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The conect4children (c4c) Consortium: Potential for Improving European Clinical Research into Medicines for Children

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The need for information about new and existing drugs used in children was recognized in the European Union (EU) with the implementation of the Paediatric Regulation in 2007. In 2017, the 10-year review of the Paediatric Regulation identified barriers to the conduct of clinical trials, including delays in setting up and completing paediatric trials. Across Europe, the difficulties with clinical research are compounded by variation within countries and between countries. Ethics and regulatory review have national specificities. This paper describes the Collaborative Network for European Clinical Trials for Children (conect4children, c4c), which addresses selected difficulties in the design and conduct of paediatric clinical trials. c4c is a time-limited public–private consortium funded by the Innovative Medicines Initiative (IMI2). The elements of c4c are as follows: expert advice providing input on study design and/or paediatric development programmes (including patient involvement activities); a network of sites following harmonised procedures coordinated by National Hubs and a single point of contact for Europe; a facility for education and training for sites and trial teams; and support for managing data used by the network and a common paediatric data dictionary. c4c does not sponsor trials. c4c is taking a phased approach with careful piloting through industry and non-industry studies intended to demonstrate the viability of the network (proof-of-viability studies). c4c uses a co-design approach involving industry and academics within a clearly defined scope. A sustainable, successor organization open to all potential service users will be open for business before the end of IMI2 funding in 2024.
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Vol.:(0123456789)
Pharmaceutical Medicine (2021) 35:71–79
https://doi.org/10.1007/s40290-020-00373-6
LEADING ARTICLE
The conect4children (c4c) Consortium: Potential forImproving
European Clinical Research intoMedicines forChildren
MarkA.Turner1,15 · HeidrunHildebrand2· RicardoM.Fernandes3· SaskiaN.deWildt4· FennaMahler4·
RégisHankard5· RebeccaLeary6· FedeleBonifazi7· PatrickNobels8· KatharineCheng9· SabahAttar10·
PaoloRossi11· FrancescaRocchi12· JoanaClaverol13· BegonyaNafria13 · CarloGiaquinto14
Accepted: 15 December 2020 / Published online: 4 February 2021
© The Author(s) 2021
Abstract
The need for information about new and existing drugs used in children was recognized in the European Union (EU) with
the implementation of the Paediatric Regulation in 2007. In 2017, the 10-year review of the Paediatric Regulation identified
barriers to the conduct of clinical trials, including delays in setting up and completing paediatric trials. Across Europe, the
difficulties with clinical research are compounded by variation within countries and between countries. Ethics and regulatory
review have national specificities. This paper describes the Collaborative Network for European Clinical Trials for Children
(conect4children, c4c), which addresses selected difficulties in the design and conduct of paediatric clinical trials. c4c is a
time-limited public–private consortium funded by the Innovative Medicines Initiative (IMI2). The elements of c4c are as
follows: expert advice providing input on study design and/or paediatric development programmes (including patient involve-
ment activities); a network of sites following harmonised procedures coordinated by National Hubs and a single point of
contact for Europe; a facility for education and training for sites and trial teams; and support for managing data used by the
network and a common paediatric data dictionary. c4c does not sponsor trials. c4c is taking a phased approach with careful
piloting through industry and non-industry studies intended to demonstrate the viability of the network (proof-of-viability
studies). c4c uses a co-design approach involving industry and academics within a clearly defined scope. A sustainable,
successor organization open to all potential service users will be open for business before the end of IMI2 funding in 2024.
Key Points
c4c is a time-limited public–private consortium that is
co-designing a clinical trials network that will address
problems with designing and executing trials that recruit
babies, children and young people.
c4c is piloting its work with a small selection of studies
but will scale up when a successor organization is estab-
lished before mid-2024.
1 Introduction
The European Union (EU) has recognized the need to
facilitate the development of medicines for children with
the Paediatric Regulation launched in 2007. The Paediat-
ric Regulation requires all sponsors who wish to market a
new medicine, such as an application for a new indication,
new pharmaceutical form or a new route of administration,
to discuss a Paediatric Investigational Plan (PIP) with the
European Medicines Agency (EMA) [1, 2]. The PIP may
result in a paediatric development programme, or may be
waived if the condition does not exist in children. Similar
approaches are taken in countries that are within geographi-
cal Europe but not members of the EU and in the United
States of America. Many trials are not done to support mar-
keting so a significant number of paediatric clinical drug and
biologic trials conducted across Europe take place outside
the requirements of the Paediatric Regulation.
