Supplement Article

The Path to Perfect Pediatric Posology — The Journal of Clinical Pharmacology

2018, 58(S10) S48–S57
Drug Development in Pediatrics 
C 2018, The American College of

Clinical Pharmacology
DOI: 10.1002/jcph.1081

Joan M. Korth-Bradley, PharmD, PhD, FCP, FAAPS

Abstract
Reluctance to enroll pediatric subjects in clinical trials has left gaps in information about dosing, safety, and efficacy of medications. Pharmacotherapeutic
information for pediatric patients may be available for only a small range of ages and may be deficient, as children respond differently as they grow and
mature from prematurity to adolescence. Current regulations, however, require early planning for the participation of children in drug development, as
pediatric plans must be submitted at the end of phase 1 (European Union) or the end of phase 2 (United States). These plans are extensive, outlining
planned studies, subjects to be enrolled, dose and dosage form justification, planned observations, and statistical analysis as well as planned modeling,
simulation, and extrapolation analyses. The extent to which efficacy information in adults can be extrapolated to children depends on how similar the
disease is in adults and each of the 5 pediatric age groups. Extrapolation may not be possible for conditions that do not occur in adults, requiring a
complete development plan in adults, or extrapolation may be complete because of similar pathology and response to treatment. Pharmacokinetic and
safety information cannot be extrapolated and must be collected in children of all ages, unless a waiver is granted. Physiologically based pharmacokinetic
modeling, optimal design, population pharmacokinetics, and scavenged samples are all examples of new methodologies being used to study pediatric
therapeutics. Clinicaltrials.gov and EU Clinical Trials registry are good sources of results of pediatric trials, although sponsors are also working toward
prompt publication of study results in peer-reviewed journals.

Keywords
clinical research, pharmacodynamics, pharmacokinetics, physiologically based pharmacokinetic models, neonates

It is not enough to simply tailor information available
in adults to fit children. In the not-too-distant past, the
use of Clark’s rule and other formulae assumed children
were small or young adults and scaled accordingly.1
Doses for children were determined by multiplying
the adult dose by the ratio of the child’s weight to
150 pounds, for example. Studies to verify that doses
so calculated were appropriate, safe, and effective were
rarely conducted, in part because of the hesitancy to
subject children to the demands of participation in clin-
ical trials. Information about the stability, palatability,
or acceptability of either the commercially available or
extemporaneously prepared dosage forms was limited.
Unfortunately, we have learned from therapeutic
misadventure that pediatric-specific pharmacokinetic,
safety, and efficacy data must be collected across the
age and developmental spectrum so that clinicians can
use medication optimally and avoid potentially severe
adverse reactions. It is useful to consider an example
to understand why pediatric subjects must be included
in drug development. Chloramphenicol at doses of
100 mg/kg/day in divided doses was administered to
neonates to treat or prevent infections in hospital
nurseries.2 Cases were reported of babies who had
been treated for 3 or 4 days and were then observed
to have abdominal distention with or without emesis,
progressive pallid cyanosis, and vasomotor collapse,
frequently accompanied by irregular respiration and
who sometimes died with a few hours of onset of
distress. The collection of symptoms was referred to
as gray syndrome because of the ashen appearance of
the skin. Assay of 200-μL blood samples, collected
using finger- and heel-sticks, in affected infants showed
their chloramphenicol concentrations to be unusually
high. A series of focused clinical studies subsequently
conducted in groups of 3 to 5 patients showed
greatly prolonged half-lives (26 hours) in the very
young children who were 1 to 2 days of age, compared
with half-lives of 10 hours in babies who were 10 to
16 days of age. Ultimately, it was determined that
slow conversion of chloramphenicol to metabolites
and immature renal tubular excretion were likely
responsible for the high concentrations. It was
subsequently recommended that full-term infants
receive 50 mg/kg/day and premature infants receive
25 mg/kg/day for the first week of life. The report
summarizing the investigation,2 published almost
60 years ago, encapsulates solutions to many of the
Clinical Pharmacology, Global Product Development, Pfizer Inc., Col-
legeville, PA, USA
Submitted for publication 6 October 2017; accepted 21 December 2017.
Corresponding Author:
Joan M. Korth-Bradley, PharmD, PhD, Pfizer Inc, 500 Arcola Road,
Collegeville, PA 19426
Email: joan.korth-bradley@pfizer.com
Korth-Bradley
challenges of determining the best dose in young
infants and even recommends the use of therapeutic
drug monitoring for prolonged therapy.
