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Global Research in Paediatrics

Final Report Summary - GRIP (Global Research in Paediatrics)

Executive Summary:
GRiP has been funded with the principal aim to implement an infrastructure matrix to stimulate and facilitate the development and safe use of medicine in children. This implementation entails the development of a comprehensive training programme as well as the integration of key existing research capacity in a structured organisation, so that reducing the fragmentation and implementing interoperability and innovative methods at a large Network level. Organised by 8 collaborative Work Packages, plus Project Management, GRiP objectives have been fully achieved.
A comprehensive training programme has been implemented. It entails a) a detailed core curriculum of specialisation in paediatric clinical pharmacology available for international use, b) a 2-year Master’s Programme encompassing all the important qualifications within the scientific and regulatory area of paediatric clinical pharmacology with 60 ECTS divided in ten modules; c) The Training Programs for Investigators and Clinical Trials Support Staff; d) the GRiP Roadshows, a series of 1 to 3-day face-to-face training courses on Basics of Paediatric Clinical Pharmacology and Investigation of Medicines in Children developed to complement the other GRiP WP1 Training programs and available worldwide; e) a Webinar series on paediatric formulations. All these educational products, have been assessed in order to test interest in them among the scientific and developing medicines community. All are available to be translated in new initiatives by the partners, by Academia and by other interested stakeholders.
Structured paediatric Research capacity. Under a well consolidated scientific coordination, for effect of a strong collaborative work among partners and a number of internationally recognised experts and ongoing initiatives, great strides and progress have been made including:
Developing electronic infrastructures for a) epidemiological, pharmacovigilance and post marketing research, b) formulation platform to share, educate and develop paediatric drug formulation knowledge and skills
Developing paediatric research tools to facilitate interoperability in paediatric research allowing to improve efficiency in running clinical research and to compare study results (biomarkers, outcome, endpoints, etc)
Developed international collaboration to harmonize terms for child health use including neonates, and to harmonise procedures (including ethic procedures) by creating data standards and data exchange models
Identifying and validating new methods for running CT in children, tools and recommendations were realised for the correct adoption of: Modeling&Simulation approaches, innovative study design, data extrapolation, sample size and comparator definition in paediatric trials
Finally, an ad hoc strategy for knowledge translation, exploitation and mobilisation (KTEM) has covered the need of spreading excellence and Knowledge
Project Context and Objectives:
Global Research in Paediatrics - Network of Excellence (GRiP) is an EU-funded project (FP7/2007-2013, ECGA HEALTH-F5-2010-261060) which aims to stimulate and facilitate the development and safe use of medicine in children. The main reason for the existence of GRiP is the lack of appropriate testing of paediatric drugs, with most drugs having inadequate information about dosing regimen, dose adjustment and administration. The lack of adequate labelling recommendations means that physicians are often required to prescribe medicines to children on the basis of customary clinical practice and anecdotal medical knowledge, rather than on the basis of information that has been independently reviewed by regulatory authorities. Many drugs are used for indications, dosages, formulations, routes of administration and in combinations that are not approved for the paediatric population. Various drugs have been studied only in some paediatric age ranges, but often not in babies or adolescents. This means that medicines are often prescribed empirically by extrapolating data from a well-studied group of children to a poorly-studied group of children. These are longstanding problems that have required concerted efforts at the international level. Examples of these efforts are represented by the ‘policies initiatives’ in the US and EU leading to new and appropriated regulations. In addition, public funds are also devoted to stimulating participation of the scientific community to implement new and advanced knowledge in the field of paediatric medicines.
In this context, GRiP has been funded with the principal aim to implement an infrastructure matrix to stimulate and facilitate the development and safe use of medicine in children. This implementation entails the development of a comprehensive training programme and integrated use of existing research capacity, whilst reducing the fragmentation and duplication of activities. Implementation of paediatric studies requires well trained researchers, investigators and other experts in number and capacity that currently do not exist. A consequence of inadequate research in the past was a lack of readiness among the paediatric research community when more opportunities arose following the implementation of the Regulation.
The lack of readiness to develop medicines for children included:
• Restricted awareness of, and experience with, paediatric clinical pharmacology due to the lack of a widely available training programme
• Lack of awareness of best practice, which had not always been captured
• Limited capacity to investigate the safety or comparative effectiveness of medicines using population registries or databases of adverse events. There are a large number of registries and databases but data could not be shared between them due to procedural and methodological uncertainties
• Suboptimal use of methodologies in medicines development. These deficiencies were partly due to a lack of awareness of the methods used in other populations and partly due to a lack of information about how to use the methods in children
• Uncertainty about how to develop medicines that children and young people can take easily, that is a lack of expertise in age-appropriate formulations
• Redundant effort and a lack of synergies when complementary expertise existed.
Each of these aspects could be addressed effectively with a Europe-wide approach.
GRiP has addressed this problem by developing, as its main objective, a joint paediatric clinical pharmacology training program in collaboration with International stakeholders.
In addition, GRiP has promoted sharing of best practices in research, including methodologies and research tools that can be used not just across the Atlantic, but globally. Central to these efforts will be activities that evaluate methodologies and research tools that are implemented following GRiP recommendations in a manner that reflects the needs of researchers (including industry) and patients. That is, GRiP has paid close attention to knowledge translation, exploitation and mobilization.
Reaching these objectives will require close collaboration between paediatric health professionals, academics and representatives of the pharmaceutical industries, ethics bodies and regulatory authorities. For this reason, started on 1 Jan. 2011. GRiP has mobilised 22 institutions from Europe, North America and Japan, as well as the WHO. By linking the existing paediatric research networks, GRiP has involved more than 1,000 institutions worldwide.

GRiP General objectives
To facilitate the development, and promote the availability, of medicines for children by reducing the fragmentation of ongoing efforts in relevant fields of research. In addition, GRiP aimed to create consensus on international standards, methodologies and tools for paediatric research. The day-to-day work of the consortium primarily focused on:
o The development of a Paediatric Clinical Pharmacology Training Program;
o Filling important “gaps” in paediatric medicines research by validation and harmonisation of research tools specific for paediatrics;
o Sharing of strategies and plans.

