbitrary division of pediatric subgroups by
chronological age for some conditions may have no scientific basis and could unnecessarily
delay development of medicines for children by limiting the population for study. Depending
on the condition and treatment, it may be justifiable to include pediatric subpopulations in
adult studies or adult subpopulations in pediatric studies.
Advances in medical care have led to better survival of high-risk newborn infants, especially
preterm newborn infants, which makes drug development research in newborn infants or
“neonates” increasingly important. Neonates include both term and preterm newborn infants.
The neonatal period for term newborn infants is defined as birth plus 27 days. The neonatal
period for preterm newborn infants is defined as beginning at birth and ending at the expected
date of delivery plus 27 days. As the neonatal population represents a broad maturational
range, the conditions that affect this population can vary considerably. A rationale for the
selection of a neonatal population in clinical studies should be provided.
V. APPROACHES TO OPTIMIZE PEDIATRIC DRUG DEVELOPMENT (5)
The concepts presented in ICH E11 (2000) section II.D (2.4) still apply. The principles
outlined in ICH E4, E5, E6, E9, and E10 should be consulted. The number of pediatric
studies and knowledge in the field of pediatrics has increased since ICH E11 (2000).
Respective regulations for pediatric drug development worldwide have also evolved.
However, drug development in pediatrics continues to present challenges and opportunities.
In some cases, there are difficulties with generating data across a pediatric population due to
a variety of ethical considerations and feasibility issues. Alternative approaches may provide
opportunities to address these issues when structured and integrated into the development
program as per the principles outlined in this addendum. Early multidisciplinary dialogue
regarding the acceptability of such approaches with regulatory authorities is recommended.
The planning for development of the drug for children should not begin when development in
adults reaches its conclusion.

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A. The Use of Existing Knowledge in Pediatric Drug Development (5.1)
To better inform the design of a pediatric drug development program, there is an opportunity
to use existing knowledge. Existing knowledge includes evidence already or concurrently
generated with the drug that is under development in adult and pediatric populations with the
same disease or condition. Existing knowledge also integrates nonclinical data, data about
related compounds, disease pathophysiology, as well as consideration of the developmental
physiology of the pediatric population or subgroup. Use of such information can optimize
pediatric drug development programs without reducing evidentiary standards. Safety and risk
consideration based on the existing knowledge should guide the decision whether specific
mitigation, such as staggered enrollment based on age group, is necessary. However, any
uncertainties related to the use of existing knowledge should be identified and managed
prospectively. As data are generated through the drug development cycle, it is possible that
the assumptions behind the parameters that have gone into the development strategy and
methodology may need to be revisited to take new information into account. This new
information will continue to inform the strategy and present an opportunity to further address
uncertainties.
Additional approaches to optimize pediatric drug development may include, but are not
limited to, statistical and pharmacometric methods, including M&S that integrate and
leverage existing knowledge, as well as extrapolation of information from other populations
(adults or pediatric subgroups).
B. The Use of Extrapolation in Pediatric Drug Development (5.2)
The concept of extrapolation is used in different ways in drug development. Pediatric
extrapolation is defined as an approach to providing evidence in support of effective and safe
use of drugs in the pediatric population when it can be assumed that the course of the disease
and the expected response to a medicinal product would be sufficiently similar in the
pediatric and reference (adult or other pediatric) population.
When a drug is studied in a pediatric population, consider all factors which may result in
different drug responses, such as intrinsic (e.g., developmental) and extrinsic (e.g.,
geographic) factors that could have an impact on the extrapolation of data from one
population to the other.
Where an extrapolation approach is scientifically justifiable, it should be a dynamic process
that examines several factors. including disease pathogenesis; criteria for disease diagnosis
and classification; measures of disease progression; and pathophysiological,
histopathological, and pathobiological characteristics that support the assumptions of
similarity of disease and similarity of response to therapy between the pediatric and the
reference populations. A thorough understanding of the differences between pediatric and
reference populations is critical relative to the pathophysiology of the disease; available
biomarker/endpoints; organ systems physiology (i.e., renal, hepatic, central nervous system,
skeletal, and immune systems), as well as clinical context of therapeutics; and
pharmacological behavior of the drug.
Support for the assumptions of similarity of disease and response to therapy, including
exposure-response relationship, and prediction of an effective dose for the intended
population, may be derived from existing data, published literature, expert panels and
consensus documents, or previous experience with other products in the same therapeutic

