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Challenges and Planning of Pediatric Clinical Trials: an Overview



Children should be considered different from adults in terms of pharmacodynamic and pharmacokinetic effects associated with administered drugs. There is still a paucity of robust data in children on safety and efficacy of medicines giving rise to either sub-optimum therapeutic effect or unknown harmful side effects. Strict governance by regulatory authorities worldwide has necessitated formulation development of age-appropriate, safe and effective medicines specifically for children. The current review covers logistical and methodological challenges, major steps in planning and conduct of bioavailability-bioequivalence studies in children and pediatric clinical trial. It aims to provide knowledge that will fulfill the goal of optimised pediatric pharmacotherapy will heighten the possibilities of public funding and industry sponsorship and facilitate implementation of the present regulations and initiatives thereby improving the scope, reliability and relevance of clinical trials in pediatric population. Close integration between validated clinical research and patient care will foster low risk therapy for the highly vulnerable therapeutic population.
Journal of Applied Biopharmaceutics and Pharmacokinetics, 2019, 7, 29-36 29
E-ISSN: 2309-4435/19 © 2019 Sci entif ic Array
Challenges and Planning of Pediatric Clinical Trials: an Overview
Sutapa Biswas Majee1,*, Soupayan Pal1, Dipanjana Ash2 and Gopa Roy Biswas1
1Department of Pharmacy, NSHM Knowledge Campus, Kolkata-Group of Institutions, 124 B.L.Saha Road,
Kolkata- 700053, West Bengal, India
2Department of Pharmaceutical Technology, Brainware University, 398, Ramkrishnapur Road, Barasat,
Kolkata- 700125, West Bengal, India
Abstract: Children should be considered different from adults in terms of pharmacodynamic and pharmacokinetic effects
associated with administered drugs. There is still a paucity of robust data in childr en on safety and efficacy of medicines
giving rise to either sub-optimum therapeutic effect or unknown harmful side effects. Strict governance by regulatory
authorities worldwide has necessitated formulation development of age-appropr iate, safe and effective medicines
specifically for children. The current review covers logistical and methodological challenges, major steps in planning and
conduct of bioavailability-bioequivalence studies in children and pediatric clinical trial. It aims to provide knowledge that
will fulfill the goal of optimised pediatric pharmacotherapy will heighten the possibilities of public funding and industry
sponsorship and facilitate implementation of the present regulations and initiatives thereby improving the scope,
reliability and relevance of clinical trials in pediatric population. Close integration between validated clinical research and
patient c are will foster low risk t herapy for the highly vulnerable therapeutic population.
Keywords: Bioavailability-bioequivalence (BA-BE), BCS, Clinical trial, Pediatric, Population pharmacokinetics.
Policies controlling formulation development,
review, clinical investigation and approval of medicines
are primarily aimed at the adult population and
industry-sponsored research is mainly focussed on this
section of population because of political pressures and
also chances of reaping greater profits with
comparatively lower investment. Surveys have
documented very little data on safety and efficacy of
medicines in children giving rise to either sub-optimum
therapeutic effect or unknown harmful side effec ts.
Unpredictable and unknown adverse drug reactions are
reported to occur after administration of well-known
drugs and resulting toxicity may affect maturation,
development in children and reproductive ability in
future [1]. For this reason, children are often regarded
as “therapeutic orphans” [2]. A major issue in treatment
of children is the practice of off-label prescribing which
is more serious in case of critically ill neonates and
infants suffering from relatively uncommon pathological
conditions because of insufficient labelling information
available with the prescribers [3]. Economic pressure
impedes pharmaceutical companies from investing in
studies concerned with the drugs or formulations
specially developed or designed for pediatric
population. Children are thus exposed to potential risk
[4]. This problem is more acute with anticancer drugs
intended for pediatric cancer. This occurs because of
Address corr espondenc e to this author at th e Department of P harmacy, NSHM
Knowledge Campus, Kolk ata-Group of Institutions, 124 B.L.Saha Road,
Kolkata- 700053, West Bengal, India;
diverse types of cancer with numerous molecular
alterations affecting a very small section of children [5].