GRiP Specific objectives
1. To increase the number of internationally trained paediatric clinical pharmacologists, researchers and formulation scientists by developing an internationally recognised paediatric clinical pharmacology training program. To this aim a joint paediatric clinical pharmacology training programme has been developed aimed to prepare experts in paediatric clinical pharmacology able to work both at regulatory and clinical research level. It built a qualifications framework encompassing all the important qualifications within the scientific area of paediatric clinical pharmacology. The program was co-ordinated by experienced educators from Europe, North America and Japan, delivered by a broad range of experts using a diverse and well-adapted palette of educational interventions and carried out in collaboration with relevant International stakeholders (International Union of Basic and Clinical Pharmacology – IUPHAR, WHO, Pharmaceutical Industries Associations, ESDPPP, etc) and academic and scientific Institutions.
2. To develop an integrated electronic infrastructure for epidemiological, pharmacovigilance and post marketing research. This infrastructure exploited and linked existing healthcare databases in Europe and the US to assess the occurrence of diseases in children, plus the use and effects of drugs (including vaccines) on a large scale. It responded to the need of building pharmaco-epidemiological research capacity to better exploit the evidence that is being compiled in real life. Methodologies for harmonization, data exchange across national boundaries (including ethical and governance issues), data mining and comparative safety and effectiveness studies will were developed.
3. To develop paediatric research tools to facilitate interoperability in paediatric research which will improve efficiency in clinical research and enable comparison of study results. This section represents one of the main GRiP objectives and represents a key element of the long-term integration of research activities and outcomes. There is a crisis of credibility facing child health communities today because of the paucity of reliable estimates of effects of interventions in children. More and better trials need to be conducted but we also need better methods to determine their overall efficacy. This include harmonisation of terminology and data standards for paediatrics across the world and identification, development and harmonisation of outcome measures, endpoints and biomarkers to evaluate paediatrics drug responses.
4. To develop and evaluate models for information sharing for Human Research Subject Protection among ethics committees and Institutional Review Boards to facilitate review and support consistency in review practice. Until now, few data were available on the procedures followed by different countries in implementing the paediatric ethical provisions. In general, national and international provisions are not based on ‘binding rules’ and it seems legitimate to fear that in different part of the world, many differences might exist both related to the quality of ethical protection and on the procedures adopted to provide ethics opinions. This work aimed to develop common models applicable word wild.
5. To explore and validate the use of new studies’ designs, procedures and methodologies for clinical trials in children. Starting from the wide experience accumulated in this sector by some partners (in particular CVBF, ULIV-NIHR, AMC, UL, NICHD-NIH, NCCHD, PENTA etc.) GRiP ad hoc working groups in WP4 reviewed paediatric clinical research methods based on studies that have already been performed as part of drug registration programmes and explored alternative approaches in the design of clinical studies in newborns, infants and children. Special consideration was given to the role of PK/PD modelling and the use of clinical trial simulations intended to optimise the design of the studies and the number of children to be enrolled as well as the number of samples for lab tests.
6. To create and maintain an international platform to share knowledge and educate professionals on paediatric drug formulation to support clinical trials worldwide. Previous experience in Europe has shown that the lack of expertise and considerations of formulation issues have led to many problems in paediatric medicines clinical trials. Moreover clinical researchers are unlikely to have sufficient understanding of biopharmaceutical, physical and chemical considerations of the drugs formulations. From GRiP, both pharmacists and clinicians has received appropriate training and education programmes. Particular attention was given to the needs of children under 5 years.
7. To set up an international initiative for implementation of clinical trials in neonates. There are considerable medical, scientific, practical and ethical issues in relation to studying medicines in the vulnerable group of preterm and term neonates. Due to the specific characteristics of this population a specific WP (WP6) has been dedicated to coordinate and develop research initiatives in neonates, including the establishment of effective links with North American and other European networks.
8.To create a durable collaboration between participating partners and expand network activities to other countries and settings including low income countries. Implementing Strategies for Medicines for Children is a long-term effort that justifies the need for a cohesive tool to ensure effective co-operation between existing initiatives. For this reason, GRiP was strongly committed to provide durable collaborations among the Partners and to expand its activities to new groups and new geographical areas.
9. To base dissemination and implementation of GRiP outputs on well-planned activities relating to knowledge translation, exploitation and mobilisation. As a key component in the work plan, dissemination activities were undertaken according to a well-defined communication plan for publicizing the training program and project’s output among different stakeholders (including researchers to be trained, regulatory authorities, patients association, pharmaceutical companies etc.).
Project Results:
Global Research in Paediatrics – Network of Excellence (GRiP) is an EU-funded project, which aimed to stimulate and facilitate the development and safe use of medicines in children. In addition, GRiP aimed to create consensus on international standards, methodologies and tools for paediatric research. The consortium worked to develop an international network to:
• Develop a Paediatric Pharmacology Training Program
• Develop and Harmonise research tools specific for paediatrics
• Share strategies and plans
• Use ongoing and planned research studies to evaluate the feasibility of proposed research tools and strategies
These objectives have been fully reached also considering that a project of this large scope has never been attempted before. The GRiP network made a positive impact on a variety of issues in so influencing the paediatric drug development and research capacity across many institutions, MSs and stakeholder groups. The different WPs have made relevant progress linked to the scope of the deliverables. In addition, many products including peer-reviewed publications, book chapters, conferences, presentations, webinars, and e-tools have been made available for a prolonged impact on the concerned area. Details on the achievements and main results of each work package are presented below.

WP1 - JOINT PAEDIATRIC CLINICAL PHARMACOLOGY INTERNATIONAL TRAINING PROGRAM
Within WP1, different activities have been conducted in order to promote and implement a coherent Curriculum for a comprehensive training programme. Extensive supportive and enabling measures included among others an inventory of existing training programs and courses, a needs assessment of training in Paediatric Clinical Pharmacology, the establishment and operation of the GRiP Virtual Learning Environment, for global delivery of distance learning, a Quality Advisory Committee to help ensure the quality of GRiP education, and the GRiP Training Program Palette (TPP).
The major GRiP Training programmes developed include:
The GRiP Paediatric Clinical Pharmacology Fellowship curriculum - A detailed core curriculum of specialisation in paediatric clinical pharmacology, was developed and made available for international use. The current capacity and unmet needs for advanced clinical training programmes in paediatric clinical pharmacology (i.e. Fellowship programmes), the state of existing Fellowship programmes in paediatric clinical pharmacology within Europe were investigated. Four existing European Fellowship programmes (in Basel, Switzerland; Paris, France; Rotterdam, the Netherlands; and in Derby, United Kingdom) were identified and described. This investigation was further expanded to those offered in the USA and Canada. The results of the study showed that in Europe Paediatric Clinical Pharmacology is a recognized paediatric medical subspecialty only in the UK, so that most of the programmes identified are more or less informal when it comes to certification. Consequently, setting up joint European university programmes was not possible in the absence of official recognition of the discipline in each jurisdiction (except for UK). In such situations, European collaborations have been set up by existing European scientific societies, by creating a common European examination and/or accreditation processes for the education.
The International Master’s programme The International Master programme Paediatric Medicines Development and Evaluation is a two-year part-time programme with 60 ECTS (European Credit Transfer and Accumulation System) credits divided over 10 modules, comprising of 4 ECTS per module with 1 ECTS for an induction week and 19 ECTS dedicated to work placement (corresponding to at least 10 weeks’ full time, thesis preparation and defence). The University of Rome Tor Vergata (Unitov), acting as third party to the GRiP beneficiary Children’s Hospital Bambino Gesù (OPBG) in Italy, hosted the programme and enrolled 18 students from the beginning of the first edition of the Master. This programme acted also as a pilot programme for the development of a Joint Degree MSc programme, which is an on-going collaboration among 3 universities: University of Rome Tor Vergata, Diderot University in Paris, and Erasmus University in Rotterdam.
The Master Programme included 10 novel modules that covered the full range of information and skills in paediatric clinical pharmacology. The modules were:
Module 1 MED, Introduction to Paediatric Medicines
Module 2 DEV, Developmental Pharmacology – Pharmacokinetics
Module 3 RET, Regulatory and Ethical Issues Regarding Paediatric Medicines Research
Module 4 EXP, Experimental Drug Evaluation in Paediatrics
Module 5 FOR, Paediatric Drug Formulations
Module 6 TRI, Paediatric Clinical Trial Management
Module 7 PPP, Post-Licensure Paediatric Drug Evaluation: Pharmacovigilance & Pharmacoepidemiology
Module 8 PREG, Pharmacology in Pregnancy and Neonates
Module 9 BIO, Biomarkers and Innovative Tools in Paediatric Clinical Pharmacology
Module 10 VAC, Paediatric Vaccines
Work placement and/or training stage for a duration corresponding to at least 10 weeks’ full time was obligatory within the Programme. The following organisations provided opportunities for placements: Office of Clinical Pharmacology Office of Translational Sciences, CDER U.S. – FDA, USA; Medicines Authority
Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann , Malta; St. George’s University of London, UK; Childrens’ Hospital Bambino Gesù (OPBG) Rome, Italy; Department of Paediatrics and Adolescent Medicine Rigshospitalet, Copenhagen, Denmark in collaboration with Hopital Robert Debré Paris – France; Penta Foundation, Padova, Italy; European Medicines Agency (EMA) London, UK; Paediatric Haematology and Bone Marrow Transplantation Unit, MBBM Foundation, Monza; PharmaMar, Clinical Development Department Madrid – Spain; Department of Medical and Surgical Sciences of Mothers, Children and Adults, University Modena & Reggio Emilia, Paediatric Unit; Pharmacologie Pédiatrique et Pharmacogénétique Hopital Robert Debré Paris – France; University of Erasmus, Rotterdam, Netherlands; Dept of Medical Informatics, Rotterdam, The Netherlands in collaboration with Ghent Univ; Univ Children’s Hospital Basel, Switzerland; Centro Trials Dipartimento Pediatrico Universitario Ospedaliero IRCCS Ospedale Pediatrico Bambino Gesù (OPBG) , Rome, Italy; University College of London, UK
In summary: 18 students were enrolled in the Master programme from November 2014. 13 Master-students completed their Master-theses defence by 23 September 2016 with great success and were awarded their Master-degree with the English title “International Master in Paediatric Medicines Development and Evaluation – a 60 ECTS programme”.
Following the end of the pilot Master course, the entire syllabus has been revised, based on the experiences acquired and in view of any next edition or an agreed Joint Degree Master-programme. A practical demonstration of this potentiality is represented by the inclusion of the reference to the GRiP Master into the IMI-2 call Topic: Creation of a pan-European Paediatric Clinical Trials Network as one of the tools to be used in that contest.
The Masters programme is fully detailed in the deliverable D1.18 “Final report on a Masters program in paediatric clinical pharmacology”.
The Training Programme for Investigators and Clinical Trials Support Staff. This Programme is in the form of a webinar “Everything you wanted to know about paediatric clinical trial conduct and logistics that is not in the book!” developed during this period. In addition, training for nurses in French was developed entitled “Les médicaments: comment les utiliser chez l’enfant” (Drugs: how to use them in children). It has been presented 5 times to groups of nurses (from 10 to 30) to test and improve the contents and is now ready for diffusion and use in an English version.
The Training Program in Paediatric Clinical Pharmacology available worldwide (GRiP Roadshow) is a 1 to 3-day face-to-face training course on Basics of Paediatric Clinical Pharmacology and Investigation of Medicines in Children developed to complement the other GRiP WP1 Training programs and act as a “stepping stone” to other more advanced and demanding training programs. It is based on common content packages developed by GRiP together with its Third Parties IUPHAR and ESDPPP. The GRiP Roadshow exists in 5 variants: Standard GRiP Roadshow 1- or 2-day, GRiP Roadshow for Resource Limited Settings (RLS) 1- or 2-day, and GRiP Patient Roadshow (1-day). The Roadshow was delivered by 2-3 tutors per course with sufficient expertise within paediatric clinical pharmacology and investigation of medicinal products, and experience as teacher to function as convincing tutors to deliver the content. GRiP Roadshow was run 20 times in 17 countries (11 times in Europe, with 9 of them in 7 EU countries, 2 times in India, and once in Argentina, Australia, China, Japan, La Réunion, Sri Lanka and Canada) and was able to reach out to investigators and clinical support staff in many continents of the world. More than 1200 persons have participated in the GRiP Roadshows. Moreover, representatives of patient organisations requested an adaptation of this Training Program to the needs of patients and parents. This additional GRiP Patient Roadshow was run 2 times (in Finland and Italy).
A series of 13 Meet the Experts Webinars was launched by GRiP Work Package 5 on paediatric formulations. These webinars gave the audience an amazing opportunity to hear about the challenges and issues in paediatric drug development and the approaches used by the experts to create better & safer medicines for our children. The webinars were available live from the GRiP website, and followed by a live Q&A session with the speaker. The Webinars fulfil the quality criteria for GRiP Education, and have been evaluated in practice, and were included on the GRiP Training Program Palette.
Programme evaluation
An additional relevant activity performed by WP1 is the assessment made to better understand the learning needs of members of the European healthcare community in the area of development and testing of medicines for children, and to tailor GRiP Educational offerings for sustainability. A web based survey was developed and distributed with the help of GRiP Partners and some other stakeholders to an estimated 1000 persons. The survey was open December 2015 to January 2016. With 100 responses received, the response rate was in the order of 10% (good). The final analysis included answers from 98 persons representing the most relevant professional groups. They were mostly from the EU, but also Europeans from outside the EU and persons all over the world, except from South-America. More than half (57%) were working in paediatric research, and (54%) in the development of paediatric medicines. Less than half of all responders (43%) indicated that they were working directly with children. 95% of the survey participants indicated at least some need for specialized training in Paediatric Clinical Pharmacology. As a learning topic in the GRiP paediatric clinical pharmacology training programme, respondents expressed the most interest in the GRiP Roadshow, followed by the internet based distance-education modules on Paediatric Drug Formulations and Regulatory and Ethical Issues Regarding Paediatric Medicines Research. The training programs Comprehensive MSc programme in Paediatric Medicines Development and Evaluation and Specialization in Paediatric Clinical Pharmacology or Paediatric Clinical Pharmacology Fellowship were considered less interesting, possibly because of the commitment in time (1-2 yrs) and work required. The demand for the training on paediatric clinical trials for investigators and support staff was more for web-based distance education than for the F2F courses originally planned.