It is now expected that medications come to market
with directions for safe and effective use for patients
of all ages or, alternatively, with statements that use
in certain age ranges is not indicated for the approved
indications. The directions, including contraindications
and cautions, should be based on data collected in
appropriately designed studies or robust documenta-
tion from epidemiological and toxicology studies. It is
unfortunate that previous hesitancy to include children
in clinical trials has resulted in gaps in the informa-
tion available. Current drug development practices will
hopefully make these deficiencies a thing of the past.
If we agree that all drugs that are developed should
include children of all ages in clinical trials, let us
first look at the drug development process in general.
The potential list of pharmaceutical products that
could be developed is almost endless. With thousands
of diseases already described, continuing investigation
into pathophysiology and identification of potential
targets that could be manipulated to remediate or
even cure and huge expansion of types of medicines
that can be synthesized, there is a very long list of
potential products that could be developed. Choices
about which particular projects to advance are based
on many factors. What therapeutic areas is the sponsor
(company, manufacturer) of the development project
already working in? It is easier to develop and market
products to an existing community. What are the largest
threats to public health or well-being that demand
immediate attention and are likely to be supported
by payers? Big, messy problems, such as Alzheimer’s
disease, may be solved more readily if there are many
different sponsors working on the problem. Ongoing
collaboration between academic researchers and pri-
vate industry may also suggest emphasis on particular
diseases.
Drug development begins with the end in mind,
by making a mockup of what would be the ideal
product labeling, including the indication, posology
for all age groups, and the anticipated adverse reac-
tions and precautions required for the most effective
and safe use. With ideal product labeling outlined,
a development plan is prepared that includes all the
clinical and nonclinical studies required to provide
information needed to support the specific language in
the label. Each discipline, including discovery, clinical
and nonclinical pharmacology, clinical and medical
research, product formulation, toxicology, safety and
epidemiology, among other functions, then expands
its portion of the development plan to assess what is
already known about the new chemical entity and what
studies need to be performed to gather new information
S49
Table 1. Pediatric Age Ranges Used for Labeling
European
Medicines Agency
and International
US Food and Drug Conference on
Classification Administration Harmonisation
Preterm newborn <37 weeks of age = PMAa
infant
Neonate (full-term Birth to 1 month 0 to 27 days
newborn)
Infant (toddler) 1 month to 2 years 1 to 23 months
Children 2 to 12 years 2 to 11 years
Adolescent 12 to <17 years 12 to <18 years
a
PMA is postmenstrual age.
required either for the label itself or by other disciplines,
so that they may perform their studies. Drug develop-
ment is highly regulated, and so the data required for
approval and, in turn, the studies required to provide
much of the data are described in regulatory guidance
statements and regulations, including the definition of a
child.
Definition of Pediatric Age Groups
To be sure to gather data across the spectrum of pe-
diatric development milestones, children are separated
into 5 age groups, shown in Table 1, and each age group
must be considered in clinical development. Jurisdic-
tions other than the United States3 and the European
Union4 may have slightly different limits to the age
ranges. In some development programs, there may be
further subdivision of the 2- to 12-year age group of
those younger than than 6 years and those at least 6
years old. Specific developmental milestones or conven-
tions in medical practice may impose other restrictions
on age. For example, tetracycline causes discoloration
in developing teeth, and so is not recommended for
children younger than 8 years old.5 Hemophilia re-
placement products include children aged 12 years
and older in the clinical trials of adults.6 These age
groups are not simply arbitrary divisions, but were
developed to map onto stages of development that
coincide with stages of maturity and milestones in
development. Those who care for children recognize
that there are different body systems influencing re-
sponses to pharmacotherapy and that these systems
mature at different rates with added variability because
of genetic, environmental, and social influences.7 In
addition to the obvious differences in weight between
different age groups, there may also be differences
in gastric pH, body composition, cytochrome P450
metabolic capacity, transporters, renal function, and
hepatic function. For example, neonates have elevated
intragastric pH and lower total volume of gastric secre-
tions and immature conjugation and biliary function.8
S50
As therapeutic proteins become common, more will be
learned about the ontogeny of target engagement and
the elimination of monoclonal antibodies and fusion
proteins, among others.9 Children may also differ in
the signs, symptoms, and pathology of diseases from
children in different age groups or adults with similar
disease. Some conditions are present at birth but may be
delayed in manifesting pathology or may not respond
to delayed treatment. By including children from each
of these age categories in drug development, it is hoped
that there will be adequate information available when
a drug is first available on the market that will enable
prescribers caring for children who may be maturing at
different rates or who are smaller or larger than average
to make good choices of doses to use.