Similar situation is also observed in the field of pediatric
ocular drug delivery. This happens owing to very few
incidences of degenerative ocular diseases in children
and also major differences in pathophysiology of such
diseases and their models between children and
adults. There is a report of a study designed to
compare the licensing and availability status of ocular
medications marketed in Italy, United Kingdom and the
United States of America based on data obtained from
randomised clinical trial for the active pharmaceutical
ingredients in the children only [6, 7]. Professional
bodies, research organisations and disease specific
groups that have been developed or formed and global
initiatives that have been adopted to disseminate
information about the policies involved in manufacture,
license and research of pediatric medicines, to improve
the quality of design, conduct and reporting of pediatric
clinical trials include Network of Paediatric Research at
the European Medicines Agency (Enpr-EMA), the
Paediatric medicines Regulator’s Network
(PmRN)(WHO initiative), WHO Millennium
Development Goals including ‘Make medicines child
size’ initiative, World Health Assembly “Better
Medicines for Children” Resolution WHA60.20,
National Institute for Health Research (NIHR),
Medicines for Children Research Network (MCRN) in
the UK, Standards for Research in (StaR) Child Health,
International Paediatric Association, Academy of
Paediatrics (AAP), Children’s Oncology Group,
Paediatric Rheumatology International Trials
Organization (PRINTO)and Paediatric European
30 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2019, Vol. 7 Majee et al.
Network for the Treatment of AIDS (PENTA) [1]. ICH
E11 and its addendum provides a structural framework
for ethical planning and implementing clinical trials for
drugs in pediatric population [8, 9]. The European
Regulations permits marketing of a new medicinal
product for children only after it has been investigated
in accordance with an agreed pediatric investigation
plan (PIP) or European Medicines Agency decision on
waiver or on a deferred PIP [10]. Recently, a multi-
stakeholder workshop was organised at EMA in March
2018 to discuss the roles and responsibilities of the
patients, academics, healthcare providers,
pharmaceutical industry, regulatory authority, ethical
committee in improving the implementation of the
pediatric regulation. Urgent need was felt for co-
operation between international bodies, timely
completion of PIP and sharing of data involving
pediatric medicines. The ultimate objective of all of
them is to optimise drug development pathways for the
pediatric population, to provide access to evidence-
based therapies in children and finally to ensure safety
for the child [11]. A positive approach has been
observed in the United States regarding enrolment and
treatment of pediatric cancer patients in public-funded
clinical trial networks and partial sponsorship by
industries. Moreover, Food and Drug Administration
Reauthorization Act of 2017 (FDARA) has done away
with the previous practice of exemption of pediatric
studies of oncology drugs based on orphan drug
nomenclature especially when the therapeutic molecule
is targeted to more than one type of children-specific
cancer [5]. The Canadian government has also
reviewed its regulatory policy and made necessary
amendments involving accessibility of pediatric
medicines in 2016 [4].
The present review article focusses on the various
challenges faced by the clinicians, protocol elements
and steps in planning and conduct of successful
pediatric clinical trials which is still in its infancy and
prospects for future progress. Consideration of the
above factors will increase awareness among the
pediatric investigators and impart training, improve
research standards by providing better data
interpretation methods, pave new paths for overcoming
the logistical and methodological challenges in
conducting clinical trials for diseases of low occurrence,
may heighten the possibilities of funding and
sponsorship and bring about revisions in the present
regulations and initiatives thereby improving the scope,
reliability and relevance of clinical trials in pediatric
Developmental Changes in Children
Pediatric population constitutes a unique group and
any inappropriate procedure or element in the clinical
investigation can result in an unpleasant experience or
risk of liability for the child, its parents or legal guardian,
health authority, the investigator, the manufacturer and
the sponsor [8]. The manufacturers are usually
apprehensive of the legal ramifications of the long-term
effects of their products on the children in their later life
and also the expenses on the concerned lawsuits due
to negative impact. Due to lack of documented
evidences for the approved use of pediatric medicines
and laxity in practices concerning the pediatric clinical
trials, each child becomes the only participant of an
uncontrolled and unmonitored trial [12].
Children, spanning from newborns to adolescents
are characterised by unique constantly changing
physiological, developmental, psychological and
pharmacological features owing to the continuous
process of maturation. Differences can be seen in
disease pathophysiology, its manifestation, in the effect
of maturation and growth on pharmacokinetics and
pharmacodynamics [12]. The foremost challenge is
observed age- and size-related variations in
pharmacokinetic parameters and expression of protein
receptors involved in pharmacodynamics among the
heterogeneous pediatric population [13, 14].
Developmental changes that occur in children do not
always correlate with increase in body weight and the
inferences drawn from the studies may not be reflective
of the role of development and maturation on the drug
biodisposition of the highly vulnerable population [14,
15]. Absorption profiles of acid-labile drugs or lipophilic
drugs show different pattern in neonates. Bioavailability
of drugs undergoing active transport or intestinal
metabolism also changes. Changes are attributed to
changes in the body composition, leading to age-
dependent content in body water and fat, delay in
gastric emptying, lower intestinal motility, splanchnic
blood flow, differences in binding affinity of proteins,
immaturity of liver and kidney, lower glomerular
filtration rate and a different hepatic enzyme profile.