WP2 INTEGRATED INFRASTRUCTURE FOR PAEDIATRIC EPIDEMIOLOGICAL AND POST MARKETING DRUG STUDIES
Work package 2 was aimed at creating a combination of large scale research databases from various countries to allow for estimating disease burden, drug and vaccine utilization, safety of drug and vaccine use in paediatrics as well as effectiveness of drugs. Different steps have been successfully conducted.
Literature studies. Systematic literature reviews were conducted 1) to evaluate and review comparative effectiveness and safety studies; 2) to generate reference sets of positive and negative drug-event combinations for drugs and vaccines. For the first purpose, papers were reviewed and abstracted for to understand the state of the art on the type of designs, data sources that are used and the specificity for the paediatric population such as age stratification, type of outcomes, type of drugs and the quality and areas of improvement for the studies. These reviews demonstrated that very few paediatric pharmacoepidemiological studies have been conducted, and these were limited to high income settings. Many studies look at charts and do not optimally utilize electronically available data or proper methods to deal with confounding, results were published. Conclusions were that Paediatric pharmacoepidemiological studies on comparative safety and effectiveness lag behind, and would benefit from additional attention in terms of funding, researchers, global scope and methods development. The current realm of big data may help if resources will be dedicated and investigators are well trained. For the second purpose (reference sets) literature review helped to generate a set of positive and negative drug-event combinations, which can be used to test associations and methods in spontaneous reporting databases and electronic healthcare databases, the same was done for vaccine-event relationships. The reference sets were published and used for methods testing.
Identification of data sources. Since much data is available on a global scale, but very fragmented, WP2 set out to identify different electronic data sources with routine care data that can be utilized to conduct studies on the effects of drugs in children. We differentiated between key international spontaneous reporting databases and population based electronic claims/general practice databases.
1)Spontaneous reporting databases: we downloaded the publicly available data from the FDA Adverse Event Reporting System (FAERS), the CDC Vaccine Adverse Event Reporting System (VAERS), and we obtained access to an academically available dataset for EUDRAVIGILANCE (EU). All databases were described. The WHO VIGIBASE did not provide data.
2)Population based databases: A web-based survey was performed to all electronic data-bases that were identified through manual review of the pharmacoepidemiology/ pharmacovigilance conference abstracts, the ‘Bridge.to.Data’ database or by direct knowledge of the GRiP network members. A total of 125 population based databases were identified around the globe (in Europe, North- and South-America, in Asian-Paci c area, and Africa), all were invited to participate. 64 answers were received (49%), with 53% of respondents (n= 34) agreeing to collaborate with the GRiP network in future pharmacoepidemiology studies. These data sources comprised a total of more than 40 million children (<18 years).
Required power: Two data networks (SOS consortium and EU-ADR consortium data, with more than 5 million children) were used to estimate what the size should be of a collaborative effort, since drugs are used a lot, but for very short times, we concluded that global collaboration is needed for the ability to estimate the effects of drugs, especially serious safety issues in children. Data sources in Europe do not suffice and active collaboration with e.g. Sentinel, CNODES or ASPEN should be sought.
Tools and methods. To allow the combination of large scale research databases from various countries in the European Union and the US, we created and described tools and infrastructures that were needed for data pooling. These comprised: the Octopus Remote Research Environment (RRE) where the FAERS, VAERS and EUDRAVIGILANCE database were placed. The RRE also hosted the data collected through proof of concept studies, which were collected by electronic data capture forms (e.g. Chameleon). To transform data and quality check Jerboa was used for analytics (data transformation tool in JAVA). Safe sharing of files was possible using Armadillo. A full assessment of the ethical implications of data sharing and assessment of the RRE was conducted by CVBF, recommending that for future sustainability and privacy impact assessment may need to be done.
Methods
In order to use the data from spontaneous reports several methodological steps needed to be tackled. First all of the different data sources were harmonized to a common data model. This allowed for running same scripts and pooling. Subsequently data needed to be cleaned and completed in terms of MEDDRA codes or ATC codes. We developed machine learning algorithms to complete drug names and diagnosis codes. Subsequently the spontaneous reporting databases were used to test signal detection methods and the impact of stratification by age and by type of drug: vaccine/non-vaccine by using the reference sets. We concluded that stratification by age is necessary to avoid masking of signals, as well as by drug type. We recommend that signal detection in children is done in refined age categories and by drug type as stratification, as well as overall.
Electronic health care databases
The use of data from HERs (electronic health records) allowed us to generate information on the use and effects of drugs in children. However, these datasources (not collected for research but for other purposes) have certain features. One issue is that not all children enter at birth and may also not be followed for their entire lives, we just observe a piece of persontime. An additional issue is that children will only seek healthcare when they are sick not when they are better. These issues have an impact on algorithms and assumptions. We verified methods to estimate incidence and prevalence of recurrent and chronic disease, drug utilization and the method to control for confounding in comparative effectiveness studies. All papers are published in a thesis.
Proof of concept studies. Several proof of concept studies were conducted: estimation of incidence and prevalence on EHR data, look back periods for estimation of propensity scores, drug utilization on psychotropics, and vaccine safety on a global scale. All studies demonstrated the ability to use electronic healthcare data to generate evidence on disease occurrence, drug use, comparative effectiveness and safety in children. Of particular interest was the global vaccine safety multi country study which was done in distributed fashion across 16 countries, using a common protocol and tools and allowed for data pooling. Papers have been published.
Training. The training program in paediatric pharmacoepidemiology and pharmacovigilance as well as vaccinology was developed and well received. GRiP WP2 made excellent progress in drawing attention, developing methods and providing solutions for the current lack of knowledge. It requires collaboration on a global scale