The 10-year review in 2017 of the Paediatric Regulation
recognized a significant increase in the number of studies
* Mark A. Turner
mark.turner@liverpool.ac.uk
Extended author information available on the last page of the article
72 M.A.Turner et al.
that are designed to support a paediatric indication [3]. The
10-year review also identified some barriers to the conduct
of clinical trials included in PIPs. The barriers identified by
the review included significant difficulties with recruitment
due to scarce populations, particularly in rare diseases; dif-
ficulties with formulations; and problems with endpoints.
Forty-three percent of modifications to PIPs related to time-
lines because of delays completing studies while 14% of
modifications related to reductions in sample size. Delays
in setting up and completing paediatric trials arise due to a
number of challenges. These include developing contracts
between sites and sponsors that are specific to each site.
Templates for contracts can speed up this process; templates
for clinical trial agreements are available in some, but not
all European countries. Other challenges include obtaining
approvals from ethics committees or institutional review
boards (IRBs), and obtaining parental consent. Other dif-
ficulties are symptomatic of problems with the ‘clinical trial
enterprise’ that are not unique to paediatrics and have been
recognized for some time, including inadequate investiga-
tor training and recruitment, insufficient support staff and
support systems for clinical trials, inconsistent data harmo-
nization and lack of opportunities to incorporate the voices
of participants and their families [4]. Across Europe, the
difficulties with clinical research are compounded by vari-
ation within countries and between countries. Ethics and
regulatory review have national and local specificities that
relate, for example, to variation in attitudes to risk when
participants cannot give consent [5].
Paediatric research needs to adapt to the specificities of
babies, children and young people [6, 7]. Paediatric spe-
cificities include (1) ontogeny, so that study designs need
to account for differences in drug disposition and effect
between age groups; (2) practical issues such as the size
of the child, behaviour during health care and capacity for
assent and consent. The paediatric specificities are best
addressed continuously throughout the drug development
process so that study design and conduct are integrated.
There is an acute need to address the problems of the
clinical trial enterprise in general, the variation across Euro-
pean countries and adaptation to paediatric specificities.
This paper describes a time-limited consortium, the Col-
laborative Network for European Clinical Trials for Chil-
dren (conect4children, or c4c), that addresses selected dif-
ficulties with the conduct and design of paediatric clinical
trials. c4c does not aim to address all of the difficulties but
focuses on difficulties that can be addressed operationally
through a public–private partnership. c4c is not a lobbying
organization so cannot address the nature and content of
the Paediatric Regulation or variation between ethics com-
mittees/IRBs. c4c will work within the European legal and
regulatory framework and will not lead on scientific issues.
Rather, c4c will provide coordination between scientific
groups. Clinical trial scientists and teams have been work-
ing to improve the way paediatric trials are conducted for
several decades with partial success. We posit that enhanced,
transnational coordination will improve the delivery of pae-
diatric clinical trials. The aim of this review is to describe
c4c’s roles in the European context and progress toward a
harmonized, operational approach to the implementation and
coordination of clinical trials.
2 c4c: The Initiative andits Approach
c4c is an action under the Innovative Medicines Initiative 2
(IMI2) Joint Understanding [8], Grant Agreement 777389.
IMI2 is a public–private partnership that aims to improve
health by speeding up the development of innovative medi-
cines, particularly in areas where there is an unmet medi-
cal or social need. IMI is the world’s biggest public–private
partnership in the life sciences. The partnership includes
the European Commission (EC) (representing the EU) and
the European Federation of Pharmaceutical Industries and
Associations (EFPIA) (representing the pharmaceutical
industry) and is funded jointly by these two parties. While
industry contributes to the projects with in-kind consortium
capacity and knowhow, the EC matches these contributions
to fund activities provided by academia, small- to medium-
sized enterprises, and other non-industry groups. The c4c
consortium includes 10 large pharmaceutical companies
and 34 non-industry partners including academia, hospitals,
third-sector organizations and patient advocacy groups [9].
The goal of the c4c consortium is to set up and evalu-
ate selected elements of a paediatric-focused clinical trial
infrastructure that are tailored to meet the needs of chil-
dren involved in clinical trials. The elements are as follows:
expert advice providing input on study design and/or paedi-
atric development programmes (including patient involve-
ment activities); a network of sites following harmonised
procedures and coordinated by national hubs (NH) and a
single point of contact (SPoC) for Europe; a facility for edu-
cation and training for sites and trial teams; and support for
managing data used by the network and a common paediat-
ric data dictionary. c4c does not sponsor trials. The progress
and goals of c4c are shown in Fig.1.
