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: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
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 
  Contains Nonbinding Recommendations 
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 
 
 
  Contains Nonbinding Recommendations 
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, FDAs guidance documents do not establish legally  enforceable responsibilities.   
Instead, guidances describe the Agencys 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. 
1  Contains Nonbinding Recommendations 
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. 
2  Contains Nonbinding Recommendations 
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 
childs 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 childs 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) 
3  Contains Nonbinding Recommendations 
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. 
 
 
 
 
4  Contains Nonbinding Recommendations 
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 
5  Contains Nonbinding Recommendations 
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 
6  Contains Nonbinding Recommendations 
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 
7  Contains Nonbinding Recommendations 
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 
8  Contains Nonbinding Recommendations 
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 
9  Contains Nonbinding Recommendations 
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. 
 
 
   
10  Contains Nonbinding Recommendations 
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 systems behavior in future 
experiments.  In modelling  and simulation,  existing knowledge is often referred to as prior 
knowledge. 
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