WP3 RESEARCH TOOLS TO FACILITATE INTEROPERABILITY IN PAEDIATRIC RESEARCH
This WP has produced great progress in creating solutions for the most common challenges to clinical drug development in children, particularly with regard to exchange of information with ethics committees, terminology, biomarkers, analysis of comparators, and facilitating patient and family input into clinical trial designs. The methodology has been to identify existing methods, tools, and resources that could either serve as models for paediatric research or could be adapted to apply to paediatric research. If there were no pre-existing resources or tools to address a particular purpose, then gap identification and, if feasible, a new tool or resource was developed. The main areas covered by WP3 activities have been:
Developing Guidance aimed to harmonise and facilitate paediatric research;
• Tool to reduce the risk of bias in paediatric trials,
• Guidance for involvement of parents and patients in the trial design process,
• An evidence and consensus based tool related to the roles and responsibilities of Data safety and Monitoring Committees in paediatric CTs
Guidance and tools have been prepared following a standardised consensus strategy (also including Delphy procedures) and involving many experts and different stakeholders. This process has contributed strongly to disseminate the awareness on GRiP and the participation to its activities. In addition, the tools created on the mentioned issues have been applied on the GRiP website and are available for scientific uses.
Identify gaps and coordinate efforts to harmonise procedures and methodologies regarding the use of outcome measures, endpoints and biomarkers in efficacy and safety trials.
The work has been focused on the assessment of biomarkers for the diagnosis of Sepsis in children, a condition associated with high mortality, and for which there is a need for more sensitive and specific assays. Deliverable 3.21 was focused on the accuracy of procalcitonin and the regulatory qualification as biomarker. In addition the soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) has been considered to be used in paediatric trials. Results have been published.
Harmonise terminology and data standards for paediatric research and medicinal use
A resource for researchers planning studies involving children to harmonise terminology in implementing protocols, data collection and data analyses has been implemented. It allows to:
• achieve precision in describing concepts;
• perform meta-analyses with other data sources including health care records;
• link data and outcomes to other resources;
• contribute to the development of standards for child health concepts and nomenclature in classification schema and nosologies.
Through a strong international collaboration more than 5,000 terms for child health use have been harmonized. Two international conferences with videocasts have been held.
Harmonise the technical acquisition of clinical data in paediatric research.
A “Report on harmonised technical acquisition of clinical data in paediatric research” – has been produced aimed to describe a framework for researchers planning studies involving children to harmonise data acquisition in implementing protocols, data collection and data analyses to:
• achieve precision and consistency in acquiring data and consequently improve quality;
• perform meta-analyses with other data sources including health care records;
• link data and outcomes to other resources;
• improve efficiency with consistent training and implementation of data acquisition
Evaluate models for information sharing for Human Research subject protection among ethics committees, Institutional Review Boards to facilitate review and support consistency in review practice.
This work addressed a still unsolved issue linked to the large variability in Ethic Committees/Institutional Review Boards procedures in conducting protocols review and supporting paediatric patients protection during the studies. A piloted model among 65 institutions have been done to demonstrate proof of concept and feasibility with quantitative measurable performance gains and harmonisation across all institutions. This model is to be transferred in other EU and non-EU countries

WP4 NEW METHODS FOR CLINICAL STUDIES IN PAEDIATRICS
The driver of WP 4 activities has been to cover the existing gaps in paediatric clinical research, through the generation of specific outputs (e.g. recommendations, tools, guidelines) able to support the choices of stakeholders involved in the paediatric drug developmental process. To validate these outputs and get the final approval, two levels of consensus were agreed and required by the project, an internal consensus involving GRiP representatives and, as a second step, an external consensus based on the work of relevant experts outside the GRiP network.
Five ad hoc Experts Groups (EGs) were also established to address the major issues in this WP. Results from the activities of these groups are reported below.
Modelling and Simulation (M&S) This groups have explored the opportunity that PKPD modelling offers in terms of improved evidence generation and systematic evidence synthesis (adopting a mechanism-based manner) and has reported a range of examples elucidating the points to consider during the implementation of modelling and simulation activities in paediatric research:
• Data analysis: compartmental pharmacokinetic modelling of dexmedetomidine for sedation; Pharmacokinetic-pharmacodynamic modelling of epileptic seizures for topiramate
• Integration of prior information: Pharmacokinetic-pharmacodynamic modelling of topiramate in conjunction with in vitro information on a new compound are integrated to identify a suitable dosing regimen and predict treatment response with a new compound in development
• Optimisation of experimental protocol design, dose selection and measures of response: a carbamazepine pharmacokinetic model extended with maturation from literature is used to predict pharmacokinetics in a new population (neonates) and to optimise protocol design; dose optimisation is shown for vancomycin in neonates based on a literature model, with the ultimate objective of individualising the dose during therapeutic drug monitoring; dose adjustment is shown for the pharmacokinetic interaction between valproic acid and other antiepileptic drugs. Following a critical evaluation of these examples, Recommendations were developed to implement a model-based trial to be disseminated to the scientific community and Regulators
Innovative design The main achievement in this area is the development of a pharmacometric-based strategy for a multi-dimensional comparison of different study designs. The result is the selection of the optimal design fitting a specific clinical condition. The classical parallel design (PaD) was compared with several innovative designs based both on frequentist and Bayesian approaches, including sequential design, crossover, randomized withdrawal (RWD), fixed sample Bayesian design (BD) and two alternative Bayesian sequential designs (BSD) (non-hierarchical (NON-H) and semi-hierarchical (SEMI-H). This approach was tested in the design of a clinical trial to assess the efficacy of topiramate (TPM) used as adjunctive therapy in paediatric patients between 2 and 10 years of age with epilepsy and then has been applied to three case studies, referring to real-life clinical trials in three different medical conditions: epilepsy (drug tested: lamotrigine); thalassemia (drug tested: deferiprone) and chronic pain (drug tested: gabapentin). With reference to lamotrigine, a feasibility study supporting a Paediatric Investigation Plan (PIP) was also developed while a population pharmacokinetic model and a bridging modelling study was prepared in the context of GRiP-WP4 and practically adopted in two approved PIP for deferiprone and gabapentin respectively.
Data extrapolation The discussion about extrapolation within GRiP occurred in a framework of huge discussion on the same topic at the scientific and regulatory level. As a consequence, the original contribution of WP4 activities to this issue has been mainly related to the provision of real world cases in which the extrapolation principles were applied and critically evaluated in order to support the use of this methodology as essential step in paediatric drug development. Hypotheses for its application as well as outcomes (e.g. avoiding unnecessary studies in the target population, overcome ethical and feasibility problems) were also evaluated. The following case studies have been provided:
1-For the epilepsy case, the approval of brivaracetam by EMA was analysed: in support of a specific regulatory request, a systematic review of published trials in Partial Onset Seizure (POS) was performed, to demonstrate that the effect measures were comparable between adult and paediatric studies, thus extrapolation of efficacy from adults to children aged more than 2 was feasible.
2-For anti-infective agents, extrapolation was historically viewed as a relatively straightforward exercise, because the PKPD targets of therapy were considered directly comparable between adults, children, and neonates. Nevertheless, several concerns to this approach were highlighted, with reference to: non-linearity of clearance-body weight relationship, incomplete maturation for children aged <2, functional immunodeficiency of neonates and different safety profiles.
3-In the field of anti-coagulants, the example of warfarin was brought. A genetic-based warfarin paediatric dosage regimen was investigated, but it was concluded that because of the developmental features in coagulation for children aged <2, additional clinical data were needed.
Sample size A tool for the sample size calculation in paediatric randomized clinical trials with a superiority design was prepared. The tool is based on an algorithm and was created following a large and iterative consultation process and tested among potential end-users, who were asked to give feedback in a semi-structured interview. A list of topics was used to elicit comments from GRiP members across several work packages and from the Scientific Coordination level, as well as from external parties. To date the tool is publicly available as a web-based module.
Comparators Considering that comparator selection in a paediatric trial must consider/address the complexities of comparator selection in the paediatric population, it has been deemed relevant to generate a tool to inform on the appropriateness of comparators. To develop the process at the basis of the tool, studies included in Paediatric Investigation Plans and European Public Assessment Reports in a timespan (year 2013) were analysed, in terms of comparator selection and use and other evidence provided in justification of the comparator selection. Moreover, a literature review on the topic was performed. The whole outcome was used to draft a list of considerations for the justification of comparator. Then, the list was formulated into a flowchart that guides the researchers to give answers on comparator justification in paediatric clinical trials. All considerations should be “yes” in order for either active or placebo comparator arm. This tool was presented to the EMA-PDCO and implemented with EMA-PDCO comments and contributions.