In order to develop a robust approach to the research
infrastructure, c4c has adopted the following principles:
1. A phased approach with careful piloting of the proce-
dures used by c4c. The expert advice groups are taking
requests for advice from within the consortium. The net-
work of sites is working with studies intended to dem-
onstrate the viability of the network (proof-of-viability
[PoV] studies). c4c is working with three non-indus-
try trials and at least four industry trials and learning
73
conect4children (c4c) and European Paediatric Research
from real-world experience before scale-up to sponsors
outside the c4c Consortium. The educational and data
workstreams are collaborating with the expert advice
groups and the network of sites to facilitate their work
addressing the challenges outlined in the Introduction.
2. Collaboration and partnership with representatives of
big pharma, NH, sites, investigators and patient experts.
The development of each aspect of the network (particu-
larly processes and workstreams) is co-led by industry
and academia to ensure alignment between the two cul-
tures and future buy-in from both.
3. Focus on quality and performance management. c4c
has a unified quality framework that states principles by
which the consortium will ensure that it delivers what
it plans to do, when it plans to do it. The principles are
operationalized for each workstream. Quality manage-
ment is owned by each workstream which are account-
able to the Project Steering Committee (the successor
organization will have similar, well-defined reporting
lines). A Quality Committee ensures that each work-
stream has the tools to manage the quality of its work
and will selectively review work to control and assure
quality. The consortium has defined metrics for its activ-
ities that will inform performance management of all
activities.
4. Work with existing strengths when possible. c4c does
not aim to replace or duplicate what is already available
and effectively working, but to address specific gaps in
the paediatric clinical trials enterprise. The consortium
includes specialty networks Penta (HIV/AIDS and pae-
diatric infectious diseases) [10], PRINTO (paediatric
rheumatology) [11], Treat-NMD (neuromuscular dis-
orders) [12], ECFS-CTN (cystic fibrosis) [13], SIOPE
(paediatric oncology) [14] and ECNP (child and adoles-
cent mental health) [15]. In addition, c4c is represented
in the European Joint Programme on Rare Diseases [16]
and the European Network of Paediatric Research at the
EMA [17].
5. Support sustainability. The goal of the c4c consortium
is to develop a sustainable set of key services relating
to scientific feasibility, (expert) advice on trial design,
preparedness, planning, operational feasibility, imple-
mentation and coordination of clinical trials, education
and training and the information systems that support
its work. The nature of the services that become sustain-
able, and the mechanisms for sustainability, have not
been defined in advance but will be identified based on
the needs of key stakeholders (investigators, sites and
trial sponsors) and the experiences gained during work
with the PoV studies. Work on the business model and
legal structures for a successor organization is under
way. The aim is to set up a successor organization as an
independent legal entity before the end of the funded
Consortium in 2024.
6. Develop processes for work within c4c that can be
adapted to the needs of service providers and customers
as the organization grows.
7. Facilitate patient-centric clinical trials. c4c will provide
services along the drug development pathway that will
give sponsors opportunities to engage with patients,
Fig. 1 Goals and progress of c4c. c4c conect4children, CDISC Clinical Data Interchange Standards Consortium, GCP good clinical practice
74 M.A.Turner et al.
families and caregivers to work on the co-design of
clinical trials according to patients’ needs.
8. Coordination and synergy within the consortium, with
cross-cutting work between different workstreams,
such as education for investigators (network of sites and
education team), well specified and tested information
systems (information team and all other workstreams),
quality assurance of expert advice (quality team and
expert advice team).
9. Contribute to global interoperability for paediatric clini-
cal trials by working with similar initiatives outside the
EU.
As an IMI project, c4c services can only be used by
members of the consortium. This is because the consortium
is funded by commitments from IMI2 with in-kind con-
tributions from the industry members of the Consortium.
After end of the IMI funding, when network operations are
transferred to an independent new legal entity, services will
be available to all sponsors, industry, academia, advocate-
driven groups and to intermediary organizations such as con-
tract research organizations (CROs). The final organizational
and revenue structure of the successor organization has not
yet been defined, as it will be developed as part of the work
of the IMI2-funded consortium.
3 The Work ofc4c
The work of c4c is summarised in Table1, which describes
the selected difficulties with paediatric clinical trials that
c4c is addressing.