Composition of the infant diet affects renal clearance of
drugs administered to children [16].
Difficulty in Assessment of Pharmacodynamic
The second challenge is the precise assessment of
pharmacodynamic end point, an appropriate measure
Challenges and Planning of Pediatric Clinical Trials Journal of App lied Biopharmaceutics and Pharmacokin etics, 2019, Vol. 7 31
of response in very young children and newborns
which is a critical step in designing pediatric efficacy
and safety studies [17]. For example, estimation of
respiratory function with active participation of the
young volunteer is a major barrier in such studies [12].
Another difficult situation arises during pain
assessment as the children fail to correlate their pain
intensity with a visual analog scale. A successful
behavioural scale, COMFORT-B has been developed
and validated on the basis of six different behavioural
items as a pharmacodynamic end point for pain
assessment and sedation in children under the age of 3
years [14].
Ethical Issues in Conducting Pediatric Clinical Trial
Third important challenge in conducting clinical trials
in pediatric subjects is the ethical issue of finding
balance between the responsibility to perform clinical
trials to protect children from the risk of administration
of untested or off-label medicines and simultaneously
to protect children against unknown harmful effects that
may happen due to participation in trial [1]. It is the
moral obligation to conduct the study in such subjects
who are suffering from the particular disease for which
the investigational product is intended to be used and
thus cater to the pediatric health need in general. The
benefit-risk ratio of any study should be carefully
judged before implementing it practically. Under no
circumstances, the child should be at a
disadvantageous position [9]. Since, it is not always
possible to obtain meaningful consent from the child
participant, obtaining informed consent of the parent or
legal representative is mandatory. The consent should
be ethically obtained only after disclosing the objective,
methodology, logistics and the consequences of the
entire study protocol in details and giving them
sufficient time to make an informed decision. For
investigations to be carried out in newborns, prenatal
consent is acceptable [15]. Although children’s consent
becomes doubtful, their dissent should be respected
mainly if it differs from their normal response to the
same medication or procedure during usual clinical
setting [1]. Moreover, if not properly informed and
explained, children may ingest ophthalmic preparations
leading to incidences of severe systemic toxicity and
mortality [6]. Inspite of detailed clarification, there are
some issues over which parents can still raise
objections. These include presence of trace amount of
alcohol as a formulation ingredient, dosage regimen
that may affect school ac tivities, need for administration
of refrigerated medicines or requirement of DNA
analysis for studying therapeutic effects. Need of
insertion of indwelling catheters may also act as a
detrimental factor against permission by parent [8]. The
protocol should include well-documented protective
measures and the level of protection to be offered to
the participant in case of untoward incident. It is to be
kept in mind that parents are vulnerable in giving
consent under emotional pressure in case of a critically
ill child. Administration of placebo per se is not
regarded unethical [12]. Repetition of trial in child
volunteer either for the purpose of validation or for the
purpose of establishing minutest of differences
between competitive products in the market is
considered totally unethical. Therefore, the protocol
elements should be robust enough to produce reliable
data on the first attempt. It is the duty of the
investigating authority to publish the results of the study
for the benefit of the society and to protect the child
from future unnecessary exposure. For global pediatric
clinical trials, additional points need to be taken care of.
Definition of disease should be same for all the
participating countries. Similarly, same standard of care
including supportive palliative care should be followed.
Analytical procedures and definition of clinical,
biochemical and pharmacokinetic parameters should
be identical [8].
Biopharmaceutic Risk Assessment and
Determination of Relative Bioavailability
Due to abovementioned ethical concerns over
pediatric clinical trials, it is a challenge to obtain
detailed biopharmaceutic data in pediatric population.
However, biopharmaceutic risk assessment is an
essential part of pediatric drug development. Adult data
can be of relevance only if the observations can be
logically extrapolated to children. Pediatric
pharmacokinetic data can be generated from enabling
and final commercial formulation and employed to
determine relative bioavailability using population
pharmacokinetic approach and parametric bootstrap
technique. This procedure should be completed before
the initiation of the main trial procedure. If the two
formulations are found to be equivalent, switch over
can be done confidently and can facilitate in
determination of relative bioavailability [18].
Assessment of Palatability and Swallowability
Another difficulty frequently encountered in
evaluation of pediatric dosage forms in early stage of
formulation development is assessment of their
palatability and swallowability. Ontogenic taste profile
and panels that are employed widely are suitable for
32 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2019, Vol. 7 Majee et al.
older children and for adults but not for infants or very
young ones [16]. Palatability assessment is usually
done by using two unvalidated but widely recognised
visual analog scale and facial hedonic scale. However,
no standard statistical method is available for data
analysis and interpretation or cross-comparison of
results across various studies. It is difficult to establish
correlation between palatability and medication
adherence due to paucity of literature reports or
surveys [19]. For swallowability assessment of solid
oral dosage forms, the children should be administered
a placebo during the baseline period [16]. A single-
centre, randomised, open cross-over trial was
undertaken in 306 pediatric in-and out patients, ranging
in age from 6 months to 5 years to compare
acceptability and swallowability of uncoated/coated
mini-tablets and syrups. Mini-tablets were found to be
more acceptable [20].