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class. All data and information gathered can either confirm the extrapolation approach or
inform how it might be improved. Ultimately, the exercise should identify whether there is
sufficient data to support extrapolation, or if additional clinical information is called for.
When efficacy in the pediatric population can be extrapolated from data obtained in the
reference populations, leveraging of safety data from the reference to the pediatric population
may be used; however, additional pediatric safety data should usually be used, as data in
adults may only provide some information about potential safety concerns related to the use
of a drug in the pediatric population (ICH E11 (2000) section II.D (2.4)).
When extrapolation is considered in a pediatric drug development strategy, the following
framework of questions should be discussed to assess what additional supportive data are
important:
(1) What evidence supports a common pathophysiology of disease, natural history, and
similarity of the disease course between the reference and pediatric population(s)?
(2) What is the strength of the evidence of efficacy in the reference populations?
(3) Is there a biomarker or surrogate endpoint in the reference populations that is
relevant in the pediatric population?
(4) What evidence supports a similar exposure-response between the reference and
intended populations?
(5) What uncertainties do the existing data (e.g., clinical or historical data and published
literature) have, and what uncertainties about the pediatric population remain?
(6) If uncertainties remain, what additional information should be generated (e.g.,
information from M&S, animal, adult, pediatric subgroup studies) to inform the
acceptability of the extrapolation approach?
As evidence builds, the acceptability of the proposed extrapolation approach should be
reassessed, and it may be appropriate to change the extrapolation approach.
C. The Use of Modelling and Simulation in Pediatric Drug Development (5.3)
Advancement in clinical pharmacology and quantitative M&S techniques has enabled
progress in using model-informed approaches (e.g., mathematical/statistical models and
simulations based on physiology, pathology, and pharmacology) in drug development. M&S
can help quantify available information and assist in defining the design of pediatric clinical
studies and/or the dosing strategy. Considering the limited ability to collect data in the
pediatric population, pediatric drug development requires tools to address knowledge gaps.
M&S is one such tool that can help avoid unnecessary pediatric studies and help ensure
appropriate data are generated from the smallest number of pediatric patients. The usefulness
of M&S in pediatric drug development includes, but is not limited to, clinical trial simulation,
dose selection, choice and optimization of study design, endpoint selection, and
extrapolation. With M&S, quantitative mathematical models are built with all available and
relevant sources of existing knowledge. Provided it is well conducted, M&S can inform on
the pharmacokinetics, pharmacodynamics, efficacy, and safety of a drug.
The incorporation of M&S into pediatric drug development should be based on a strategic
plan established through multidisciplinary discussions outlining objectives, methods,
assumptions, deliverables, and timelines. When building a model, several criteria should be
considered, including the intended use of the model itself, the quality and the extent of the
existing data, and the assumptions made. Assumptions are usually structured around five

