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\begin{document}

\title{Innovative Methodologies in paediatric drug development: a
conect4children (c4c) special issue}



\author[1]{Saskia De wildt}%
\author[2]{Ian Wong (NO NEW ASSIGNMENTS)}%
\affil[1]{Radboudumc}%
\affil[2]{Department of Pharmacology and Pharmacy}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\begin{abstract}
In this special issue of the British Journal of Clinical Pharmacology,
we highlight innovative methodologies in pediatric drug development.%
\end{abstract}%



\sloppy


Innovative Methodologies in paediatric drug development: a
conect4children (c4c) special issue

Authors

\textbf{Saskia N. de Wildt\textsuperscript{1, 2,}}

1 Department of Pharmacology and Toxicology, Radboud university medical
center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands

2 Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia
Children's Hospital, Rotterdam, the Netherlands

Professor of Clinical Pharmacology and Toxicology, paediatric
intensivist

Radboud University Medical Center

P.O. Box 9101, 6500 HB Nijmegen (Route 137),

the Netherlands

Saskia.dewildt@radboudumc.nl (corresponding author)

ORCID 0000-0002-0502-0647

\textbf{Ian C.K. Wong\textsuperscript{3, 4}}

3 Centre for Safe Medication Practice and Research, Department of
Pharmacology and Pharmacy, Li Ka Shing, Faculty of Medicine, The
University of Hong Kong, Hong Kong Special Administrative

Region, China.

4 Research Department of Practice and Policy, UCL, School of Pharmacy,
London, UK.

i.wong@ucl.ac.uk

ORCID 0000-0001-8242-0014

\textbf{Funding statement}

conect4children has received funding from the Innovative Medicines
Initiative 2 Joint Undertaking under grant agreement No 777389. The
Joint Undertaking receives support from the European Union's Horizon
2020 research and innovation program and EFPIA. The publication reflects
the author's view and neither IMI nor the European Union, EFPIA, or any
Associated Partners are responsible for any use that may be made of the
information contained therein

Disclaimer

\emph{The publication reflects the author's view and neither IMI nor the
European Union, EFPIA, or any Associated Partners are responsible for
any use that may be made of the information contained therein.}

\textbf{Authorship statement}

SNW, ICKW wrote the article

\textbf{Conflict of interest disclosure}

IW reports grants from Research Grants Council of Hong Kong Government,
European Commission, NIHR, Medical and Health Research Fund of the Hong
Kong Government; speaker fees from Medice and Janssen and educational
grants from various pharmaceutical companies, outside the submitted
work.

SNW reports grants from European Commission, Bill and Melinda Gates
Foundation, consultancies with Khondrion, AM Pharma BV and is director
of board of the Kinderformularium B.V.

On average, half of all children in Europe take medicines, either for
acute or chronic illness. At the same time almost half of these
prescriptions are off-label, due to a historic lack of medicines
specifically developed for children \textsuperscript{1}. For ethical,
practical and economic reasons, academic and industry researchers were
reluctant to study drugs in children. With the 2007 EU Paediatric
Regulation, and similar initiatives across the world, this situation has
changed, as companies are now mandated to submit paediatric
investigation plans early in the course of drug development. While these
legislative efforts have resulted in huge increase in paediatric trials
to be initiated, new paediatric registrations have severely lagged
behind \textsuperscript{2}. Several causes can be identified, but a
major reason for this disappointing result has been the failure to
successfully perform paediatric clinical trials, not only in Europe, but
across the world. Many studies were started but did not manage to
recruit sufficient numbers of patients, other studies failed to provide
adequate answers on efficacy or safety due to suboptimal study design.