Selection of Test Population
The composition of the study cohort in the US is
governed by the Written Request issued to a sponsor
by the FDA. The sample size is usually small due to
restriction imposed by prevalence of the target disease
across different age groups. In order to overcome the
data scarcity, statistical methods have been developed
and collaboration between multinational groups and
clinical trial networks is facilitated for data and resource
pooling. Inter-subject variability in response due to the
investigational product or due to development process
should be considered [1], [16].
Selection of Dosing Approach and Dose
Various approaches can be employed for selecting
dose or strengths in children during trials. Knowledge
of dose-response relationship of the compound in
adults is a prerequisite for initiating the trial and
obtaining a comparable pharmacodynamics profile
between adults and children. Other highly significant
and relevant necessary information for conducting the
study and deciding patient-tailored dose include
therapeutic index, pharmacokinetic data from
preclinical studies and existing non-clinical data.
Individual child can either be adminis tered weight-
adjusted dose (normalised to body mass or surface
area) or a fixed dose can be given to all the subjects
irrespective of age, especially in the situations when
titrable formulation is not available [16, 21]. However,
dose fixation based on linear extrapolations from adult
dose may sometimes result in therapeutic failure. To
avoid such consequences, population PK-PD studies
should be preferably adopted which enables calculation
of individualised dosing regimen irrespective of age,
body weight and genetic background. Population PK-
PD has also helped in developing software packages
such as WINPOPT, PopED and PFIM. Other
approaches include targeted pharmacometric strategy,
microdosing, modelling and simulation-based
approach. For microdosing to be successful, dose
linearity study should be carried out from microdose to
the therapeutic adult dose in adult population.
Following the administration of first dose, Bayesian
studies enable dose titration to reach the desired
therapeutic window rapidly, within individual and
sequential patients [14, 15].
Selection of Age-Appropriate Medicine
The major issue of concern regarding administration
of medicines to children in Phase I or II clinical trial is
the formulation’s acceptability, tolerability and
palatability. For formulations to be tested globally, the
choice of flavour and color varies from one region to
the other. Among various factors governing the child or
its parents’ preference include the child’s
developmental stage, route of injection, dosage form,
dosing frequency, availability of suitable delivery
devices, effect on lifestyle of the children, need for
refrigeration to protect safety and efficacy. Other
factors include possibility of personalised dosing
regimen or dose banding appropriate for effective
therapy, availability of non-toxic approved excipients
and ultimately cost-effective manufacturing process
[22]. Parenteral administration in neonates needs
special consideration as it may lead to electrolyte, fluid
or nutritional imbalance if not properly monitored.
Intramuscular and subcutaneous routes may preferably
be avoided due to unpredicted bioavailability and pain
involved [9]. Information about the safety and toxicity of
excipients for paediatrics can be obtained from user-
friendly STEP database developed by European
Paediatric Formulation Initiative (EuPFI) in
collaboration with United States Paediatric Formulation
Initiative (USPFI). It is an exhaustive compilation acting
as a resource for storage and rapid, effortless access
to clinical, non-clinical and in-vitro data of the
excipients in one single freely accessible source [23].
Non-clinical safety studies are performed in juvenile
animals for assessment of specific toxicities or
sensitivities. To obtain complete safety profile, safety
Challenges and Planning of Pediatric Clinical Trials Journal of App lied Biopharmaceutics and Pharmacokin etics, 2019, Vol. 7 33
assessment studies should take into consideration total
number of doses, maximum concentrations of the
excipients, dosing regimen, duration of treatment, route
of administration, as well as the indication and the
minimum age groups where the formulation is intended
to be administered [24]. European Regulation on
Pediatric Medicines has made it mandatory to develop
child-specific dosage forms by pharmaceutical industry
as a part of pediatric investigation plan. The European
Medicines Agency (EMA) has questioned the suitability
of oral solid dosage forms to children aged less than 2
years [20]. Some of the commercially available age-
appropriate dosage forms for pediatric population
include liquids, suspensions, chewable tablets of
appropriate strengths, mini tablets, milk dispersible
tablets, scored tablets, easy to swallow gels and wafers
[8, 25-28] A shift to novel delivery devices for easy and
safe administration to the children has taken place.