Regulatory Guidance
Drug development has evolved such that inclusion of
pediatric subjects in clinical development or, at a min-
imum, justification for why their involvement should
be deferred or waived, is now a legal requirement.
Most potential drug products are developed with the
goal of global registration in mind, and so clinical
development programs are planned to include elements
that will satisfy the requirements of the major markets
of the United States, Europe, and Japan and be in
accordance with recommendations of the International
Conference on Harmonisation. The key regulations
and summary documents that provide a framework on
how pediatric trials will be incorporated into clinical
development include an alphabet soup of the Food,
Drug and Cosmetics (FD&C) Act in the United
States, the Food and Drug Administration Safety and
Innovation Act, enacted in 2012, in which regulations
originally approved in the Best Pharmaceuticals for
Children Act (BPCA, 2002) and the Pediatric Research
Equity Act (PREA, 2003) are included. Under the
BPCA, sponsors of certain applications could obtain
an additional 6 months of exclusivity if the sponsor
submits information responding to a written request
relating to the use of a drug in the pediatric population.
All new medications including both drug and biological
products are covered, although those with “orphan
drug” designation are exempt from PREA regulations.
Under the PREA, studies in pediatric patients are
required for the indication that will be part of the new
drug application unless granted a waiver or deferral.
Waivers may be issued if the indication is not present in
pediatrics, would not represent a significant therapeutic
advantage, or poses a significant safety concern.
Studies in rare diseases in pediatric subjects may also
be eligible for the added incentive of a priority review
voucher. Priority review vouchers may be transferred
to other programs or sold to other sponsors.10
The Journal of Clinical Pharmacology / Vol 58 No S10 2018
Recently enacted legislation, the Pregnancy and
Lactation Labeling Rule (PLLR),11 which requires
inclusion of information about the safety and
pharmacokinetics of medications in pregnant and
lactating women, is being implemented and will be
largely completed by 2019. Studies of pregnant and
lactating women are not part of drug development
in children, and further discussion is beyond the
scope of this article, but implementation of the PLLR
provides important information about indirect dose
administration to infants.
In the European Union, the Paediatric Regulation,
which was enacted in 2007, resulted in the establish-
ment of the Paediatric Committee (PDCO). The main
responsibility of the PDCO is to determine the studies
that sponsors must conduct in children as part of
Paediatric Investigation Plans (PIPs). Because the PIP
is rate limiting among these various legislations, clinical
development plans for children will frequently begin
with it. PIPs are the development plans describing the
necessary data to be obtained through studies in chil-
dren that will support the approval of a medicine, in the
European Union. All applications for new medicines
have to include the results of studies as described in an
agreed-on PIP, unless the medicine is exempt because of
a deferral or waiver. This requirement also applies when
a sponsor wants to add a new indication, a new dosage
form, or a route of administration for a medicine that
is already approved. PIPs are rate limiting because they
must be submitted to the PDCO no later than the end
of the first phase 1 studies to assess pharmcokinetics
in healthy adult subjects or patients.12 They cannot be
submitted after the initiation of pivotal trials, confir-
matory, phase 3 trials, or trials conducted in children.
It is important to note that the PIP must be agreed to
by the European Medicines Agency (EMA) and must
be fulfilled by the sponsor, unless an amendment is also
agreed to by the EMA. Failure to complete the PIP to
the satisfaction of the EMA will result in the sponsor
being unable to file the application for the applicable
new pharmaceutical product.13
As noted previously, drug development in the United
States is governed by the FD&C Act. One of the
important milestones is the end of the phase 2 meeting.
This meeting is held between the Food and Drug
Administration (FDA) staff in the division that is
reviewing the ongoing development and the sponsor.
The meeting’s purpose is to review the safety informa-
tion that has been gathered in phase 1 and phase 2
studies, to evaluate the phase 3 plan and protocols, to
identify additional information necessary to support a
marketing application, and to review plans for studies
in pediatric subjects. The initial pediatric study plan
(iPSP)14 describing these studies and/or justification for
waivers and deferrals should be discussed with the FDA
Korth-Bradley
Queson 1: Do children has similar disease progression and response to treatment as adults?
If no – then proceed to ‘no extrapolaon’, if yes, proceed to queson 2.
Queson 2: Is it likely that similar exposure-responses
will be observed in children and adults?
If no – proceed to queson 4, if yes, proceed to queson 3.
Queson 3: Does drug/metabolite concentraon predict clinical response?