WP5 PAEDIATRIC FORMULATIONS
So far, there has been little sharing of best practices between formulation scientists and paediatric drugs research experts. This lack of communication and sharing of experiences acts as a significant hindrance to adequacy of paediatric medicine. Work package 5 (WP5) is collaborating to maintain an international platform to share knowledge and educate professionals on paediatric drug formulations with a special focus in children under 5 as they are more challenging and more neglected when it comes to formulation R&D. Results have been:
Networking exercise. An interactive map showing names and contact details of international formulation experts, divided by WHO region to provide support to allow a wider membership of academics, relevant practitioners and industry partners to be connected globally. This map was used to scope experts and interested parties more globally resulting also in many GRiP related contributions.
Webinars 13 webinars were organised and delivered (5 from Academics / 4 from Industry / 3 from Clinicians / 1 from Regulator with a total Participants of 1317). The topics covered are as follows:
1. Age Appropriate Formulations
2. Pharmaceutical Excipients in Neonates – The Propylene Glycol Example
3. Compounding & Manipulating Medicines for Children - Problems & Solutions
4. Framework for Developing Palatable Paediatric Drug Products – the Tools & Approaches for Taste Masking
5. In-vitro Biopharmaceutic Methods in the Development of Oral Dosage Forms for Children
6. Quality and the European Medicines Agency Paediatric Investigation Plan
7. Nanomedicines for Children: Minimising the Size to Maximise the Benefit
8. Challenges of Administering Medicines to Neonates
9. IQ Consortium’s Survey of Pediatric Formulation Development: The Industry Perspective
10. Using the STEP Database for Information on Safety & Toxicity of Excipients
11. How do Carers Actually Give Medicine to Children?
12. Considerations Associated with Dosing Medicine to Children Using Food and Beverages”
13. Real Time Adaptive Manufacturing – A New Paradigm to Drive the Clinical Development of Paediatric Formulations
Collaboration with International Key Initiatives. The main initiatives to which WP5 has collaborated are listed below
1-Participation to the STEP Database. Responding to the need for a comprehensive source of computerized information concerning the toxicity and safety of the excipients for paediatric medicine, the European (Eu) and United States (US, Eunice Kennedy Shriver NICHD, NIH) Paediatric Formulation Initiatives (PFIs) are working together to create and maintain a database of Safety and Toxicity of Excipients for Paediatrics (STEP). WP5 has collaborated to this effort and to a follow-on long-term project started in 2015. The STEP database now includes 65 excipients and is being used by approx. 3000 users worldwide. It serves as an excellent source of diligently curated data of excipients for development of safer medicines for children. This has been acknowledged by regulators (EMA, FDA) at several conferences and meetings. It has already shown to be of value during the development of the 1st excipient monograph of propylene glycol for paediatrics by European Study of Exposure of Excipients (ESNEE) network.
2- FIP–WHO technical guidelines: Points to consider in the provision by health-care professionals of children- specific preparations that are not available as authorized products. Some work at UCL as a model country was undertaken to determine the feasibility of this proposal from the perspectives of needs (mainly measured type of API compounded formulation for paediatrics), manufacturability, and end-user acceptability in Nigeria as an example of a developing country.
3- EDQM European Paediatric Formulary, the initiative aimed ‘to improve accessibility to suitable and age-appropriate medicines for children throughout the European continent by compiling acceptable unlicensed preparations from existing national formularies or individual existing formulations described by relevant national experts. They are currently investigating the prioritised development of suitable monographs.
Research activities. Over all the aim of WP5 was to facilitate global paediatric formulation research worldwide mainly and avoid duplication of work. In that respect, the following gives an overview of the level of engagement with various stakeholders.
1- In collaboration with EuPFI WP5 contributed to European Survey on Paediatric Medicine Administration Devices done in HCP by involving EU patients and family in collaboration with VSOP-EGAN.
2- in collaboration with GRiP WP6, WP5 supported a Survey on Neonatal Care Practices. It was done at EU level but a Collaboration with the DURG-LA (Drug Utilisation Research Group for Latin America) led to similar Survey on Neonatal Care Practices with Lanetwork. It was interesting as, despite of the geographic distance, results were not that dissimilar to those found in Europe. This generated Knowledge of global current medicine use and the collective views of the international neonatal community are useful to construct an updated research framework for neonatal medicines.
3- in collaboration with the University of Liverpool, WP5 worked on developing methodologies for the evaluation of age-appropriate formulations in Children to examine, evaluate and describe the impact of the lack of age appropriate formulations. This included development of a Tool looking at medicine usage from a carer/user perspective and identifying reasons for when age-inappropriate formulations are used, within a clinical setting. A qualitative study was also conducted to find out parental views when suitable formulations are not available on the market for use in children and the difficulties and barriers to administration that this can cause to patients and their families.
Proof of concept papers on innovative/alternative drug delivery technologies for children. WP5 have been guest editor of a seminal series of review papers [Nunn A, Wong IC, Tuleu CL. Paediatric drug delivery. Preface. Adv Drug Deliv Rev. 2014 Jun;73:1. doi: 10.1016/j.addr.2014.05.013. Epub 2014 May 27] reviewing many of the problems identified and the solutions introduced or under development.

WP6 DRUG DEVELOPMENT IN NEONATES
Within GRiP WP6, we involved and collaborated with European and American leaders in neonatology, developmental pharmacology, along with regulators and ethicists to identify and solve all the challenges that limit neonatal drug research and trials in order to harmonize European practices and improve neonatal care.
Identify neonatal networks in developing and developed countries A report on existing neonatal networks (NN) outside EU has been realized and has allowed to reach the following objectives: 1) to identify and characterise activities of all NN outside the EU; and 2) to develop a Registry of NN around the world. This Registry has been made available outside the Network including the DG research at its request.
To identify common elements and standardised definitions in neonates (for risk factors, interventions, complications and short- and long-term outcomes). In order to harmonize research practices and set standards, we first conducted a Delphi study to identify the criteria that would help neonatologists to organize a NICU research infrastructure in order to conduct drug evaluation trials. We collected their research experience and identified areas for improvement that included in particular, increasing time dedicated to research, organizing training both to Good Clinical Practices and specific to each research, involving parent.
To make an inventory of unadapted formulations / presentations, therapeutic protocols and strategies. Two European surveys (22 participating countries) identified key issues in neonatal drug use. In a first step, the survey on all therapeutic protocols for antibiotic administration (drug, dose, variables for dosage individualization...) was conducted, inviting NICUs to participate: 437 dosage regimens were identified in French NICUs for 41 antibiotics and for most of them, unique mg/kg doses for all neonates were used, that does not take into account the physio-pathological differences between preterm to full-term neonates. Our research activities were then oriented to dosage adaptation in neonates by clarifying the role of animal studies in the preclinical safety aspects of neonatal drug development, developing renal maturation models using amikacin and vancomycin, evaluating the impact of neonatal variables (such as gestational age, weight, renal maturation, disease, genetic factors) on drug dosage. The results contributed to the improvement of knowledge gap in developmental physiology and pharmacology with the design and use of age-appropriate methods adapted to neonates.
To define standards for biological banking (including tissue and DNA samples) that can be used for pharmacokinetic, pharmacogenomic and proteomic studies in neonates during clinical drug development and to improve knowledge in developmental physiology and pharmacology. A consensus document has been finally disseminated.