3.1 Design ofPaediatric Investigational Plans (PIPs)
andClinical Trial Protocols
Some PIPs and protocols do not succeed because they do
not fit with clinical practice or because assumptions about
participant availability are flawed. In addition, methodol-
ogy may be suboptimal: extrapolation, adaptive designs
and innovative methodologies are underutilized. In order to
address these problems, c4c has set up a database of >300
experts in methodology and clinical subspecialties, as well
patient and parent representatives. This database is man-
aged by the advisory group secretariat, which reports to the
c4c Network Management Committee (Fig.2). The clini-
cal experts are organized in subspecialty groups, as much
as possible in connection with the relevant learned society
or existing research network. The innovative methodology
experts are organized in groups that include study method-
ology (classical and innovative), pharmacometrics, health
technology assessment (HTA), developmental pharmacol-
ogy, formulations, ethics, pharmacogenomics and other
omics technologies and pharmacovigilance. Parent and
patient experts are connected by a network of young patient
advisory groups (YPAGs), disease-oriented patient organi-
zations (PO), as well as individual patients. When academic
or industry sponsors seek advice from c4c on their paediatric
studies or programmes, the advisory group secretariat forms
an ad-hoc strategic feasibility group including two to eight
relevant clinical, methodology and/or parent/patient experts.
The ad-hoc expert group then meets face to face or online
to address the sponsor’s specific questions. These questions
can be simple, such as evaluation of an informed consent
form or a specific outcome measure, or more complicated
such as advice on strategic decisions for PIPs. To optimize
the contracting process of experts, a centralised contracting
process will be implemented with a single master agree-
ment between each industry or academic sponsor and c4c
advisory group secretariat. With respect to transparency and
compliance related to working with health care profession-
als, c4c has implemented processes where payment in line
with fair market value and adherence to the EFPIA Code of
Practice for industry sponsors is ensured. Since the inclusion
of our experts in the standing expert groups in 2019, c4c
has handled 12 advice requests, addressing different issues
with different combinations of expertise. For example, one
completed advice request asked for c4c advice on (1) the
proposed research population, (2) ethical challenges of the
proposed design, (3) clinical perspective on risk and ben-
efits as well as feasibility of the proposal, (4) methodologies
and possible approaches to study design and (5) the patient
parent perspective on the proposed trial design including
assessments and follow-up. c4c provided the requester with
written advice following meetings with experts and several
patient/parent interviews.
To share innovative methodology approaches and their
potential application in paediatric drug development, the
expert groups will prepare and publish white papers during
the course of the IMI project.
Patient and public involvement (PPI) activities are usually
set up as an ad-hoc service that is mainly performed using
an online format. c4c is also ready to conduct face-to-face
activities with patients. PPI experts contribute during all
of the advice process and facilitate appropriate PPI activi-
ties. Young adult patients, caregivers, experts from POs
and facilitators of YPAGs are part of a dedicated patient
involvement database of experts that is consulted once the
c4c advisory group secretariat receives a request for patient
involvement. Liaison with disease-specific and umbrella
POs is also done with the aim to select the right experts
to be involved in these activities. All the results are shared
with the sponsor who will decide how or whether to include
the advisory outcomes in the final design of their project
(protocol design, patient information documents, etc.). A
dedicated analysis of the return on investment and the return
75
conect4children (c4c) and European Paediatric Research
Table 1 The challenges in European clinical research into drugs for paediatric diseases that are being addressed by c4c and envisaged contributions of the successor organization
c4c conect4children, GCP good clinical practice, PIP Paediatric Investigation Plan, PPI patient and public involvement, SPoC single point of contact
Element of drug development Difficulty to be addressed c4c contribution Network contributors How to access after c4c has scaled-up
Design of PIP or protocol Availability of population Input from networks and individuals Expert groups and secretariat Apply to SPoC, which will then route
the request to the relevant team
Awareness of standards of care
Knowledge on (innovative) study
designs and regulatory requirements
PPI Input from patients, parents and young
people’s advisory groups
Patients, parents and young people’s
advisory groups, secretariat
Set-up of studies Site identification: low number of sites
known to sponsors
Systematic approach to all sites National hubs and network infrastruc-
ture office
Apply to SPoC, which will then route
the request to the relevant team
Site preparation Standards and training National hubs and education team Work through hubs after relationship
established through SPoC
Delays with contracts Prompts to key contacts, escalation
within organizations, mediation to
clarify sticking points
National hubs and network infrastruc-
ture office
Variation and delays in ethics/regula-
tion
Budget templates and identifying
capacity needs for specific activities
Interface of third parties with sites
Suboptimal contact with investigators
Planning for recruitment Validated estimates of site perfor-
mance
National hubs
Study supplies Advice on regulations
Conduct of studies Delays with recruitment Prompts to key contacts, escalation
within organizations, mediation to
clarify sticking points
National hubs and network infrastruc-
ture office
Work through hubs after relationship
established through SPoC
Data quality
Delays with data
Investigator preparedness GCP training Paediatric-focused course with Trans-
Celerate accreditation
Education team Apply to SPoC, which will then route
the request to the relevant team
Understanding of drug development Advanced training for investigators Education team Apply to SPoC, which will then route