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main areas: (1) clinical pharmacology (the compound and the patient), (2) physiology, (3)
disease considerations, (4) existing data, and (5) the mathematical and statistical assumptions
underpinning the model.
Complexity in M&S calls for a careful assessment of the impact of each of the above
assumptions because the impact of each one can vary between populations. In pediatrics, it is
particularly critical to consider the maturation of organ systems with the understanding that
data from older subgroups may not necessarily be informative for the younger subgroups.
Once assumptions are set, different scenarios should be defined to support the analysis of the
impact of potential uncertainty in existing knowledge.
Emerging knowledge is incorporated into the model in an iterative approach to revisit and
improve the model. A series of learn and confirm cycles should be used for model building
and simulation/prediction, and be confirmed as soon as new information is generated. Using
several models may be important to support a given pediatric drug development program,
depending on the question(s) to be addressed, the confidence in the model, and the emerging
data generated.
Risk assessment is a critical part of M&S. The clinical and statistical consequences of a
specific approach should be discussed with experts to define the risks to be handled. The
risks associated with accepting the M&S assumptions should accordingly be assessed and
weighed against the confidence in the model predictions and the validity of the assumptions.
VI. PRACTICALITIES IN THE DESIGN AND EXECUTION OF PEDIATRIC
CLINICAL TRIALS (6)
Before deciding which types of methodological approaches are to be used in clinical trial
design and execution, one should consider several practical factors that influence the design
and execution of pediatric clinical trials. Three key practical factors to consider are
feasibility, outcome assessments, and long-term clinical aspects, including safety.
A. Feasibility (6.1)
Pediatric drug development faces unique feasibility issues, including a small number of
eligible children for clinical research, limited pediatric specific resources at research centers,
and the lack of dedicated pediatric trial networks. Consideration should be given to the
available centers willing to participate that have access to eligible pediatric participants.
When studying pediatric conditions, it may be important to consider implementing clinical
trial operational strategies, including, but not limited to, the use of pediatric research
coordinating centers, the development of master protocols for clinical trials planned and
conducted in a collaborative manner to evaluate multiple therapies for the same disease or
condition with a single control arm, and the enhancement of pediatric clinical research
networks. These operational strategies may be challenging to implement, but may result in
improved feasibility and increase timely and efficient pediatric drug development.
The expectations of children and their guardians, including the emotional and physical
burden, and the convenience of participation, should be considered. Current standards of care
can influence physician/patient treatment choices that may have an impact on pediatric
clinical trial design. Strategies that foster input from children, their caregivers, and the

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advocacy communities can facilitate participation, recruitment, and acceptability of a clinical
study.
B. Outcome Assessments (6.2)
As stated in the ICH E11 (2000) section II.D.2 (2.4.2), it may be important to develop,
validate, and employ different endpoints for specific age and developmental subgroups. The
relevant endpoints and outcome measures for the pediatric population should be identified as
early as possible. It is important to include protocol design features that allow pediatric
participants at appropriate ages to contribute directly in these measures when possible.
Where relevant, it may be prudent to assess potential pediatric endpoints in the adult
development program.
C. Long-Term Clinical Aspects, Including Safety (6.3)
The concepts on safety presented in ICH E11 (2000) section II.D.3 (2.4.3) and section II.D.4
(2.4.4) still apply. It is acknowledged that rare events may not be identifiable in pre-
registration development, and that pediatric-specific adverse events are unlikely to be
detected in development programs that are limited in size and duration. Planned collection of
safety data in nonclinical studies, adult clinical studies regardless of dose or indication, or
data from other sources (e.g., M&S) should serve to improve the design of pediatric studies
and pharmacovigilance activities to address specific pediatric safety concerns.
Long-term effects of drug treatment in children can include impacts on development, growth,
and/or maturation of organ/system function. Therefore, adequate baseline assessments of
growth/development and organ function, and regular follow-up measurements, should be
planned. Early planning for follow-up in a development program offers the opportunity to
systematically capture and evaluate long-term effects in a disease or condition, and increase
data interpretability.
VII. PEDIATRIC FORMULATIONS (7)
Principal considerations for the development of age-appropriate pediatric formulations to
allow for safe and accurate use of pediatric medicines as outlined in ICH E11 (2000) section
II.B (2.2) continue to apply. Additional considerations for pediatric formulations to optimize
efficacy and reduce the risk for medication and dosing errors should include age-appropriate
dosage forms, ease of preparations and instructions for use for caregivers, acceptability (e.g.,
palatability, tablet size), choice and amount of excipients, delivery systems, and appropriate
packaging.
Adult dosage forms are not always appropriate for use in the pediatric population, and if a
preparation for adults is used, it may pose a safety risk. When pediatric considerations are
not addressed early during the development process, the final medicinal product may call for
such manipulation for use in children that it increases the likelihood for inaccurate dosing and
changes in stability or bioavailability. Examples of this include multiple small-volume
acquisitions from a vial designed for a single adult use, use of an opened adult capsule
formulation or crushed tablets to administer a pediatric dose mixed with food, and broken
tablets that do not have a score line. Therefore, planning for development of age-appropriate
dosage forms for pediatric populations should be incorporated into the earliest stages of

