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Introduction
Conducting clinical trials in the paediatric population is difficult for a host of reasons that include logistical, methodological, financial and ethical problems. Indeed for many paediatric conditions, their low prevalence means that multicentre studies performed on an international scale often represent the only possibility to gather a sufficient number of patients (ie, to obtain clinically and statistically valid results) over a reasonable period of time, especially for drug trials. However, such studies are difficult to conduct for several reasons including ethical issues such as assignment to placebo, lack of adequate paediatric methods to assess response to therapy, lack of adequate paediatric formulations, the need for specific study designs, inadequate funding as the consequence of the small potential market and limited funding for investigator led academic studies. In addition, there are several bureaucratic constraints related to ethics approval and clinical trial authorisation that often hinder investigator led academic sponsored clinical trials, which do not have the extensive logistical support normally provided by pharmaceutical companies.1 The overall result is that, until recently, evidence regarding the safety and effectiveness of available treatment regimens tended to be from small, open, uncontrolled trials or from anecdotal reports and non-randomised case series.
From a logical and scientific point of view, one of the key issues to overcome these problems is to work with established clinical trials networks that have a wide international representation and a good scientific reputation.
In this regard, the adoption of legislations to encourage paediatric clinical trials both in Europe and in the USA has opened a new era in the assessment of drug safety and efficacy in children. In particular, the new European Paediatric Regulation2 required the European Medicines Agency (EMA) and the Paediatric Committee to develop a European network of existing national and European networks, investigators and centres with specific expertise in the performance of studies in the paediatric population. Hence, the Paediatric Regulation called on the EMA to foster high quality ethical research on medicinal products for use in children through efficient internetwork and stakeholder collaboration. To meet this objective, a European paediatric research network of national and European/international networks, investigators and centres with expertise in performing drug trials in the paediatric population has now been established and is called the European Network of Paediatric Research at the EMA (Enpr-EMA).
This paper describes some of the current national and international paediatric networks in Europe, the legal and methodological framework used by the EMA to set up the operational structure of Enpr-EMA, the recognition criteria for the identification of paediatric networks, and the challenges to and opportunities for implementing clinical trials in the paediatric population.
European paediatric networks
The implementing strategy of the EMA published on 15 January 20083 defined a ‘network as a virtual structure defined by a formal agreement between individuals, organisations or structures sharing and collaborating towards the same objectives, goals and quality standards’. According to the implementation strategy, the network's objectives are to coordinate studies relating to paediatric medicinal products and to build up the necessary scientific and administrative competences at the European level in order to avoid unnecessary duplication of studies. Additional benefits sought are the facilitation of patient recruitment and the strengthening of the foundations of the European Research Area. An informal inventory conducted by the EMA originally identified about 60 different European paediatric networks, with specific expertise and interest in the development of medicinal products.4 These networks can be divided into three main categories: national networks, disease-oriented networks and others representing special activities or age-related networks (eg, neonatology).
Examples of paediatric national networks
Several national paediatric networks have been identified in European countries (eg, Finland, Italy, The Netherlands, the UK).4 The goals of these national networks, usually not for profit, are to provide facilities and access to paediatricians, children and their families for the proper conduct of clinical trials in children.
An example of a national network is the UK National Institute of Health Research Medicines for Children Research Network (NIHR-MCRN; www.mcrn.org.uk) which supports paediatric research, non-commercial, pharmaceutical/biotech-sponsored and investigator led partnership studies in over 100 National Health Service sites serving approximately 6 million children. The MCRN supports the development of national studies through its infrastructure, which includes the MCRN Coordinating Centre in Liverpool, six local research networks across England, 12 clinical studies groups covering most paediatric specialty areas, clinical trial units and a neonatal network. The NIHR-MCRN is funded by the Department of Health and works in partnership with the UK Clinical Research Network to improve the clinical research environment in the UK and maximise the development of safe and effective medicines and formulations for children.
As a complement, the ERA-NET PrioMedChild (Priority Medicines for Children; www.priomedchild.eu), funded initially by the European Commission's DG Research, is a network of 11 research funding organisations from different EU member states (Estonia, Finland, France, Italy, Latvia, The Netherlands, Poland and the UK) working for the development of research priorities concerning medicines for children. The network does not run clinical trials but provides funding to support European calls for research projects up to 3 years.
Pros and cons
National networks have the advantage of providing facilities and a one-stop access point to paediatric centres speaking the same language and working in the same health system. While national networks will be of foremost importance for studies involving childhood diseases of high prevalence, the same does not hold necessarily true for clinical trials in more rare diseases, which usually require international participation.