If no – proceed to queson 4, if yes, proceed to ‘full extrapolaon’
Queson 4: Is there a PD measurement that will predict efficacy in children?
If no – proceed to ‘no extrapolaon’; if yes, proceed to ‘paral extrapolaon’
Figure 1. Algorithm to determine extent of extrapolation.
prior to the end of phase 2, and the PSP should be
submitted within 60 days of the end of the phase 2
meeting. All marketing applications including a new
active ingredient, new indication, new dosage form,
new dosing regimen, or new route of administration
are required to submit an iPSP. iPSPs are reviewed by
the Pediatric Review Committee, which will provide
comments to the sponsor and ultimately issue the
agreed initial PSP. The goal of the PSP process is to
identify the necessary pediatric studies so that they
can be completed prior to the submission of the new
drug application or biologics license application in the
case of biological therapeutics. For most sponsors, the
iPSP is modeled on the PIP, which is required earlier in
development.
Pediatric Studies
As noted previously, the road map to clinical
development is the clinical plan, which is mapped out
prior to administration of the very first dose to a human
subject and is discussed with regulatory authorities in
meetings prior to submission of the investigational new
drug. The pediatric components may not be completely
described at the pre—investigational new drug meeting,
but as noted above, a PIP is required soon after the
completion of the first-in-human study conducted and
the iPSP prior to the end of phase 2, so there will be
some vagueness in the initial plans, although the general
outline of what studies will be performed in what age
groups is expected. To determine the degree to which
adult data may be used to support pediatric indications,
an algorithm, shown in Figure 1, that includes 4 key
questions has been developed. Depending on the
responses to the 4 questions, sponsors will be able
to assess the extent of extrapolation possible for
adult data. Neither pharmacokinetic nor safety
observations can be extrapolated, and some data must
be collected in every age group for which labeling is
expected. As shown in Figure 2, full extrapolation
of efficacy information from adults means that only
S51
No extrapolaon
(1) Conduct a dose-ranging study in children to establish dose
(2) Conduct safety and efficacy studies at established dose in children
Paral extrapolaon
(1) Conduct dose-ranging study in children to idenfy dose
that achieves the target PD effect
(2) Conduct safety study at idenfied dose
Full extrapolaon
(1) Conduct PK study in children to idenfy dose
that achieves similar exposure to adults
(2) Conduct safety study at the idenfied dose
Figure 2. Studies required by degree of extrapolation.
pharmacokinetic and safety data need to be collected
in children, whereas partial extrapolation will mean a
dose-finding study is required, and no extrapolation
of information from adults means a sponsor is obliged
to conduct separate dose-finding, safety, and efficacy
studies in children.15 It must be remembered that the 4
questions must be answered for each of the 5 pediatric
age categories, and different answers to the questions
may result in different degrees of extrapolation. For
example, drugs used to treat infections are examples of
medication for which full extrapolation is likely.16 It is
reasonable to assume that if similar concentrations of
an antibiotic are achieved in children, whether neonates
or adolescents, then the infection should respond in a
similar way, but as described in the chloramphenicol
example, pharmacokinetic data and safety data cannot
be extrapolated and must be collected in all age groups.
An example of an indication that does not al-
low extrapolation is treatment for retinopathy of
prematurity.17 This condition does not occur in adults,
and so all data supporting the safety, efficacy, and phar-
macokinetics must be collected in children, specifically
in those who are premature infants. Bevacizumab is
an antivascular endothelial growth factor monoclonal
antibody approved for the treatment of adults with
metastatic colorectal cancer, nonsquamous, non–small
cell lung cancer, metastatic breast cancer, and glioblas-
toma. After experimental use in adults with intraocular
neovascular diseases without severe adverse reactions,
investigators explored its use in combination with stan-
dard nonpharmacological therapy in an 8-week-old
infant who was born at 25 weeks’ gestation.18 Then,
a large prospective, randomized trial was conducted
in 150 infants 33 to 35 weeks postmenstrual age, who
were treated with 0.625 mg administered by intravitreal
injection into each eye.19 Efficacy was based on pho-
tographs taken at 54 weeks’ postmenstrual age that were
evaluated for recurrence of retinopathy, again unique
to this condition. Because the dosing was empiric,
additional trials are ongoing to assess the effectiveness
S52 The Journal of Clinical Pharmacology / Vol 58 No S10 2018

of lower doses.17 The safety profile of systemically General Study Considerations for
administered bevacizumab was well described from Pediatric Subjects
studies in adults being treated for cancer but was not
The age range in a dedicated pediatric pharmacokinetic
applicable to infants treated with intravitreal injections
or pharmacokinetic/pharmacodynamic study should
who would receive 1 or 2 doses in each affected eye, with
be consistent with the pediatric age range for the
minimal anticipated systemic availability.