the request to the relevant team
76 M.A.Turner et al.
on engagement will be performed during the project to help
in the final definition of the services portfolio of the future
c4c legal successor entity in the field of PPI activities. The
definition of engagement used by c4c is “the direct and
constructive interaction with patients in various roles at all
appropriate points within the medical product life cycle to
ensure the best possible alignment between patient needs
and products and services that improve health outcomes for
patients” [18]. Return on engagement considers the impact
of initiatives that are participant-centred on the participant
and on the financial and operational aspects of clinical tri-
als. For a specific participant-centred initiative, return on
engagement considers the impact the initiative has on the
experience of the participant (or other desirable objective
for the participant) and the impact on the quality, speed, or
other key performance indicator of the trial. The assessment
of return on engagement takes account of the cost and ease
of conducting the participant-centred initiative [18].
3.2 Set Up andConduct ofStudies
Table1 describes the challenges and delays experienced by
many sponsors that will be addressed by c4c. c4c will not
be able to address the ‘structural’ reasons for these delays.
For example, c4c will not be able to change a hospital’s
policy on intellectual property or electronic signatures. c4c
will address ‘modifiable’ contributions to these delays, with
a key contribution from c4c NH. NH comprise a scientific
lead with support and administrative staff. The roles of NH
include acting as a national point of contact for c4c; sup-
porting sponsors in coordinating trial conduct in their coun-
try, they may support sites in discussions about contracts,
regulatory and ethics approvals by aligning templates and
providing mediation when needed; managing c4c feasibility
requests at country level and supporting sites during clinical
trials. NH are hosted by one organization. Depending on
national circumstances, NH can be hosted by a hospital,
university, or a legal entity that is specific to the hub. NH
can be distributed or based in a single location. NH have
ongoing relationships with most or all of the sites in their
country. These relationships extend beyond individual stud-
ies or companies. NH capture ‘national corporate memory’
of clinical capacity and context for research in ways that
commercial entities cannot do. NH can clarify topics under
discussion and facilitate steps to study set up as part of for-
mal or informal negotiation; for example, the basis for vari-
ation in costings, contracts, ethics, etc. within a country or
in comparison with other countries. Furthermore, NH will
troubleshoot within a metrics-driven performance manage-
ment and quality framework, intervening when needed in
a flexible, efficient and coordinated way. NH can promote
buddying and mentoring for inexperienced sites and sharing
practice when some sites have more success with recruit-
ment than other sites. Standards for sites, NH and the pan-
European coordination of the network will indicate what
service users can expect. Standards will facilitate training
and quality improvement. Investigators will have access
to training about how to contribute to industry trials and
support during feasibility assessments. Investigator prepar-
edness will also include intelligence about future research
and training about drug development and how to work with
children, young people and their advocates during all stages
of drug development.
4 Elements ofc4c
The c4c SPoC provides one e-mail address and one online
form to direct the requestor to relevant sources of help for
paediatric research in Europe. This includes cascading
Fig. 2 The organization of the
c4c trials network and strategic
feasibility service across and
within countries. c4c Govern-
ance groups are shown as
rounded rectangles. Countries
are shown as circles. Sites are
shown as triangles and experts
(scientific, clinical or par-
ticipants) are shown as small
squares. Sites are only shown
for two countries in the interests
of clarity. c4c conect4children,
SPoC single point of contact
Network Infrastructure Office
Network Management Commiee
SPoC
Service Requests
Advisory Group Secretariat
77
conect4children (c4c) and European Paediatric Research
requests to all NH, sites, the advisory group secretariat and
expert groups. SPoC does not resolve queries but will man-
age the process to resolve queries.
4.1 Information Systems
A c4c information system (c4c-IS) is being implemented
to support the establishment of the performance manage-
ment and quality framework of the network. c4c-IS is a
distributed system designed to support the governance of
the network, to virtually aggregate all the operational levels
(SPoC, NH, sites, experts and PPI), to support the execution
of each incoming service request collected by the SPoC and
to empower interactions between elements of the network.
The c4c-IS will sustain c4c daily operations, support
for trial conduct, and coordination of the information flow
across the network by facilitating the collection of datapoints
that feed the business intelligence engine. The business intel-
ligence engine will populate the dashboards that will allow
performance monitoring and effective decision making.
Moreover, the c4c-IS will promote the set-up of a virtual
community, in which communication, collaboration and
information sharing will be strongly enhanced by means of
a dedicated set of IT tools.
4.2 Patient andPublic Involvement
c4c will provide sponsors with the right services to ensure
that they can involve patient experts in the design and per-
formance of clinical trials. Several activities are underway:
On-line training for researchers and sponsors to edu-
cate them about PPI and to ensure they know the poten-
tial benefits of co-designing studies with patients and
families.