WP7 DISSEMINATION AND NETWORKING
WP7 has created and used a range of tools to maximise the awareness about GRiP activities. The WP has also created content used for communication purposes drawing on the activity of each WP. The tools that have been made available to GRiP to raise its profile are:
GRiP Website (www.grip-network.org)
This is the main communication portal. Contains detailed information about how GRiP originated, its main objectives, participants, components and up to date news about the project. There are very detailed sections on each WP, describing the objectives and results. Deliverables met by WPs are also collated to provide a comprehensive view of the overall GRiP achievements. The website contains descriptions of all the GRiP partner organisations involved as well as biographies of the individual partner members. There is a news section, constantly kept up to date, which contains information about initiatives, achievements, events and other aspects of GRiP. The user-friendly, state-of-the-art website contains a list of scientific articles produced by GRiP. This body of work represents one of the most concrete evidence of GRiP’s work.
Newsletters
WP7 has produced a series of newsletters that were widely disseminated. Each WP contributed to the development of the database of contacts to which newsletters were sent. The newsletters offered details on the achievements of GRiP and the current, as well as interviews with GRiP staff and GRiP Masters Programme students. Newsletters were made to be as streamlined as possible, in order to maximise the number of readers among recipients. All editions were also uploaded to the website. A targeted email campaign was carried out to promote interest in the GRiP Masters programme.
Webinars
The WP7 team facilitated the process by circulating news about webinars organised by other WPs, publicising webinars through social media, registering participants and uploading information and links to webinar recordings on to the various online channels. A free-access archive of the webinars produced by the WP5 team is available on the website, constituting a significant source of current knowledge about paediatric formulations.
Online Social Media Pages GRiP has been active on social media through LinkedIn, Twitter, Facebook and YouTube. The WP7 team sourced and produced content, mainly consisting of news about the network’s activities. The content has been uploaded on to the GRiP social media pages in order to make GRiP a recognised entity within relevant social media circles. The feedback has been positive. A global audience has demonstrated increasing interest in GRiP’s activities.
Videos The WP7 team has produced video interviews with key GRiP staff for communication purposes. The interviews were carried out at general GRiP meetings and the content was uploaded on to the network’s YouTube channel. The videos represent a useful resource to present the project to a wide audience, as personal testimonies of network members on their thoughts about the significance of GRiP.
Brochures and Leaflets The WP7 team has produced printable material containing the essential information about GRiP and its various initiatives. The material is available online and downloadable by anyone who wishes to raise awareness of GRiP. The material has been particularly useful in context
Masters’ Marketing & Communication Strategy WP7 has focused its efforts on a marketing and communication strategy to raise awareness of the GRiP Masters programme. Specific actions targeted at prospective students have been carried out, such as distributing newsletters, interviewing current and former GRiP students and circulating interviews on various aspects of the course, including the application process, the syllabus and the faculty. Such material is available for use to facilitate the upcoming editions of the GRiP Masters in Medicines Development & Evaluation. The strategy involves all available tools, from the GRiP Website to its online social media profiles.
Knowledge Translation, Exploitation and Mobilisation (KTEM) A specific objective of the GRiP network was basing dissemination and implementation of the project outputs of well-planned activities relating to knowledge translation, exploitation and mobilisation (KTEM), building this strategy within the activities of all WPs, with a regular network-level review of progress. The Knowledge Translation Strategy takes account of the diverse nature of the deliverables and the multiple contexts in which they are implemented, thus adopting a devolved approach to KTEM. The Strategy is detailed with full results in D7.9 Final Report on KTEM.
Private Sector Links Pharma industries represent the highest participant sector for registration for the GRiP Meet the Expert in Paediatrics webinars. An open meeting with Pharma industries was organised for their views of how industry can work with networks to support paediatric drug development. Topics of high interest for Industry were included in the GRiP training programme.
Links have been established through WP5 Meet the Expert in Paediatric Formulations where industry interest is higher than any other sector and continues to increase. The participants’ details are included in the contact management system. On behalf of GRiP, Mark Turner continues to be an invited speaker to many Pharma led events worldwide and has built relationships and disseminated knowledge and information at every opportunity. He has established links with EFGCP (European Forum for Good Clinical Practice) and is an invited speaker at the Joint DIA/EFGCP/EMA Better Medicines for Children Conference taking place in October 2016 and October 2017.
Patient and Public Involvement Patient Public Involvement (parents, children and young people) was recognised as very important to the success of GRiP and as such played a large role in all network meetings. This continued through the project, and as part of the education programme a patient and public involvement roadshow took place. GRiP (WP5) held a patient public involvement based Meet the Expert in Paediatric Formulations webinar in October 2015, the subject of which was “How do Carers Actually Give Medicines to Children”, outlining real experiences of the challenges families face. WP5 also worked with VSOP to develop and circulate European Survey on Paediatric Medicine Administration Devices: Experiences and Opinions of Patients and Parents/Carers.
The WP5 EuPFI administration devices working group conducted a survey on the views and experiences of patients and their carers themselves regarding their administration devices. GRiP agreed to support this initiative as an expert group working closely with pan European patient organisations and affected families. On behalf of the European patient umbrella organisation EGAN (www.egan.eu) the Dutch Alliance for Rare and Genetic Disorders VSOP (beneficiary no. 21) which coordinates the interaction between patient organisations and the researches and paediatricians in GRiP was contacted to help modifying the current questionnaire to make it suitable for the participants and help identifying and contacting the respondents.
WP3 developed the Young Persons Advisory Group (YPAG) Start Up Tool online platform http://ypag.grip-network.org/ This was developed to harmonize information and guidance for researchers looking to involve young people in the design of clinical trials. This platform is a link to research networks encouraging then and/or institutions to develop their own Young Persons Advisory Groups (YPAGs) in a systematic manner based on research findings and experiences from existing YPAGs, so that young people are actively participating as partners, advising researchers and their teams on a full range of activities in various research projects and initiatives.
Mark Turner is a member of the Scientific Board of iCAN (international Children’s Advisory Network), a worldwide consortium of children's advisory groups working together to provide a voice for children and families in health, medicine, research, and innovation through synergy, communication and collaboration. The network now includes 17 teams from 7 countries across Europe. The iCAN Summit took place in Barcelona 27 June -1st July 2016, the focus of which was nutrition, healthy lifestyle, and empowering young people to take part in medicine, research, and innovation.
ULIV-NIHR has subsequently supported the development of the European Young People’s Advisory Group Network (EYPAGNet). This network is convened by FSJD, Barcelona. Dr. Turner chairs the Scientific Board of EYPAGnet which is a key partner in PedCRIN, EPTRI and the IMI2 application described earlier in this section.
KTEM Strategies Results
A specific objective of the GRiP network is basing dissemination and implementation of the project outputs on well-planned activities relating to knowledge translation, exploitation and mobilisation (KTEM), building this strategy within the activities of all WPs, and included a regular network-level review of progress. The Knowledge Translation strategy taken account of the diverse nature of the deliverables and the multiple contexts in which they are implemented. Basically 4 key audiences were identified:
• industry
• regulators
• clinical researchers
• Public and patients
Practical implementation, exploitation and mobilisation was based less on the traditional channels of dissemination (academic channels) and more on bespoke actions that built on the existing processes for implementation that GRiP participants had previously contribute to.
KTEM versus Industry. Included in the Industry category was big pharma, SMEs with niche drug development pipelines, biotech companies, medical device manufacturers, manufacturers of medicines and trial supplies, contract research organizations etc. These audiences were interested in many outputs across GRiP workstreams. The GRiP industry action provided access to representatives of each sector of industry. Experience had shown that the most effective way to disseminate to industry is via conferences. Industry contacts provided insight as to which conferences were the most important for each sector so that individual WPs can conduct appropriate KT activities. This has been the case of a number of Conference promoted by Industry with the participation of the Scientific Coordinator and many WP leaders and also of two GRiP open meetings held at the presence of Industry representatives. Among these activities, Mark Turner has represented GRiP as an invited speaker to many Pharma led/attended events worldwide and has built relationships and disseminated knowledge and information about GRiP at every opportunity. An IMI2 (Innovative Medicines Initiative) Workshop took place in Brussels 5th April 2016 and Industry were represented at the event highlighting challenges faced when running global paediatric clinical trials. Some of the key GRiP partners attended this workshop and Mark Turner, as Chair of EnprEMA presented the experiences of paediatric research networks, including GRiP. This included successes, challenges and opportunities that have arisen. Other partners presented during the session addressing the proposal for the creation of a sustainable pan-European paediatric clinical trials network. Cor Oosterwijk presented the patient public involvement view with regard to clinical trials. The GRiP industry activities also provided opportunities to consult with specific sectors about other ways to conduct KT. These liaison activities allowed generic KT planning across the GRiP WPs.
In addition Industry has been involved in 4 of 13 GRiP Meet the Expert in Paediatrics webinars on key aspects of the paediatric drugs preparation and with a high level of participation. Those have been the following:
• Framework for Developing Palatable Paediatric Drug Products – the Tools &Approaches for Taste Masking presented by Jeff Worthington 108 participants June 2013
• IQ Consortium’sSurvey of Pediatric Formulation Development: The Industry Perspective presented by the IQ Consortium panel, led by Trupti Dixit. 71 participants Jan 2015
• Considerations Associated with Dosing Medicine to Children Using Food and Beverages” presented by Terry Ernest 115 participants Oct 2015
• Real Time Adaptive Manufacturing – A New Paradigm to Drive the Clinical Development of PaediatricFormulationspresented by Peter Scholes 61 participants Dec 2015
KTEM versus Regulatories. Similarly, regulators were a key audience. GRiP participants were able to advise about disseminating outputs to this audience and where GRiP activities would be synergistic with ongoing efforts. The key grouping is ICDRA and its Paediatric Regulatory Network (chaired by Dr. Saint-Raymond, lead scientist for Beneficiary #3, EMA). Also to be mentioned the presence of many partners at EnprEMA, that played a role of bridging regulatory and Clinical Networks involved in paediatric Research. In addition many WPs have developed collaborative activities with EMA and PDCO also participating in dedicated meetings, workshops and consultation. Here the list of the main initiatives:
• K.Hoppu (HUS): Presentation of GRiPat the Finnish Medicines Agency (Fimea) in Helsinki, Finland on 24.5.2011
• K.Hoppu (HUS): Presentation of GRiP in the WHO meeting “Technical Consultation on Medicines for Children” held in Geneva, Switzerland 5-6 May 2016 (with participation of members of the WHO PaediatricmedicinesRegulators' Network (PmRN))
• M. Sturkenboum European Network of Centers of Pharmacoepidemiology & Pharmacovigilance plenary meeting presentation on GRiP: ENCePP Plenary Meeting, 18 June 2013. http://www.encepp.eu/publications/documents/3.2_GlobalResearchinPaediatrics_GRiP.pdf
• M. Sturkenboum European Medicines Agency: Pharmacovigilance in the paediatric population workshop
• M. Sturkenboum Advancing the Development of PediatricTherapeutics (ADEPT): Successes and Challenges of Performing Long-TermPediatricSafetyIssues April 13-14, 2016
• M. Sturkenboum Food and Drug Adminstration: Meeting Sept 18-19 2017: Public Workshop- Advancing the Development of Pediatric Therapeutics (ADEPT): Application of "Big Data" to Pediatric Safety Studies
• A. Ceci (CVBF-TEDDY) Presentation at the EnprEMA meeting: Evaluation of off-patent medicines in Europe: The FP7 experience (London, 30 January 2014)
• WP4 Presentation at EMA-PDCO of the ‘Tools to inform on the appropriateness of comparators in paediatric trials’
• Piotr Kozarewicz, Scientific Officer at the EMA, Quality and the European Medicines Agency Paediatric Investigation Plan WP5 Webinar, February 2014
KTEM versus clinical researchers. Paediatric clinical research networks have exploited and mobilised extant knowledge in the areas covered by GRiP as part of their core business. This was carried out through formal training activities and “hands-on” involvement in individual clinical trials (design, setup and delivery). GRiP outputs were disseminated through these activities of clinical research networks and “networks of networks” such as the European Network for Paediatric Research at the European Medicines Agency (EnprEMA). In addition we should consider that a strength of the GRiP project has been that many participants remain active in the organizations and processes that exploit the knowledge created by GRiP activities. These GRiP participants continue to exploit knowledge and disseminate it among their clinical organizations and Networks.
KTEM versus public and patients. Specific strategies to disseminate GRiP contents and tools at a larger audience has included:
- the open access to the Website content /deliverables, reports, papers, ...)
- the organisation of the GRiP Patient Roadshow, a special version of the Roadshow aimed to serve the need of the parents and young patients, developed in cooperation with GRiP Partner VSOP. A pilot GRiP Patient Roadshow was organised in Helsinki 22.10.2015 and a second one in Rome in November 2015.
- the Young Persons Advisory Group (YPAG) Start Up Tool online platform http://ypag.grip-network.org/ This was developed to harmonize information and guidance for researchers looking to involve young people in the design of clinical trials. This platform is a link to research networks encouraging then and/or institutions to develop their own Young Persons Advisory Groups (YPAGs) in a systematic manner based on research findings and experiences from existing YPAGs, so that young people are actively participating as partners, advising researchers and their teams on a full range of activities in various research projects and initiatives.