To overcome these challenges, the EU with 10 pharmaceutical industry
partners allocated in 2018 140 million euros for the conect4children
(c4c) project through the public-private IMI2 funding
program\textsuperscript{3}. The aim of this project is to provide better
medicines for babies, children and young people through a pan-European
clinical trial network. c4c aims to generate a sustainable
infrastructure that optimizes the delivery of clinical trials in
children through: a) a single point of contact for all sponsors, sites
and investigators; b) efficient implementation of trials, adopting
consistent approaches, aligned quality standards and coordination of
sites at national and international level; and c) collaboration with
specialist and national networks; d) an education and training platform
to shape the future leaders of paediatric drug development. Moreover,
c4c aims to provide: e) high quality input into study design and
preparation, through rigorous strategic and operational feasibility
assessment and f) the promotion of innovative trial design and
quantitative scientific methods.

For these two last aims: high quality input in study design and
preparation and the promotion of innovative trial design, c4c set-up a
European c4c expert network. This network exists of more than 300
experts organized into clinical subspecialty groups, innovative
methodology groups and patient/parent representatives. During the course
of paediatric drug development, investigators, either from industry or
academia, can contact c4c to ask for strategic feasibility advice. This
advice can encompass clinical, methodology and/or PPI input and will be
provided through live or online meetings. An important goal of this c4c
activity is the implementation of innovative study methodologies in
clinical trial design for feasible, high quality, patient-friendly
studies. c4c does not only aim to reach this goal by providing advice on
single drug development programs or studies, but also by sharing the
expertise of our innovative methodology expert groups. This special
issue of BJCP is dedicated to present state of art methodology for
paediatric drug development, through a series of white papers from the
methodology groups: Developmental Pharmacology, Pharmacometrics, Omics,
Formulations, HTA, and Pharmacovigilance.

\textbf{Developmental Pharmacology} deals with the impact of growth and
maturation involved on the disposition and effect of
drugs\textsuperscript{4}. This paper, co-written by experts from c4c
developmental pharmacology group and the European Society of
Developmental Perinatal Paediatric Pharmacology presents a state of art
overview of major age-related variation in ADME pathways, including drug
metabolism and renal excretion and at the same time identifies important
information gaps in need of further study. Using several target and
disease-specific examples, the impact of ontogeny on the PK-PD
relationship is also illustrated, including pre-clinical models to study
this relationship. The authors provide several suggestions to use this
knowledge in drug development, including minimal invasive sampling,
combined with metabolite profiling, application of age-specific
assessment tools, preclinical models to study paediatric PD and
abandoning the sequential age study design.

The US FDA (United States Food and Drug Agency)
defines\textbf{Pharmacometrics} as the science that quantifies drug,
disease and trial information to aid efficient drug development and/or
regulatory decisions. As presented by the pharmacometrics group, in
paediatric drug development, pharmacometrics is largely used to
extrapolate data from adults to children and to describe
pharmacokinetics in children (REF). It has been used to inform
paediatric trial design, in particular, to support paediatric dosing.
Both, the bottom-up approach using physiology-based pharmacokinetic
models, integrating paediatric physiology, as well as top-down methods,
using adult and juvenile paediatric data, or mixed approaches are
explained and discussed. Suggestions for a standard practice for
paediatric pharmacometrics are presented.

A crucial aspect of pharmacotherapy is drug safety
and\textbf{Pharmacovigilance} . Like the disposition and efficacy of
drugs, growth and development impact the risk of experiencing adverse
drug reactions. Children may be at a higher or lower risk of toxicity,
or may develop age-specific adverse events. The detection of adverse
events may also be affected by age. E.g. headache in a non-verbal child,
may present as irritability and it will hard to identify the exact cause
of this irritability. Aurich et al, present these child-specific issues
and discuss methodological challenges during paediatric drug
development, including considerations to be taken into account to
overcome them\textsuperscript{5}.