Approaches like nipple shield dosage delivery system
(NSDS), oral syringes, medicine bottles, pulp spoon
devices, medicated straws and pill swallowing cups
have been designed and adopted [29-34].
Selection of Body Fluid Sampling Process
A thorough knowledge of various pediatric blood
sampling techniques is a prerequisite to planning a
good clinical trial protocol. Age band of children
restricts the sampling technique and volume of blood
samples necessary for pharmacokinetic analyses.
Children’s fear of needles and venepuncture for sample
collection becomes challenging especially if
intravenous route is not necessary for clinical care of
the patient. Volume of blood samples for research
should not exceed 1% at any one time or 3% over a 2-
8week period. In addition to intravenous sampling
technique, finger or heel pricks or collection of saliva
may also suffice for the purpose only if relationship
between saliva and plasma concentration can be
established. Advances in sensitivity, precision and
robustness of analytical techniques has rendered
possible use of non-invasive microsampling technique
(e.g. dried blood spots), ‘scavenged’ sampling (using
left-over blood from clinical samples) or opportunistic
sampling (sampling at the same time as clinical blood
tests) with trace amount of sample (5-10 µl). These
low-risk, population pharmacokinetic techniques use
non-linear mixed effects and are ethically acceptable
from all aspects. However, the newer protocols should
be properly validated and designed in compliance with
guidelines of regulatory authorities [1, 15].
Measuring Analyte (Drug) Concentration
Quantification of drugs in very minute volumes of
body fluids can result in drug concentration well below
the lower limit of quantification of the particular
analytical technique. In a different situation, volume
concentration can give excessively high analyte
concentration which is beyond the upper limit. These
problems also arise due to the developmental changes
in the PK parameters across different age groups of
pediatric population which are remarkably different
from those of adults. In such circumstances, reanalysis
may be necessary to generate meaningful data from
investigations that may be possible if sufficient residual
volumes are available. Examples of ultrasensitive
analytical techniques employed for pharmacokinetic
analyses of pediatric body fluid samples include liquid
chromatography with tandem mass-spectrometry,
capillary electrophoresis etc, [14, 16].
Monitoring Outcome Measures
Different age-appropriate outcome measures should
be selected as it is challenging to quantify certain
symptoms such as pain, nausea, dizziness, level of
sedation, visual and auditory responses in young
children. An innovative approach, face pain scale has
been developed for pain assessment in children [1].
Monitoring Safety and Tolerability
Toxicokinetic studies are done in juvenile animals to
assess neurotoxicity, immunotoxicity or nephrotoxicity
at different developmental stages. Local tolerance
studies should also be carried out for topical dosage
forms. Safety issue is more important because it is very
difficult to assess presence or absence of identifiable
subjective symptoms in association with the
investigational product or study-related procedures
Selection of Animal Species
Appropriate animal models should be selected on
the basis of maturation status of organs for which the
drug is targeted. Results obtained should be such that
they can be extrapolated to children. Usually juvenile
rodents are selected for performing safety and toxicity
studies of inhaled products intended for pediatric
administration or for products targeted for brain. Dogs
may also be used as animal models for studying
inhaled products for children less than 2 years of age.
For studying blood-brain barrier, juvenile rat model
younger than 8 days of age may be employed. If no
34 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2019, Vol. 7 Majee et al.
relevant animal model can be found, then new
strategies should be designed to evaluate safety and
toxicity for application in pediatric setting [10].