intended population of treatment. Clinical trials in
In addition to medications developed with either
pediatric populations are conducted in those individ-
no extrapolation or full extrapolation of efficacy from
uals who stand to potentially benefit from the treat-
adults are intermediate cases, for which information
ment. Healthy children participate in studies such as
obtained in adults can be supplemented with efficacy
immunization trials against diseases that they might
data from children. Adult to adolescent extrapolation is
reasonably be expected to contract22 or postapproval
relatively common.20 As noted above, in rare diseases,
assessment of nutritional supplements.23 Reasonably
such as hemophilia, adolescents are enrolled in adult
stable children with the target disease participate in
studies without distinction because of their age,6 and
clinical pharmacology studies as well as in clinical
for some conditions, such as migraine headache and
studies of medications used to treat diseases that occur
schizophrenia,15 there is a continuity of both disease
only in children.24 Legal regulations and social conven-
and response to treatment between adults and pediatric
tions assert that children lack the autonomy and life
populations. Adolescents are similar in size to adults
experience to judge the risk and benefit of participating
and have mature physiology. Their quest for autonomy
in a clinical trial. Institutional review boards and ethics
and potential lack of compliance may make participa-
committees reviewing and approving studies being con-
tion in clinical trials challenging but is needed to vali-
ducted in children must include adequately trained and
date assumptions of similar pharmacokinetics, safety,
experienced clinicians and researchers who are able to
and efficacy.21 Extrapolation of efficacy and response
assess the risks and benefits on behalf of the vulnerable
data from adults to children younger than 12 years
pediatric population. In addition to the consent to
of age may be more difficult than for adolescents and
participate given by parents or guardians, it is also good
becomes progressively more difficult in the youngest
practice to provide age-appropriate information about
age groups because of immature renal function and
the clinical trial and obtain assent from the potential
metabolic activity, differences in body composition, and
participants if their maturity and condition allow.
challenges in drug administration. For some, a waiver
Because there are fewer pediatric patients available to
is preferred because the disease does not manifest
participate in clinical trials and because children are a
itself or the assessment of response is not possible,
vulnerable population, study-site selection is important
such as allergic conjunctivitis in children younger than
to ensure that the clinical sites have the infrastructure
2 years of age, for example.15 Onset of disease may
in place to meet the protocol requirements, especially if
be indicative of a different pathology than disease that
special techniques or assessments are required. Fortu-
usually occurs in adults. For example, congestive heart
nately, as pediatric studies have become a regular part
failure in children is more likely from congenital heart
of drug development, expertise is becoming more avail-
disease, whereas in adults, ischemic heart disease is the
able. Sponsors have formed internal pediatric councils,
culprit.15 Partial extrapolation is possible when there is
among whose members are toxicologists, pathologists,
uncertainty in the assumption that the disease and the
clinical pharmacologists, formulators, assay specialists,
response to treatment are similar in adults and children.
statisticians, researchers, and clinicians with expertise
Either a single, adequate, well-controlled trial proving
in pediatric drug development. These councils review
efficacy in addition to safety and pharmacokinetics
clinical development plans and study protocols prior
can be performed, or when there is less uncertainty,
to submission to regulatory authorities to ensure high-
a study underpowered to demonstrate efficacy can be
quality pediatric development programs that are deliv-
conducted. Juvenile rheumatoid arthritis (JRA) is an
ered in a timely fashion while attending to the safety
example of partial extrapolation as well as evolution
of participants in the trials. In addition to internal pe-
of requirements as more children participate in clinical
diatric councils, pediatric research networks have been
studies.15 For symptomatic relief, when there was an ex-
expanded to include sponsors in addition to academic
tensive understanding of mechanism of action, extrap-
research centers.25 Research networks improve the ef-
olation was permitted, or at least inclusion of different
ficiency of drug development by providing education
subtypes in the same study. For disease-modifying
and certification for investigators that can be recog-
drugs, the FDA requires independent confirmation of
nized by different sponsors. Through their experience,
efficacy in pediatric populations in each of the subtypes
they can offer direction for improving trial design,26
of JRA.15
developing and validating standard processes for
Korth-Bradley
subject enrollment, dosing, collection of observations,
including blood sampling,27 and information about the
natural history of disease, growth, and development.