Examples of disease-oriented paediatric networks
The disease-oriented networks usually focus on a specific therapeutic area (eg, oncology, HIV, rheumatology) or are derived from learned societies such as the European Cystic Fibrosis Society.
The paediatric oncology literature is replete with studies designed as actively controlled, open-ended and randomised trials in which all treatment arms of the study receive active agent(s). Indeed, more than 60% of children with cancer are treated in Europe with prospective clinical studies at diagnosis as well as at relapse. The vast majority of these studies are investigator-driven. Since care and research are integrated and the agents being tested are approved in adults, the usual mechanism of cost reimbursement for care at the national level covers most of the patient-related expenses in investigator-driven clinical trials. The chief expenses for running the group operations centre, to sponsor and monitor trials, communications and travel to planning meetings have to be met from other sources. During the last 50 years, the aims of these investigator-driven clinical trials were not to seek regulatory agency approval for a therapeutic approach, but rather to make stepwise advances in disease management and outcomes, and to gain information about the clinical benefit of a drug in the treatment of a particular malignancy and establish prospectively validated therapeutic standards. For example, the International Berlin/Frankfurt/Münster Study Groupis dedicated to promote both research and clinical care for children and adolescents with leukaemia and lymphoma.5 The International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) runs a translational and research programme in neuroblastoma6 and Société Internationale d’Oncologie Pédiatrique – Epithelial Liver (SIOPEL)addresses the issue of very rare paediatric liver malignancies.7 The Innovative Therapies for Children with Cancer network focuses its research activity on preclinical evaluation and early phase trials.8 In 2011, the European Network for Cancer Research in Children and Adolescents has been launched within the 7th Framework Programme to avoid fragmentation and to strengthen the capacity of the European academic community to properly address paediatric needs. Another example is the Children's Oncology Group,9 which recently celebrated the milestone of 50 years of paediatric clinical trials and collaborative research in oncology in the USA. Through these networks, cure rates dramatically rose from less than 20% to 80%. Outcome in acute lymphoblastic leukaemia has gone from a 6-month median survival to an 80% overall cure rate. In the Western world, clinical research groups have been set up to evaluate therapeutic strategies for each of the 60 different paediatric malignancies.
The networking experience has clearly proven that most of what is known about the diagnosis and management of childhood cancer is a result directly related to cooperative group clinical research.9 10 The huge gains in survival for many childhood cancers bear testament to this approach of sharing consensus based protocols and has inspired the creation of similar consortia for other paediatric diseases.
Other examples are from the field of paediatric rheumatology where the presence of two very large international trial networks—the North American based Pediatric Rheumatology Collaborative Study Group (www.prcsg.org) and the Paediatric Rheumatology International Trials Organization (www.printo.it)—grouping more than 50 countries worldwide has played a critical role in the implementation of the US and European paediatric legislations and allowed for the conduct of several successful controlled studies on the safety and the efficacy of new11,–,14 and old drugs15,–,17 in paediatric rheumatic diseases. In addition, these two networks have provided the methodological framework, in terms of study design and primary outcome standardisation,18 19 accepted by both the US Food and Drug Administration and the EMA, for conducting phase II/III clinical trials in the major paediatric rheumatic diseases20,–,23 as well as providing standardised translated website information to families (www.pediatric-rheumatology.printo.it)24 and training to young researchers.1 There is no doubt that the controlled studies carried out in collaboration with the pharmaceutical industries are the best examples11,–,14 25 of the success of the US and European paediatric legislations.
The Paediatric European Network for Treatment of AIDS (PENTA; www.pentatrials.org) was established 20 years ago as a collaboration between paediatric HIV centres in Europe. Trials are principally funded by the European Commission and governmental bodies in a number of European countries and by support from the pharmaceutical industry. PENTA has successfully completed 10 large multicentre trials, a number of which have been important in antiretroviral registration. The group has focused on strategic trials, answering specific questions in children such as when to start and stop treatment, and the optimal drug combination. The network has developed a widely varied programme of education, guidelines and clinical support in addition to collaborating internationally with major cohort studies. The PENTA foundation for the treatment and care of children with HIV serves as an umbrella for the PENTA clinical trials network and is now extending its role to other infectious diseases.26,–,31
Pros and cons
Disease-oriented networks represent the majority of the collaborating groups identified by the EMA; they are usually internationally based with liaisons outside Europe. These networks have the advantage of providing facilities and a one-stop access to disease-oriented paediatric centres knowledgeable about the disease under study. For pharmaceutical industries, these networks offer the possibility to provide expert opinions on protocol development, trial implementation and results reporting. The community of specialists belonging to these networks are usually linked to each other academically, enhancing the possibility for rapid and efficient health information exchange and for study success. The disadvantage is that they require a duplication of the same structured organisation for many of the paediatric specialties therefore raising the associated costs.