Planning Bioavailability-Bioequivalence (BA-BE)
Heterogeneity of pediatric population necessitates
conducting bioavailability-bioequivalence studies in
multiple subgroups to account for the differences in the
level of maturation of various organs, biodistribution
and biodisposition [12]. The FDA decision tree looks at
the various studies essential to bridge adult and
pediatric data, data between different age groups or
subsets [35]. For diseases common to adults and
children and where disease progression, response,
concentration-response relationship are comparable,
initial dose extrapolated from adult dose should be
followed by pediatric pharmacokinetic studies and
safety evaluation at the selected dose [18]. An enabling
formulation should be developed at the initiation of
study. Bioavailability study of the enabling formulation
is mandatory and bioequivalence between the enabling
and final commercial formulation should be established
unless biowaiver is granted on the basis of
Biopharmaceutic Classification System (BCS). It is to
be mentioned at this crucial juncture that BCS
classification of the same compound may vary between
adults and children mainly if initial gastric volume is
considered. With pediatric administration, most
commonly occurring molecules are found to belong to
poorly soluble BCS Class 2 or 4 and hence biowaivers
are not applicable. Single dose study can be planned
with placebo thus obviating the need for administration
of actual formulation. Single dose pediatric studies can
also be conducted with the test formulation in different
pediatric age groups only if linear pharmacokinetics
has been demonstrated in adults. However,
formulations for multiple dose administration need to be
studied separately and this becomes problem if oral
liquid dosage forms do not possess acceptable taste
and flavors when they are rejected by the pediatric
volunteers. Certain additional points should be
considered during adult BA-BE studies in order to
generate useful data for pediatric studies. Relative
bioavailability data of liquid dosage forms versus oral
solid dosage forms, crushed tablets on soft foods
versus intact tablets can be very beneficial for the
biopharmaceutic risk assessment for pediatric study
protocol [1, 16, 18, 36]. In some cases, specific
pediatric strength product identified to deliver target
dose in pediatric population can be tested for
bioequivalence in healthy adult volunteers with a little
modification from the usual protocol. The multiple units
of pediatric product equivalent to single adult dose are
administered and bioequivalence assessed. Positive
outcome proves the pediatric strength to be applicable
in need [21]. Formulations for children and adult
healthy volunteers can be compared in silico on the
basis of physiologically-based pharmacokinetic (PBPK)
models possessing sufficient data related to solubility,
permeability, dissolution profile and the effect of
developmental physiology on gastrointestinal
absorption [35]. Allometric scaling and systems
pharmacology models may also be employed.
Standard approach of scaling involves scaling of
clearance which is a combination of allometric weight
scaling with a sigmoid function taking into consideration
the effect of organ maturation [13]. Other suitable
techniques which may prove beneficial in deciding a
new dosage regimen include model-based meta-
analysis of existing data obtained from pediatric studies
or empirical analysis of observed pharmacokinetic data
following administration to pediatric subjects.
Pharmacogenomics may also be regarded as an
alternative for studying pharmacokinetics, safety and
efficacy of drugs in children [1]. Modeling and
simulation is another strategy which is still of academic
and research interest and yet to be approved by the
new pediatric European Union (EU) directive and
permits quantitative use of sparse sampling,
characterisation and prediction of PK-PD [35].
Experimental and ethical issues are the major
obstacles to investigating pediatric clinical
pharmacology, undertaking high-quality PK-PD studies,
successful design, implementation and timely
completion of pediatric clinical trials. Determination of
first pediatric dose and dosing regimen becomes
difficult due to problems in sampling techniques,
analytical techniques and methods of data analysis. In
addition to the different techniques and strategies
currently employed to carry out pediatric clinical trial in
the light of ensuing new legal framework by various
regulatory authorities and also to ensure full protection
of the highly vulnerable pediatric population, few
changes are being made for further improvements and
to define the safeguards for the children. To facilitate
decision-making process in parents for participation of
the child in trial, consent readability is being improved,
goodness-of-fit approach is being adopted, James Lind
Library has been developed [1].
Sample population size can be increased to account
for pharmacokinetic variability. Samples may be
collected at different optimal times from different
Challenges and Planning of Pediatric Clinical Trials Journal of App lied Biopharmaceutics and Pharmacokin etics, 2019, Vol. 7 35
participants to reduce the burden and also to obtain
better results. Population pharmacokinetic studies can
be made easier by including those in the group who are
already being administered the investigational
compound [15]. The outcome of any study on pediatric
formulation excipients, their validation should be
shared properly to facilitate formulation development
process and also conduct of global trials [8]. Although
two unvalidated protocols are used for palatability
assessment of pediatric formulations, suitable and
reliable robust taste prediction techniques should be
developed and optimised in the early stages of
formulation development. Adult taste panels should be
properly validated and correlated in pediatric
A public-private consortium of industry, clinical and
pediatric advocacy groups, Global Alliance for Pediatric
Therapeutics (GAPT) updated the latest reviews and
reports on pediatric clinical studies [19]. The FDA
should work in strong collaboration with multiple
stakeholders to implement strict trial governance with
the ultimate aim of protecting the most vulnerable
population from unnecessary harmful exposure. This
type of active collaboration in the early stages of drug
development procedure will promote arrival of new
pediatric oncology drug products [5]. The
pharmaceutical indus try should allocate a proportion of
their research budget for pediatric studies and should
be able to predict return on investment from such
studies. Impetus for such studies to be taken up by
sponsors will be more if unnecessary duplication in
multijurisdictional Research Ethics Board Reviews can
be avoided, research sharing platforms can be created
and suitable standards for pooling of compatible data
are established [4]. Shifting from brand to generic
drugs may expand the possibilities to choose drug
specifically for the pediatric subgroups [36]. With
pediatric ocular therapy, more specific therapeutics
need to be developed and effective communication
should be initiated among the pediatric patients, their
legal guardians and healthcare professionals to
overcome the problems of non-compliance and gap in
knowledge [6].