Networks can be organized to span different countries
and regions to promote the highest standards of clinical
research, including attention and support of pediatric
subjects and their families to minimize the burdens of
participating in clinical trials. Networks vary in their
size, diseases, and populations of interest and funding
sources. Examples of pediatric research networks are
the Children’s Oncology Group,28 the European Net-
work of Paediatric Research at the European Medicines
Agency, the Pediatric Trials Network,29 the Institute
for Advanced Clinical Trials for Children, and the
Paediatric Trials Network Australia.
The decision to conduct a study as an inpatient or
an outpatient trial is based on considerations similar
to those in adults and include the age of the child,
the illness, the treatment required, the observations
being made, and the location of staff and equipment.
Studies of premature infants are typically inpatient
studies. Children in stable condition may be able to
participate as outpatients or with only a limited number
of overnight stays. Accommodation must be made for
parents or guardians who may need to stay with the
child and provide transportation of the child to the re-
search unit. Timing of the activities in studies must also
consider school schedules and immunization schedules,
which may make participation in trials difficult for some
age groups.
Knowledge of the impact of coadministration of
food with the study drugs is important in the design
of clinical trials in children.30 Healthy adult volunteers
and many adult patients can tolerate administration in
fasted conditions or administration with a standardized
meal. It is difficult to be confident of compliance on
the part of children. Infants and young children are
fed 4 to 6 times daily, consuming breast milk, formula,
or semisolid food, such as cereal, yogurt, and pureed
vegetables, fruits, and meats. Children may refuse to
consume standard meals or perhaps even food of any
kind, particularly if they are feeling unwell. When
the effect of food is either unknown or a source of
variability in clinical response, it is important to collect
information about the time and composition of the
last meal consumed prior to dose administration to
help to interpret the results. The effect of food on
pharmacokinetics or efficacy and safety can also be
incorporated into the study design by allowing children
to consume one of several meals or remain fasting and
noting their feeding status as a covariate.31
The decision to include children of different
races/ethnicities and sexes is made in a similar
manner as in adults. No group of children with the
target disease is excluded, but some diseases often
S53
genetically determined occur more commonly in boys,
such as hemophilia; at some ages, such as apnea of
prematurity; or predominately in some races, such as
sickle cell disease. Cultural sensitivity is needed when
enrolling girls who could potentially have achieved
menarche, and older children who may be participating
in sexual activity or illicit drug use. Thoughtful
explanation of the testing necessary to protect the
safety of the children, as well as the validity of the
interpretation of the study results, is important to the
conduct of the study. Beyond general considerations
of designing clinical trials in children, 3 common
elements, dose, observations, and analysis, require
particular attention. These will now be considered in
turn.
Pediatric Dose
To optimize the benefit:risk ratio in trials in patients,
investigators try to avoid both ineffective doses and
doses higher than required during dose-finding or phar-
macokinetic studies and include only doses predicted
to achieve concentrations that have been shown in
nonclinical studies or simulations to be efficacious
and tolerable. When the clearance of a drug can be
predicted in children, then the dose required to achieve
a target concentration can be calculated, albeit with
sometimes large variability. Differences in volume of
distribution must also be considered but are usually of
concern only when dosing is intermittent or a particular
target concentration must be achieved immediately on
starting treatment.
The most common method of determining clearance
in pediatric subjects is weight-based allometric scaling.
Clearance is assumed to be a function of weight at
three-quarters power.32 However, because age-related
maturation is not included in calculations, allometric
scaling is not reliable for young children, especially
those younger than 2 years,7 because of continuing
ongoing maturation of metabolic pathways. Segmented
allometric models, which implement different expo-
nents for different ages, have been developed to accom-
modate different age groups33 and dosage forms such
as extended-release tablets that support only limited
flexibility in dosing.34
Physiologically based pharmacokinetic (PBPK)
models may be able to overcome some of the limitation
of allometric scaling. PBPK models integrate phys-
iologic information, such as age-specific blood flow,
protein concentration, and enzyme and transporter
ontogeny with pharmacokinetic parameters such
as percent of dose eliminated by renal clearance or
metabolized by particular pathways and can be used
to predict the disposition in children of various levels
of maturity.35,36 Advances in software, the increased
S54
availability of physiological and tissue distribution data
have resulted in more frequent use of PBPK models
for drugs in development. Models have been developed
for both small molecules and biologics. Edington and
colleagues37 extended preexisting PBPK models for
acetaminophen, alfentanil, morphine, theophylline,
and levofloxacin to include data for children and
evaluated the performance of the models in predicting
pediatric plasma profiles. Eighty-three percent, 97%,
and 87% of the predicted plasma concentrations,
volumes of distribution, and elimination half-lives,
respectively, were within 50% of values reported. PBPK
models are then used to help to design dosing schemes,
PK sampling times, and times for other observations
in clinical trials in pediatric subjects. For example,
sirolimus has not been investigated in children yunger
than 13 years old, so Emoto and colleagues used PBPK
methods to develop a model for sirolimus to make
predictions for children aged 1 month to 2 years who
were to be enrolled in a phase 2 efficacy and safety trial
for treatment of vascular anomalies.38 Regardless of
the method used to select the doses to be evaluated in
protocols, it is a best practice to include a maximum
dose to avoid overdosing large or heavy children.