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product development. When manipulations of the available form are unavoidable, measures
to minimize the impact on dose accuracy, stability and bioavailability must be addressed.
A. Dosage and Administration (7.1)
To achieve the targeted drug exposure, more than one dosage form of the active
pharmaceutical ingredient (API) or its strength may be important to cover the range of
pediatric populations intended to receive the medicinal product. For pediatric drugs, the
environment where the product is likely to be administered should be considered when
selecting the formulation for development. For example, long-acting formulations may be of
importance in settings where the caregiver is not available (e.g., school, nursery).
Furthermore, certain dosage forms that reduce the requirements for handling and storage may
be more appropriate than others.
In developing a formulation for pediatric use, considerations should include the ease of
accurate measurement and capability to deliver small volumes to minimize the risk for dosing
error, especially in neonates, infants, and young children. Such approaches could include
clearly marked administration devices designed for accurate measurement of the smallest
dose volume and dose increments.
B. Excipients (7.2)
Excipients may lead to adverse reactions in children that are not observed (or not to the same
extent) in adults. Thus, the use of excipients in pediatric medicines should take into account
factors such as pediatric age group (e.g., term and preterm newborns related to their
physiological development), frequency of dosing, and intended duration of treatment. The
number of excipients and their quantity in a formulation should be kept to the minimum used
to ensure product performance, stability, palatability, microbial control, and dose uniformity.
Alternatives to excipients that pose a significant risk to children should always be considered,
and the risk posed by the excipient weighed against the severity of the disease and
availability of alternative treatments. When selecting excipients, one should always consider
the potential impact on absorption and bioavailability of the active ingredient.
C. Palatability and Acceptability (7.3)
Orally administered pediatric medicines should be palatable to ensure dose acceptance and
regimen adherence. A formulation strategy for developing palatable drugs includes
minimizing/eliminating aversive attributes of the API and formulation of favorable flavor
attributes. Taste masking is often used to improve the palatability of the medicine. As
pediatric drug development can benefit global populations, the target for taste masking
should not only be focused on ensuring a medicine does not taste unpleasant; it should also
ensure that the taste has broad cultural acceptance.
Alternative dose administration strategies should be considered for pediatric populations who
cannot be accommodated by the intended dosage form (e.g., segmenting or crushing tablets,
coadministration with food or liquids). Appropriateness of the alternative strategy for a
pediatric population, including patient and caregiver aspects (e.g., taste/palatability, ease and
accuracy of manipulation, and potential changes in bioavailability due to a variety of factors)
should be investigated before selection of the final market image formulation. Understanding
real-world use behaviors in administering pediatric dosage forms and the mitigation of

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associated risks will contribute to the development of a formulation that allows for safe dose
administration.
D. Neonates (7.4)
Formulation requirements for neonates warrant special attention, such as its effects on
electrolyte, fluid, or nutritional balance. Intramuscular injections should be avoided where
possible and the tolerability of subcutaneous and intravenous injections evaluated. For
neonates, environmental conditions (e.g., temperature, light) and equipment used for drug
administration (e.g., enteral feeding tubes) may have an effect on drug delivery and
bioavailability. When developing a parenteral dosage form, compatibility with other
commonly administered parenteral medicines or parenteral nutrition should also be
investigated, as intravenous access is often limited in this population.

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GLOSSARY
Parental (legal guardian) consent/permission:
Expression of understanding and agreement by fully informed parent(s) or legal guardian to
permit the investigator/sponsor of a clinical study to enroll a child in a clinical investigation.
The choice of the terms parental consent or parental permission in different regions may
reflect local legal/regulatory and ethical considerations.
Child assent:
The affirmative agreement of a child to participate in research or to undergo a medical
intervention. Lack or absence of expression of dissent or objection should not be interpreted
as assent.
Modelling and Simulation (M&S):
A range of quantitative approaches, including pharmacometrics/systems pharmacology and
other mathematical/statistical approaches based on physiology, pathology and pharmacology
to quantitatively characterize the interactions between a drug and an organic system that
could predict quantitative outcomes of the drug and/or system’s behavior in future
experiments. In modelling and simulation, existing knowledge is often referred to as prior
knowledge.