Potential Impact:
Impact
The impact of the GRiP project includes a general improvement in the environment for research about medicines in children, in Europe and other parts of the world. This stems from a number of specific actions that have changed research practice. Other GRiP outputs will underpin future improvements.
A valuable impact is attributable to all the main activities of GRiP project and in particular the most significant impacts for each key aspect of GRiP work, were:
Impact of developing a training programme in paediatric clinical pharmacology
a) the Master programme provided a pilot for future degrees with a large corpus of teaching materials in multiple media;
b) the Roadshow improved awareness of the issues addressed by clinical pharmacology and paediatric medicines development among many members of the paediatric community. These actions are necessary first steps to enhancing the European environment for paediatric medicines research
c) The increased understanding and knowledge the participants gained will benefit many of them in their daily work. It also served as “stepping stone” to other more advanced and demanding training programs
Socioeconomic impact. Although it is too early for final conclusions on the impact of the training programmes under a socioeconomic point of view, it is already evident that some of the students of the Master’s programme are now having a visible position in the national or international academic Paediatric Clinical Pharmacology community, and are actively involved in paediatric medicines research.

Impact of promoting sharing of best practices in research and to create standards and guidelines including new protocol designs, procedures and methodologies for clinical studies in children.
a) Improve the current research practices by the use of Evidence-based evaluation and comparison of different designs, procedures and methodologies.
b) Move from expert opinion to a hierarchy of evidence in this field
c) Support greater efficiency and consistency of Ethics Committees procedures
d) Support inclusion and acceptance by Regulatory Bodies of new methods for paediatric trials tailored for small populations and age (neonates)
e) Create a new community pooling of expertise for paediatric formulation
f) Inform on more predictable efforts to identify and recruit well-qualified neonatal units;
g) Fostered the development of a community of Young People’s Advisory Groups.

Impact of developing an integrated electronic infrastructure for epidemiological, pharmacovigilance and post marketing research.
Proof of principle now ready to be applied as big data approaches are developed. Crucially, the GRiP work has validated its methods which is a step ahead of other approaches. It is expected that the Platform validated within GRiP could become more and more attractive for public and private stakeholders in so increasing its socioeconomic value.