Dosage Forms
Important to accurate, precise, and consistent dose
administration is the availability of an appropriate
dosage form for the intended population. Although
there are many different ways that medication can be
administered and all can be adapted for different age
groups, the most common route of administration is
oral, and the most common oral dosage forms used
in children are liquids and solids, including powders,
sprinkles, dissolving tablets, minitablets, and tablets.
Discussion of dosage forms is an integral part of
PIPs, and so each of the following must be described
in the PIP document4,35 : the specific formulation, phar-
maceutical form, strength and route of administration
for each of the pediatric age groups, potential issues
concerning excipients and their predicted exposures at
the anticipated dose, administration of doses to the
different pediatric age groups, including acceptability,
use of administration devices, ability to mix with milk,
formula, or food, precision of the dose delivery and/or
accuracy of the dosage form for each of the pedi-
atric age groups, and the anticipated time frame for
development of the formulations and dosage forms.
Dosage forms used with children must be palatable and
must permit flexible dosing to accommodate reasonable
precision over the large range of doses that are required.
Use of dosing bands, by assigning children over a range
of weights to the same dose, allows use of capsules or
The Journal of Clinical Pharmacology / Vol 58 No S10 2018
tablets that may be more stable to be used in cases in
which some flexibility in dosing is permissable.35,40
The relative bioavailability between the different
dosage forms must be known so that as children are
switched, the required dosing is maintained. Stabil-
ity information is also required for all dosage forms
and understanding of the impact of excursions in
temperature, such as when doses are not refrigerated.
Dissolution testing, which is an important metric for
the development of oral dosing forms, needs to be
evaluated using a relevant dissolution media if the
product will be used in very young children whose
physiology differs from older children and adults.41
Beyond oral formulations, differences between
adults and children must also be considered.42 For
example, medications that are injected will require
concentrations that are neither too potent, when it is
difficult to accurately administer the very small doses
required for premature infants, or too dilute, which
would require large injection volumes that would not
be tolerated for subcutaneous injection. There are
many different ways of administering medication by
aerosol that vary in the effectiveness in delivery as well
as degree of cooperation required of the patient and
skill in use by research staff.43 Drugs administered as
eye drops are also challenging for treating conditions
in children. Because of the small volume administered,
the concentration of active ingredients is high. The eye
of a newborn is approximately two-thirds of the adult
size and does not reach adult size until age 3 to 4 years.
Ocular dosing is not weight or size adjusted, and so
children may receive much higher doses than adults.44
Protocols and supplementary dose administration
instructions need to be clear so that the doses are
administered as consistently and accurately as possible.
Observations
Technical challenges in collection, standardization,
and interpretation have limited the use of potentially
less invasive matrices45 such as saliva, urine, and hair,
and so blood samples are collected in almost every type
of pediatric study in drug development, whether for as-
sessment of safety, efficacy, or pharmacokinetics, even
in critically ill and very small patients. To characterize
pharmacokinetic parameters in individual subjects,
conventional pharmacokinetic sampling requires 10 to
12 samples collected over a dosing interval in multiple-
dose studies or more than 3 to 5 half-lives in single-
dose studies. A review46 of guidelines on sampling
permitted in pediatric studies reported a maximum
cumulative volume of blood of 3–7 mL/kg collected
over 8 weeks. Faced with the necessity of including
baseline and end-of-study safety assessments of serum
chemistry, hepatic, renal, and hematology values,
Korth-Bradley
pharmacokinetic sampling in young children and
infants, by necessity, is sparse, representing only a
subset of conventional sampling. Optimal sampling
designs may be used in which blood samples are
collected at the times that are most likely to provide
information about the likely model47 as well as times
linked to particular safety or efficacy signals, such as
likely peaks and troughs. Simulations of the anticipated
concentration–time profiles are helpful to avoid
sampling times that are likely to be uninformative
because the concentrations fall below the limits of
quantification of the assay.