Training for POs to introduce patient involvement in c4c
and to ensure that a train-the-trainers programme can be
performed within the POs to set up the right participatory
research culture among their members.
PPI experts are included in any activity with patients
and their families. The PPI cross-cutting theme is formed
by YPAG facilitators and senior experts in PPI and
umbrella POs.
An early discussion between the PPI c4c experts, the
advisory group secretariat of c4c, and the sponsors will
facilitate the optimal selection of the patient involvement
activities in each request to c4c.
The c4c patient involvement model is also focused on the
inclusion of innovative activities with patients. In this sense,
it is expected that two innovative activities will be performed
before the end of the project:
Electronic assent.
Simulation of clinical trials. This will allow the inclu-
sion of patients’ needs, feedback and improvements
before the trial is initiated.
4.3 Education andTraining
Site and investigator preparation needs to include training
and education. The c4c paediatric medicine academy will
develop a learning environment targeting the level of exper-
tise according to the learners’ needs. c4c has established
a portal (virtual learning environment) to host the training
courses.
Courses will include:
Generic training
Good Clinical Practice (GCP) for paediatric trials,
Key issues in paediatric trials for sites, monitors, eth-
ics committees, hospital administrators,
– Advanced Certified Course on Paediatric Drug
Development and Paediatric Clinical Trials.
Trial-specific training
Each non-industry trial will generate courses about
the protocol and assessments that sites will be able
to access remotely in a secure manner.
PPI training (see above).
In addition to hosting an efficient, rapid and high through-
put portal, c4c operates robust governance to assure the rel-
evance and quality of c4c courses. An international Edu-
cational Board oversees the development of courses from
a pedagogic perspective and reviews feedback about the
courses and the portal.
4.4 Trial Data
The lack of interoperable and standardized data is a fun-
damental issue within the field of paediatric research. The
significant variability in the data items collected—and how
they are collected—makes future re-use of the data chal-
lenging, thus limiting its potential to inform and improve
future research. One of the key outputs of c4c will be the
cross-cutting paediatric data dictionary (CCPDD). A data
dictionary is a centralized repository of information about
specific data; for instance, showing meaning, relationships to
other data, origin, usage and format. This CCPDD is based
around a list of data items that are particularly relevant to
paediatric studies and that tend to be collected in most tri-
als, regardless of the disease area. They are generally items
from demographics, vital signs, and some developmental
scales. Where possible, the c4c CCPDD is aligned to the
78 M.A.Turner et al.
Clinical Data Interchange Standards Consortium (CDISC)
and the controlled paediatric terminology hosted by the US
National Cancer Institute Enterprise Vocabulary Service.
CDISC is an important standards development organisation
since its foundational standards are mandated for submis-
sion to both the US FDA and Japanese Pharmaceuticals and
Medical Devices Agency. In addition to the CCPDD, c4c is
working closely with CDISC to develop a Therapeutic Area
User Guide (TAUG) for paediatrics, which will help all pae-
diatric studies using CDISC to generate more standardised
and interoperable data.
5 Discussion
The potential for c4c to improve European clinical research
into drugs for diseases that affect children relates to specific
activities based on relationship-driven implementation of
private–public business processes developed within a pub-
lic–private partnership. Whether this potential is realized
depends on the efficacy and efficiency of processes that aim
to deliver intended benefits. The use of a small number of
studies to test the network will allow us to assess the viabil-
ity of a successor to c4c.
One of the key goals of c4c is to reach sustainability and
to seamlessly transfer the network built during the IMI pro-
ject into a sustainable stand-alone legal entity after the end
of IMI funding. In some ways, the IMI2 project works like
an accelerator for creation and start-up of the network. It
provides the academic partners with stable funding needed
to concentrate on building the networks and allows industry
partners to cooperate in a non-competitive environment. It
is important to note that the current IMI consortium will
dissolve after the end of the IMI funding period (2024) and
the to-be-created, new legal entity will be independent from
the current consortium and will cooperate with public and
private partners and receive funding from different sources.
The network will need to expand its reach and grow its cus-
tomer base over time.
c4c will not address all challenges to paediatric trials.
The variation in ethics/regulators is beyond the scope of the
network. Pharmaceutical policy such as access and pricing
is beyond the scope of the network. c4c works with many
external stakeholders: each stakeholder could develop diver-
gent expectations of the consortium and its work. Significant
work has been done, and will continue, to learn about the
needs of stakeholders and identify how c4c’s work aligns
with those needs. It will be important to identify opportuni-
ties for synergistic work with similar initiatives and threats
to c4c due to competition from other organizations work-
ing on paediatric clinical trials. Once the key elements of
the successor organization have been identified, including
services and revenue structure, then a marketing strategy
will underpin extension of access to c4c services beyond the
consortium’s current membership.