Neuman et al. discuss the need for and benefits of
\textbf{Omics}approaches in paediatric drug development (REF). A better
understanding of the paediatric disease, the impact of ontogeny on drug
disposition and effect, as well as the interplay of drugs with the
disease warrants the use of Omics techniques. Omics includes, but is not
limited to epigenomics, genomics, transcriptomics, proteomics and
metabolomics. These studies are needed in children, as extrapolation of
adult data ignores the impact of growth and development on these
processes. The use of these techniques alone or in concert, may aid to
develop biomarkers to identify and treat subgroups of children. A strong
call is made to include the collection of biological samples for omics
studies in every paediatric clinical trial, but also to collect samples
from healthy children.

\textbf{Formulation} scientists describe the global need for
age-appropriate drug formulations. An extensive overview is presented on
the current landscape of paediatric formulation development, and address
major limitations and challenges, including
regulatory\textsuperscript{6}. The group presents a paediatric Quality
Target Product Profile as an efficient tool to facilitate early planning
and decision making across all teams involved in paediatric formulation
development. Some key attributes for this tool are for route of
administration, paediatric age range, dosage form, dose/dose
flexibility, patient acceptability, stability and patient access. The
tool can be used during paediatric formulation design phase, not only
for new chemical entities, but also to repurpose/reformulate off-patent
drugs. Moreover, they call for more collaboration between formulation
scientists, manufacturers, clinicians and children and for adding
acceptability of formulations as major endpoints in paediatric clinical
trials.

\textbf{Health technology assessment (HTA)} is an important aspect of
paediatric drug development and post-marketing use. The effectiveness
and cost effectiveness of a drug is determined in order to support
evidence-based decision making of both policy makers and healthcare
professionals and an important use of HTA are decisions related to its
reimbursement. Moretti et al, describe in their paper, paediatric
specific aspects related to value of medicines in the context of the
regulations supporting drug development \textsuperscript{7}. Moreover,
they describe challenges related to HTA evaluations for paediatric
medicines, including lack of long-term data, small study populations,
but also differences in economics of treating children, including impact
on families, society and the different weight quality-adjusted life year
may have in the evaluation of medicines for children. These examples may
not only aid drug developers, but also research funders, national HTA
bodies and patients/parents when prioritizing paediatric studies and
deciding on reimbursement.

\textbf{In summary} , this BJCP special issue provides state of art on
methodologies for paediatric drug development. We hope drug developers,
in industry and academia, will use the guidance provided by these
experts to design the best possible, innovative and child-friendly
trials.

Further details of c4c can be found https://conect4children.org/

\emph{References}

1. Weda M, Hoebert J, Vervloet M, et al. \emph{Study on off-label use of
medicinal products in the European Union.} European Union2017.

2. Commission E. State of Paediatric Medicines in the EU 10 years of the
EUPaediatric Regulation.
https://ec.europa.eu/health/system/files/2017-11/2017\_childrensmedicines\_report\_en\_0.pdf.
Published 2017. Accessed March 8, 2022.

3. conect4children. Collaborative Netwerk for European Clinical Trials
for Children. www.conect4children.org\emph{.}Accessed March 8, 2022.

4. Smits A, Annaert P, Cavallaro G, et al. Current knowledge, challenges
and innovations in developmental pharmacology: A combined
conect4children Expert Group and European Society for Developmental,
Perinatal and Paediatric Pharmacology White Paper. \emph{British journal
of clinical pharmacology.} 2021.

5. Aurich B, Apele-Freimane D, Banaschewski T, et al. c4c: Paediatric
pharmacovigilance: Methodological considerations in research and
development of medicines for children - A c4c expert group white
paper.\emph{British journal of clinical pharmacology.} 2021.

6. Walsh J, Schaufelberger D, Iurian S, et al. Path towards efficient
paediatric formulation development based on partnering with clinical
pharmacologists and clinicians, a conect4children expert group white
paper. \emph{British journal of clinical pharmacology.} 2021.

7. Moretti F, Ruiz F, Bonifazi F, Pizzo E, Kindblom JM. Health
technology assessment of paediatric medicines: European landscape,
challenges and opportunities inside the conect4children
project.\emph{British journal of clinical pharmacology.} 2021.

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