Pediatric drug development is a complex area.
Pharmaceutical industries, government as well as the
regulatory authorities and all stakeholders have a moral
collective responsibility to generate sufficient
information and should collaborate actively with non-
profit funding agencies in order to ensure that
developing children have access to age-appropriate,
quality, safe and effective medicines with supporting
documents and proofs to establish prescriptions of the
particular product for the children only.
[1] Joseph PD, Craig JC, Patrina HY. Clinical trials in children.
Br J Clin Pharmacol 2013; 79(3): 357-69.
[2] Sachs AN, Avant D, Lee CS, Rodriguez W, Murphy MD.
Pediatric information in drug product labeling. J Am Med
Assoc 2012; 307(18): 1914-5. 10.1001/jama.2012.3435
[3] Schreiner MS. Paediatric clinical trials: Redressing the
imbalance. Nat Rev Drug Discov 2003; 2(12) : 949-61. 10.1038/nrd1253
[4] Hepburn CM, Gilpin A, Autmizguine J, Denburg A, Dupuis
LL, Finkelstein Y et al. Improving paediatric medications: A
prescription for Canadian children and youth. Paediatr Child
Health 2019; 24(5): 333-5. 10.1093/pch/pxz079
[5] Barone A, Casey D, McKee AE, Reaman G. Cancer drugs
approved for use in children: Impact of legislative initiatives
and future op portunities. Pediatr Blood Cancer 2019; 66(8): 6
pgs. 10.1002/pbc.27809
[6] Sheybania ND, Yang H. Pediatric ocular nanomedicines:
Challenges and opportunities. Chin Chem Lett 2017; 28(9):
1817-21. 10.1016/j.cclet.2017.07.022
[7] Fortinguerr a F, Clavenna A, Bonati M. Ocular medicines in
children: The regulatory situation related to clinical research.
BMC Pediatr 2012; 12: 13 pgs. 10.1186/1471-2431-12-8
[8] Kathleen GR, Paul VP. The evolution of legislation to
regulate pediatric clinical trials: Pr esent and continuing
challenges. Adv Drug Deli Rev 2006; 58(1): 106-15. 10.1016/j.addr.2005.12.00 5
[9] Committee for Human Medicinal Products. European
Medicines Agency 2017. ICH E11(R1) guid eline on clinical
investigation of medicinal products in the pediatric
population: 16pgs.
guidelines /GMP-guideline/ICH-E11-clinical -investigation
[10] Silva-Lima B, Theilade-Thomsen MD, Carleer J, Vidal JM,
Tomasi P, Saint-Raymond A. Juvenile animal studies for the
development of paediatric medicines: A description and
conclusions from a European medicines agency workshop
on juvenile animal testing for nonclinic al assessors. Birth
Defects Res B Dev Reprod Toxicol 2010; 89(6): 467-73. 10.1002/bdrb.20257
[11] Mulb erg AE, Cripps T. Global harmonization of pediatric drug
development: critical f or progr ess for developing safe and
effective therapeutic agents for children. Curr Ther Res 2019;
90(1): 10 9-12. 10.1016/j.curtheres .2019. 01.006
[12] Raymond AS, Brasseur D. Development of medicines for
children in Europe: Ethical implications. Paediatr Respir Rev
2005; 6(1): 45-51. 10.1016/j.prrv.2004 .11.008
[13] Germovsek E, Barker CIS, Sharland M, Standing JF.
Pharmacokinetic- pharmacodyna mic modeling in pediatric
drug dev elopment, and the importance of standardized
scaling of clearance. Clin Pharmacokinet 2019; 58(1): 39-52. 10.1007/s402 62-018-0659- 0
[14] Cock RFWD, Piana C, Krekels EHJ, Danhof M, Allegaert K,
Knibbe CAJ. The role of population PK-PD modelling in
36 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2019, Vol. 7 Majee et al.
paediatric clin ical research. Eur J Clin Pharmacol 2011;
67(Suppl): S5-16. 10.1007/s00228-009-0782-9
[15] Barker CIS, Standing JF, Kelly LE, Faught LH, Needham AC,
Rieder MJ et al. Pharmacokinetic studies in children:
Recommendations for practice and research. Arch Dis Child
2018; 103: 695-702. 10.1136/archdischil d-2017-3145 06
[16] Abdel-Rahman SM, Reed MD, Wells TG, Kearns GL.
Considerations in the rational design and conduct of phase
I/II pediatric clinical trials: Avoiding the problems and pitfalls.
Clin Pharmacol Ther 20 07; 81(4): 48 3-95. 10.1038/sj.clpt.6100134
[17] Kelly LE, S inha Y, Barker CIS, Standing JF, Offringa M.