Impact of creating a durable collaboration between participating partners - Networking
The most important networking activity has been to embed GRiP (work and members) in successor networks that will use the GRiP outputs to continuously improve the ability of the European Research Area to conduct research about medicines used in children. To this end, Mark Turner and Carlo Giaquinto, on behalf of ULIV-NIHR and PENTA respectively and on behalf of the GRiP network, carried out an extensive work to build a consortium to develop a bid for an IMI2 Paediatric call for a project to build a sustainable paediatric clinical trials network. The call was issued in December 2016. 9 members of the GRiP consortium are members of a consortium that submitted an application to the IMI2 Call 10 Topic 4 call in March 2017. This academic consortium extended the range of the GRiP network by including 54 members, most of those were not part of the GRiP consortium. The academic consortium was successful in the first stage of the IMI2 call and spent the summer of 2017 preparing a full application. This preparation involved very close collaboration with 10 pharmaceutical companies. The hearing relating to the full proposal was held in Brussels on 15 Nov. 2017.
If funded, this infrastructure would transform paediatric medicines research and speed up the availability of high quality medicines for children. This call will follow on from the work achieved by the GRiP Network integral in the sustainability of the project with many of the outcomes used to inform bid application. Specifically, the IMI2 application incorporated and extended work from GRiP WP1, 3, 4, 6, 7, 8 and 9.
This is also an opportunity to address the need for public and private collaborative research for paediatric drug development focused on partnership between experts from industry, academia, patient and parents with real life experience of paediatric diseases and experts from regulatory agencies. Following the closure of the GRiP project the need for paediatric research networks was highlighted in two key policy documents: the revision of ICH E11 that captures international consensus about drug development in children and the European Commission’s 10-year review of the Paediatric Regulation. GRiP outputs anticipated these policy drivers for successors to GRiP.
During 2015 Dr Turner (ULIV-NIHR), on behalf of GRiP, also led the development of the European Paediatric Clinical Trials Research Infrastructure (EPCTRI) which was submitted to the European Strategic Forum for Research Infrastructure (ESFRI), which is developing Europe’s research infrastructure roadmap. This application was highly rated and has been recognised as a complementary research infrastructure in the 2016 Infrastructure Roadmap.
On this basis, 5 members of the GRiP consortium partnered with the European Clinical Research Infrastructure Network (ECRIN), and ESFRI landmark research infrastructure, and 10 partners who are not part of the GRiP consortium to develop a funding application for INFRADEV-003. This application, PEDCRIN, was successful and is developing a strategic plan for the European Paediatric Clinical Trials Research Infrastructure. This extends on GRiP WP 1, 3, 4, 6.
If the IMI2 application is funded, it will include a WP relating to sustainability, and PEDCRIN includes a similar activity. The plan is to integrate the work prepared under PEDCRIN and IMI2 into a sustainable network and research infrastructure.
During 2016 – 2017 Prof Ceci (CVBF) led an application for H2020 INFRADEV001 funding to develop a conceptual design report for the European Paediatric Translational Research Infrastructure (EPTRI). This successful application included 7 GRiP partners and extended the reach of the GRiP Network of Excellence by partnering with 26 institutions. This project will use work done in GRiP WP2, 4, 5.
The intention of EPTRI is to provide a reference point for paediatric issues for all health research infrastructures on the ESFRI roadmap. This would provide a full pipeline for paediatric drug development to be led by public sector organizations. EPTRI will support work that lays the foundations for research, including clinical trials that recruits children and young people. The IMI2 project would support the conduct of clinical trials.
In summary, networking activities have captured the legacy of GRiP in three European grant applications (2 successful and 1 under review at the second stage at the time of writing). This involves 11 GRiP participants who have partnered with 49 further participants. Work from all GRiP WPs has informed these applications providing pilot data, templates and outputs that can be implemented to maintain and extend the infrastructure matrix proposed in the call text. The infrastructure will be managed by a total of 75 participants in 26 European countries who will provide services to hundreds of participants in Europe and beyond.
Socioeconomic impact. Two funded collaborations worth €6.3 million. One further funding application worth €67 million is in the final stages of evaluation. Successor organizations will deploy all GRiP outputs in work that involves 59 institutions that were not part of GRiP.

Dissemination Activities
To disseminate the project results, the ad hoc GRiP tools have been widely used according to the GRiP communication and dissemination Plan. This Plan was aimed of publicising the project and its results among different stakeholders in order to maximize awareness of the project. The consortium developed the communication tools (such as the project website, social media channels, newsletters and brochures) drawing on the work carried out by each WP and disseminating as widely as possible.
GRiP website is the main repository of contents about GRiP achievements allowing consultation by different users, from stakeholders directly involved in the drug development process up to patients, caregivers and general public. Other priority ways of communication were targeted selected audiences (e.g. the Paediatric Committee was presented and required for comments about the tool on comparator) and more standard mean of communication within the scientific community, namely publications. In this latter case, not only scientific findings were considered for publication but also in-house data useful for replicating procedures and outcomes (e.g. the source code of the tool for testing the performance of different design is available on publications). Thus, dissemination activities include a total of 65 published papers. There was a total of 36 official project meetings including external partners, 20 workshops (roadshows), 13 educational webinars and 44 courses.
In addition, many different tools have been adopted by the Network also according to each WP/Partner specific needs as summarised below.
WP1- training programme. Dissemination trough GRiP website and through posters and leaflet.
WP2- integrated electronic infrastructure. Dissemination through FDA, EMA and industry, and datasources that are GRiP partners
WP3- sharing of best practices in research. Dissemination through research networks, the European Network of Research Ethics committees and the European Young People’s Advisory Group Network
WP4 - new protocol designs, procedures and methodologies. Dissemination: through academic societies, publications, workshops and research networks
WP5- formulation. Dissemination through webinars, other professional groupings
WP6-neonates. Dissemination through academic societies, publications, workshops and research networks
To be underlined the special efforts devoted to raise awareness of the GRiP Masters programme. Specific actions targeted at prospective students have been carried out, such as distributing newsletters, interviewing current and former GRiP students and circulating interviews on various aspects of the course, including the application process, the syllabus and the faculty. Such material is available for use to facilitate the upcoming editions of the GRiP Masters in Medicines Development & Evaluation. The strategy involves all available tools, from the GRiP Website to its online social media profiles.
Dissemination has been very positively facilitated by the strong Networking activities, as cited above, conducted by the Network Coordinators and all the other partners. encompassing various interested parties, with particular attention given to organisation and Institutes from Eastern Europe and mid-developed countries where GRiP partners have several contacts.

Exploitation
The most important exploitation of the GRiP outputs has been to embed GRiP (work and members) in successor networks that will use the GRiP outputs to continuously improve the ability of the European Research Area to conduct research about medicines used in children.
10 participants in GRiP are members of the European Network of Paediatric Research at the European Medicines Agency (EnprEMA). This allows discussion of GRiP activities and dissemination of outputs to 24 networks that are not linked with GRiP in 10 countries.
9 members of the GRiP consortium are members of a consortium that submitted an application to the IMI2 Call 10 Topic 4 call in March 2017. This academic consortium extended the range of the GRiP network by including 45 members who were not part of the GRiP consortium. Specifically, the IMI2 application incorporated and extended work from GRiP WP1, 3, 4, 6, 7, 8 and 9.
5 members of the GRiP consortium partnered with the European Clinical Research Infrastructure Network (ECRIN), and 10 partners who are not part of the GRiP consortium to develop a funding application for INFRADEV-003. This application, PEDCRIN, was successful and extends GRiP WP 1, 3, 4, 6.
The H2020 INFRADEV001 funded project to develop conceptual design report for the European Paediatric Translational Research Infrastructure (EPTRI) included 7 GRiP partners and extended the reach of the GRiP NoE by partnering with 26 institutions. This project will use work done in GRiP WP2, 4, 5.
More in details exploitation of GRiP results embedded in other forthcoming activities are:
Develop a training programme in paediatric clinical pharmacology: Efforts are underway to extend this to clinical trial activities using materials and infrastructure developed by GRiP (IMI2 project proposal and links with ESFRI RIs)
Promote sharing of best practices in research: GRiP participants and new partners will extend this approach to a range of other activities based on GRiP ways of working and templates (IMI2 project proposal and links with ESFRI RIs)
Develop an integrated electronic infrastructure for epidemiological, pharmacovigilance and post marketing research: this work will be used and extended in commissioned projects and IMI2 project proposal
Explore and validate the use of new protocol designs, procedures and methodologies for clinical trials in children: this work will inform expert advisory groups which will use the model for further work (IMI2 project proposal)
Sustain an International platform to share knowledge and educate professionals on paediatric drug formulation: Activities will continue in EPTRI and IMI2 project proposal
Create a durable collaboration between participating partners: this will be done through personal links, institutional partnerships, and links with ESFRI RIs.
List of Websites:
www.grip-network.org