In addition to minimizing the volume of blood
collected, investigators must also minimize the number
of collection times. Opportunistic study designs, also
known as scavenged sampling, which schedule research
sample collection to coincide with sample collection
for routine laboratory draws,48 may be used in studies
in children. Authors have suggested that opportunistic
study designs are useful for further investigation of
medications that are already prescribed to children
rather than investigational drug products. The decision
to prescribe the medication is made outside the clinical
trial, but once the order has been written, enrollment in
the study occurs, with consent focused on the collection
of extra blood volume to answer the research question.
The limitations of varied timing and number of samples
make opportunistic sampling strategies difficult to use
in drug development.
Monitoring for safety and efficacy in pediatric sub-
jects is incorporated into research protocols in much
the same manner as for adults. Baseline assessment
takes place prior to administration of the study drug
to verify that subjects are eligible to enroll, do not
have any exclusion characteristics, and will be able
to cooperate with study assessments. For the study
results to be meaningful, assessments must be age
appropriate and capable of detecting safety signals
unique to children, such as interference with growth49
and development. Specific systems may be more (or
less) tolerant of drug effect as a result of a combination
of differences in physiology and body composition. For
example, higher brain penetration of medications in
neonates, both human and animal, may be the result of
active transport systems evolved to transport nutrient
and other molecules needed for development of the
central nervous system, as well as differences in volume
of distribution related to body composition, reduced
blood plasma protein-binding capacity, and reduced
renal flow.50
Data Analysis
Data analysis methods used for pediatric studies are
similar to those used for adult studies. Because of
S55
the limited number of samples collected, individual
determination of pharmacokinetic parameters for each
subject may be only post hoc estimates based on a
population pharmacokinetic model. Naive pooled esti-
mates may also be used to determine pharmacokinetic
parameters,51 although care must be taken to normalize
for dose administered and size of the sample of the
subjects studied.
Disclosure/Publication of Study Results
Important to the protection of subjects who participate
in clinical trials are the processes requiring quick, com-
plete disclosure. All interventional studies conducted
in the United States must be registered on the website
www.clinicaltrials.gov. The clinicaltrials.gov informa-
tion resource was initiated as a result of the Food
and Drug Administration Modernization Act of 1997.
The registry was established by the National Institutes
of Health for experimental treatments for serious or
life-threatening diseases or conditions and was initially
intended to provide patients searching for available
trials a central place to look. It was expanded in 2007
to require additional types of trials to be registered
as well as reporting summary results, including ad-
verse events. Under most circumstances for studies in
children, results must be posted within 12 months of
the date of final data collection for the prespecified
primary outcome measures.52 European regulations
established Article 46 of Regulation (EC) 1901/2006,53
under which studies, of products that are registered in
the European Union, enrolling pediatric subjects must
provide a completed clinical study report to the EMA
within 6 months of study completion. The requirements
apply to all studies with pediatric subjects, even if not
included in a PIP. The EMA will in turn make all
results available through the EU Clinical Trials Register
(www.clinicaltrialsregister.eu).
Publication of study results in a peer-reviewed jour-
nal is the final step in making information available
to the public. Guidelines54 have been developed en-
couraging prompt and balanced reporting of all com-
pleted clinical trials, regardless of whether they were
positive. Because of the difficulty in enrolling pediatric
subjects, it is particularly important that these data be
presented and made available to add to the literature.
The primary publication is the initial publication of a
clinical trial and should be submitted for publication
ideally within 12 months (18 months at the latest) of the
completion of the clinical trials.54 Although data are
not available specifically for trials of pediatric subjects
or of clinical pharmacology studies, approximately
90% of studies registered at clinicaltrials.gov have been
published.55
S56
Next Steps and Remaining Questions
With the inclusion of pediatric subjects as a standard
part of clinical development, more data are being
collected so that drug development in children has ex-
panded far beyond simple description of a small group
of heterogeneous subjects. Beyond studying children of
all ages, the problem of the correct dose for obese56
or underweight children is beginning to get attention.
Perhaps more importantly, the advances that are being
made to support drug development work in children,
including in fragile newborns, can be extended to the
study of other vulnerable populations such as pregnant
and lactating women.57 The goal of perfect pediatric
posology may indeed be at hand.
Declaration of Conflicting Interests
Joan M. Bradley is a Senior Director, Clinical Pharma-
cology, Pfizer Inc. She is an employee and shareholder
of the company.
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