Useful pharmacodynamic endpoints in children: Selection,
measur ement, and next steps. Pediatr Res 2018; 83: 1095-
1104. 10.1038/pr.2018.38
[18] Purohit VS. Biopharmaceutic planning in pediatric drug
development. AAPS J 2012; 14(3): 519-22. 10.1208/s122 48-012-9364- 3
[19] Squires LA, Lombardi DP, Sjostedt P, Thompson CA. A
systematic literature review on the assessment of palatability
and swallowability in the dev elopment of oral dosage forms
for pediatric patients. Ther Innov Re gul Sci 2013; 47(5) : 533-
41. 10.1177/2168479013 500288
[20] Klingmann V, Spomer N, Lerch C, Stoltenberg I, Fromke C,
Bosse HM et al. Favor able acceptance of mini-tablets
compared with syrup: A randomized controlled trial in infants
and preschool children. J P ediatr 2013; 163(6): 1728-32. 10.1016/j.jpeds.2013.07.014
[21] WHO/PQT: Medicines 2018. Guidance document. Paediatric
products in PQT medicines: 3 pgs.
prequal/news/n ote-pediatric-products-pqt-medicines
[22] Batchelor HK, Marriott JF. Formulations for children:
Problems and solutions. Br J Clin Pharmacol 2013; 79(3):
405-18. 10.1111/bcp.12268
[23] STEP Database. European Paediatric Formulation Initiative
(EuPFI)|United States Paediatric Formulation Initiative
(USPFI). 2015.
[24] Schmitt G. Safety of excipients in pediatric formulations- A
call for toxicity studies in juvenile animals? Children 2015;
2(2): 191-7. 10.3390/children2020191
[25] Tissen C, Woertz K, Breitkreutz J, Kleinebudde P.
Development of mini-tablets with 1 mm and 2 mm diameter.
Int J Pharm 2011; 416: 164-70. 10.1016/j.ijpharm.2011.06.027
[26] Shah H, P arikh D, Butani S. Formulation development &
optimisat ion of milk dissolving tablets as novel paedia tric
dosage form. Int J Drug Formln Res 2014; 5: 84-96.
[27] Kayitare E, Vervaet C, Ntawukulilyayo JD, Seminega B,
Bortel V, Remon JP. Development of fixed dos e combination
tablets containing zidovudine and lamivudine for paediatric
applicati ons. Int J Pharm 20 09; 370: 41-6. 10.1016/j.ijpharm.2008.11.005
[28] Kabuto A, Sugiura Y, Suzuki E, Okabe H. Process for
producing preparation for oral administrati on. United States
Patent 2012; US 8,303,741 B2: 17 pgs.
[29] Hart CW, Israel-Ballard KA, Joanis CL, B aniecki ML, Thungu
F, Gerrard SE, Knee n E, Sokal DC. Acceptability of a nippl e
shield delivery system administering antiviral agents to
prevent moth er-to-child transmission of HIV through
breastfeeding. J Hum Lactatn 2015; 1-8. 10.1177/0890334414 559980
[30] Gerrard SE, Orlu-Gul M, Tuleu C, Slater NKH . Modelling the
physiological factors that affect drug delivery from a nipple
shield delivery system to breastfeeding infants. J Pharm Sci
2013; 102: 3773-83.
[31] Walsh J, Bickmann D , Breitkreutz J, Chariot-Goulet M.
Delivery devices for the administration of paediatric
formulations: Overview of current practice, challenges and
recent developments. Int J Pharm 2011; 415: 221-31. 10.1016/j.ijpharm.2011.05.048
[32] Botts LM. Medicine dispensing baby bottle. United States
Patent 1993; US patent No 5,244,122: 8 pgs.
[33] Farkas B, Balogh A, Farkas A, Domokos A, B orbás E, Marosi
G, Nagy ZK. Medicated straws based on electrospun solid
dispersions. Period Polytec h Chem Eng 2018; 62 : 310-16. 10.3311/PPch.11931
[34] Crossley DW. Pill cup. United States Patent 2007; US
2007/0068949 A1: 6 pgs.
[35] Mano lis E, Pons G. Proposals for model-based paediatric
medicinal development within the current European union
regulatory framework. Br J Clin Pharmacol 2009; 68(4): 493
501. 10.1111/j.1365-2125.2009.03484.x
[36] Illamola S M, Birnbaum AK, Sherw in CM. Generic drug
products in p aediatr ics: Where are the data? Br J Clin
Pharmacol 2019; 85(9): 1871-3.
Received on 01-12-2019 Accepted on 15-12-2019 Published on 24-12-2019
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