Examples of age-related networks
Possibly the best example of age-related paediatric networks are the neonatal networks that have been developed at the regional, national or international level in Europe and other parts of the world.32 Most of these networks offer benchmarking and quality improvement initiatives to participating neonatal units, but some have also developed pharmaceutical and non-pharmaceutical clinical trials.33 In Europe, there is only one neonatal network at a European level, EuroNeoNet (www.euroneonet.org) that has been funded by the European Commission, Direction Générale de la Santé et des Consommateurs (DG SANCO) (projects EuroNeoStat I and II). More than 150 neonatal intensive care units from most European countries34 have joined this network, with a plan to set up a platform to design, promote and conduct neonatal trials.33
Other examples include the European Society for Developmental Perinatal and Pediatric Pharmacology (www.esdppp.org), the Treat Infections in Neonates initiatives (TINN2; www.tinn2-project.org) and the European Society for Paediatric Research that has recently established a section on Paediatric and Neonatal Pharmacology to promote drug studies in neonates, children and adolescents (www.espr.info/paediatric-research/Pages/Sections.aspx).
Pros and cons
These networks offer comparison of standardised perinatal, neonatal and neurodevelopment outcomes from a large number of neonatal units that could facilitate the performance of trials at a global level. An inconvenience is that not all networks use the same indicators; however, an international harmonisation process is being developed under the Global Research in Paediatrics project (www.grip-network.org) funded under the EC 7th Framework Programme.
The methodological approach of the EMA
As reported in the Introduction, the EMA was tasked by the EU paediatric legislation2 to foster the development of a European network of paediatric networks, named Enpr-EMA.
Enpr-EMA will not function as a clinical research organisation nor will it decide on paediatric research priorities, but rather it will promote high quality research, by strengthening collaboration among high quality networks, and facilitate communication, build competencies and define scientific and operational quality standards through application of rigorous recognition criteria.
Following the publication of the implementing strategy, the EMA35 convened several meetings and formed two working groups.
The first working group was charged with producing a structure and operational model for Enpr-EMA. Enpr-EMA will have a standing coordinating group of no more than 20 members: 2 from the Paediatric Committee and 18 members of existing networks fulfilling the recognition criteria.
The second working group dealt with quality standards and recognition criteria for inclusion in Enpr-EMA that were derived by consensus formation techniques (Delphi and nominal group techniques).36 37 The six criteria are reported in online supplementary table 1. In addition, a minimum set of criteria to be fulfilled in order to become a member of Enpr-EMA was adopted in March 201038 (see online supplementary table 1). The implementation strategy foresaw that networks would assess themselves and that these self-assessments would be reviewed with supporting evidence and then published by the EMA. Following the publication of these recognition criteria, 32 networks submitted their self-assessment reports to the EMA.4 Three categories of networks were identified: category 1 networks fulfilling all minimum criteria for membership of Enpr-EMA; category 2 networks potentially fulfilling all minimum criteria but in need of clarifying some issues before becoming a member of Enpr-EMA; and category 3 networks currently not yet fulfilling minimum criteria (see online supplementary table 1). Eighteen networks (10 disease-oriented) fulfilled the minimum criteria and therefore became members of Enpr-EMA39 40 (see online supplementary table 2). The most frequent reasons for failure to meet all minimum criteria included lack of internal databases with adequate data security, lack of training facilities and lack of involvement of patient organisations.
To date, the main tasks identified for the Enpr-EMA coordinating group include assisting industry in identifying high quality paediatric clinical study sites, collaborating with the Paediatric Committee of the EMA in developing model paediatric investigation plans, identifying further networks capable of meeting Enpr-EMA recognition criteria, developing educational tools for patients/parents and promoting participation in paediatric trials.
Conclusions
The bringing together of several European paediatric networks under the umbrella of Enpr-EMA has established a resource aimed at enhancing the development of medicines and the conduct of high quality clinical trials in children. It is anticipated that Enpr-EMA will facilitate productive collaborations between pharmaceutical companies, regulators and paediatric academia in Europe and globally. There is increasing recognition globally of the need to coordinate study design, disease definitions and clinical end points internationally. It is anticipated that Enpr-EMA can act as part of this process of harmonisation of clinical trials methodology for the overall benefit of children.
References
Supplementary materials
Supplementary Data
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Footnotes
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.