6 Conclusion
c4c is a novel, multidisciplinary, multisectoral approach
to improving the paediatric clinical trial environment in
Europe. The staged approach to establish the network’s via-
bility underpins robust performance and quality. By 2024
a single point of contact will provide pan-European access
to multiple, coordinated services to facilitate research into
drugs for the paediatric population.
Declarations
Funding The Collaborative Network for European Clinical Trials for
Children (conect4children or c4c) is an action under the Innovative
Medicines Initiative 2 (IMI2) Joint Understanding (https ://www.imi.
europ a.eu), Grant Agreement 777389. The open access fee was paid
by the University of Liverpool.
Conflicts of interest/competing interests All the authors are associ-
ated with the c4c project because their employers are Beneficiaries of
the c4c Consortium. Cheng is an employee of Johnson and Johnson;
Hildebrand is an employee of Bayer AG.
Ethics approval Not applicable.
Consent to participate Not applicable.
Consent for publication Not applicable.
Availability of data and material Not applicable.
Code availability Not applicable.
Author contributions MAT drafted the paper and contributes to
the leadership of c4c. HH reviewed the paper and contributes to
the leadership of c4c. RMF reviewed the paper and contributes
to the leadership of c4c. SdW reviewed the paper and contributes
to the leadership of c4c. FM reviewed the paper and contributes
to the leadership of c4c. RH reviewed the paper and contributes to
the leadership of c4c. RL reviewed the paper and contributes to the
leadership of c4c. FB reviewed the paper and contributes to the lead-
ership of c4c. PN reviewed the paper and contributes to the leader-
ship of c4c. KC reviewed the paper and contributes to the leader-
ship of c4c. SA reviewed the paper and contributes to the leadership
of c4c. PR reviewed the paper and contributes to the leadership of
c4c. FR reviewed the paper and contributes to the leadership of c4c.
JC reviewed the paper and contributes to the leadership of c4c. BN
reviewed the paper and contributes to the leadership of c4c. CG
reviewed the paper and contributes to the leadership of c4c.
Open Access This article is licensed under a Creative Commons Attri-
bution-NonCommercial 4.0 International License, which permits any
non-commercial use, sharing, adaptation, distribution and reproduction
in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Com-
mons licence, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative
79
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Commons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons
licence and your intended use is not permitted by statutory regula-
tion or exceeds the permitted use, you will need to obtain permission
directly from the copyright holder. To view a copy of this licence, visit
http://creat iveco mmons .org/licen ses/by-nc/4.0/.
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Authors and Aliations
MarkA.Turner1,15 · HeidrunHildebrand2· RicardoM.Fernandes3· SaskiaN.deWildt4· FennaMahler4·
RégisHankard5· RebeccaLeary6· FedeleBonifazi7· PatrickNobels8· KatharineCheng9· SabahAttar10·
PaoloRossi11· FrancescaRocchi12· JoanaClaverol13· BegonyaNafria13 · CarloGiaquinto14
1 Institute ofLifecourse andMedical Sciences, University
ofLiverpool, Liverpool Health Partners, Liverpool, UK
2 Pediatric Development, Research & Development,
Pharmaceuticals, Bayer AG, Berlin, Germany
3 Clinical Pharmacology andTherapeutics, Faculty
ofMedicine; andSTAND4KIDS Portugal, Faculty
ofMedicine, Associação para aInvestigação e
Desenvolvimento da Faculdade de Medicina, University
ofLisbon, Lisbon, Portugal
4 Radboud Institute forHealth Sciences, Radboud University
Medical Center, Nijmegen, TheNetherlands
5 French Clinical Research Infrastructure Network
(F-CRIN)-PEDSTART , University ofTours, Institut National
de la Santé et de la Recherche Médicale, Tours, France
6 John Walton Muscular Dystrophy Research Centre,
Translational andClinical Research Institute, Newcastle
University andNewcastle Hospitals NHS Foundation Trust,
NewcastleuponTyne, UK
7 Fondazione perla ricerca farmacologica Gianni Benzi onlus,
Bari, Italy
8 Clinical Operations, The Janssen Pharmaceutical Companies
ofJohnson & Johnson, Beerse, Flanders, Belgium
9 Child Health Innovation Leadership Department (CHILD),
Johnson andJohnson, HighWycombe, UK
10 Institute ofLifecourse andMedical Sciences, University
ofLiverpool, Liverpool Health Partners, Liverpool, UK
11 Academic Department ofPediatrics (DPUO), Unit
ofPerinatal infection andcongenital infectious diseases,
Bambino Gesu Children’s Hospital-University ofRome Tor
Vergata, Rome, Italy
12 Academic Department ofPediatrics (DPUO), Unit
ofPerinatal infection andcongenital infectious diseases,
Bambino Gesu Children’s Hospital-University ofRome Tor
Vergata, Rome, Italy
13 Institut de Recerca Sant Joan de Deu, Sant Joan de Deu
Research Foundation, Barcelona, Spain
14 Division ofPediatric Infectious Diseases, Department
ofWoman’s andChild’s Health, University ofPadua, Padua,
Italy
15 Centre forWomen’s Health Research, Liverpool Women’s
Hospital, Crown Street, LiverpoolL87SS, UK
... across all disease areas, in all pediatric age groups and all phases of the clinical drug development process. 8 One focus of c4c is to promote innovative trial design to optimize pediatric development plans and protocols. This will be done through the provision of expert advice to sponsors, initially the c4c industry and academic beneficiaries, and, as of mid-2023, in the successor c4c legal entity, to any sponsor. ...
... Expert group-specific QIPs were authored for all innovative methodology expert groups, 8 15 of the 16 clinical expert groups, as well as one QIP on the overall c4c advice process, which was created by the c4c advice service leadership in 2021. In 2022, all QIPs were revised and updated to reflect the progress made and the upcoming focus areas for improvement. ...
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Purpose: A growing number of biopharmaceutical companies have been implementing patient-centric initiatives (PCIs). The Drug Information Association (DIA) and the Tufts Center for the Study of Drug Development (CSDD) collaborated on a study to gather data on the usage and impact of these PCIs to characterize company experience and impact. Methods: DIA and Tufts CSDD collaborated with 17 organizations to define PCIs used in clinical research and development and to quantify their use, and to define metrics in use to document impact and return on engagement (ROE) for these PCIs. The study used a mixed methods approach that consisted of an online survey, in-depth interviews, and literature review. Findings: Twenty-two unique companies responded to an on-line survey on the use of 23 PCIs identified by the study working group. PCIs most frequently implemented included patient organization landscape analysis, support of patient advocacy groups, use of patient advisory boards, and use of home nursing networks. Seven additional PCIs were found through a literature search and included in the group of PCIs for which impact measures were assessed. A total of 121 cases of use of the 30 PCIs and associated impact measures and impact data were gathered through literature review, in-depth interviews with the study companies, and in-depth interviews with organizations identified in the literature as having experience with patient engagement in clinical research as well as with patients who had participated in clinical trials. Analysis of the 121 case studies resulted in a list of 666 measures of impact (metrics) in use for 13 of the PCIs. Assessment of overall ROE for these PCIs found that PCIs such as support of patient advocacy groups and use of patient advisory boards indicated the greatest ROE, whereas costlier, more complex PCIs such as digital medicine and gaming indicated relatively low ROE. Implications: Activity around PCIs among the companies studied was widespread, with initiatives more frequently planned and piloted than implemented at the time of this study. Measures of impact have been identified and can be used to assess ROE, providing insights to facilitate the adoption of PCIs of highest impact for patients and biopharmaceutical research organizations.
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Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug‐response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.
European Paediatric Initiative: history of the paediatric regulation
  • Ema The
EMA. The European Paediatric Initiative: history of the paediatric regulation. 2007. https ://www.ema.europ a.eu/en/docum ents/ other /europ ean-paedi atric -initi ative -histo ry-paedi atric -regul ation _en.pdf. Accessed 13 July 2020.
State of Paediatric Medicines in the EU: 10 years of the EU Paediatric Regulation
  • Ec
EC. State of Paediatric Medicines in the EU: 10 years of the EU Paediatric Regulation. 2017. https ://ec.europ a.eu/healt h/sites / healt h/files /files /paedi atric s/docs/2017_child rensm edici nes_repor t_en.pdf. Accessed 13 July 2020.
Envisioning a transformed clinical trials enterprise in the United States: establishing an agenda for 2020
  • N E Weisfeld
  • R A English
  • A B Claiborne
  • NE Weisfeld
Weisfeld NE, English RA, Claiborne AB. Envisioning a transformed clinical trials enterprise in the United States: establishing an agenda for 2020. Washington: National Academies Press; 2012.
Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates
  • R M Ward
  • D Benjamin
  • J S Barrett
  • K Allegaert
  • R Portman
  • J M Davis
  • RM Ward
Envisioning a transformed clinical trials enterprise in the United States: establishing an agenda for 2020
  • Ne
  • R A English
  • A B Claiborne