Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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Recital 33 and Article 44 of the Paediatric Regulation (Regulation (EC) No 1901/2006)1 recently approved by the European Parliament states: “Clinical trials in the paediatric population may require specific expertise… methodology… facilities and should be carried out by appropriately trained investigators”, and “The agency [ie, the European Medicine Agency, EMA] shall… develop a European network of existing national and European networks… “with the goal to facilitate co-operation and to avoid duplication of studies and provide… expertise for industry”. This statement summarises well one of the main problems in conducting research in the paediatric population, that is, the need for well-structured networks in order to counterbalance the low prevalence of many paediatric diseases, the scarce resources and the fragmentation of centres dealing with just a few patients, especially for rare diseases.
As an example, paediatric rheumatic diseases (PRDs) are rare conditions associated with substantial morbidity, which can have severe repercussions on quality of life and result in a heavy financial burden. Conducting clinical trials in PRDs has proven difficult for numerous reasons. Due to the low prevalence of these diseases, multicentre studies performed on an international scale represent the only possibility of gathering 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 for ethical (parents often refuse enrolment into studies because they are uncomfortable with the prospect of their child being assigned by chance to placebo, especially when an alternative treatment is available),2 childhood-specific (lack of adequate methods to assess response to therapy, lack of adequate paediatric formulations, need for specific study designs)3 4 and funding-related (lack of interest from the pharmaceutical industry due to the small potential market, limited funding for academic paediatric studies) reasons. The result is that, until recently, data regarding the safety and effectiveness of available treatment regimens tended to be from small, open, anecdotal, uncontrolled, non-randomised case series.
What is already known on this topic
▶ There is a need for networks to counterbalance the low prevalence of paediatric diseases, scarce resources and fragmentation of centres.
▶ Conducting trials in paediatric rheumatic diseases (PRDs) is difficult because of low prevalence, lack of interest from pharmaceutical companies, and ethical, childhood-specific and funding-related problems.
What this study adds
▶ Two very large international networks – the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG) – have been pivotal for the conduction of successful controlled studies in PRDs.
▶ The PRINTO and PRCSG networks can be seen as a model for international cooperation in other paediatric subspecialties.
The situation radically changed about 10 years ago when the United States Congress first, and more recently the European Parliament, approved adequate paediatric legislation.1 5 The Food and Drug Administration (FDA) and the European Medicine Agency (EMA) have been delegated the task of implementing such legislation. According to this legislation, any company that wishes to register a new drug for use in adults has also to provide data on the safety and efficacy of this drug in children, if there is a disease in children similar to that for which the registration is requested in adults. In compensation, the company is granted some benefits, the most important being a 6-month extension of the patent.
The field of paediatric rheumatology was able to take immediate advantage of the approval of paediatric legislation in the USA because there were already two international networks working in close collaboration. One is the Pediatric Rheumatology Collaborative Study Group (PRCSG at http://www.prcsg.org), covering the paediatric rheumatology centres of North America and based in Cincinnati, Ohio, USA. The other is the Paediatric Rheumatology International Trials Organisation (PRINTO at http://www.printo.it), whose activities form the subject of this review.
PRINTO was founded by the two authors in 1996 and initially included members from 14 European countries. PRINTO aims are to facilitate and coordinate the development, conduct, analysis and reporting of clinical trials and outcome assessment standardisation in children with PRDs. It was founded with the idea of performing clinical trials for the PRDs, with or without the support of pharmaceutical companies. In general, if a study is not supported by a pharmaceutical company, the design is that of a randomised, actively controlled and open-label clinical trial. More classic designs are used if the study is supported by a pharmaceutical company and is part of a clinical development programme aimed at marketing an agent.
PRINTO is composed of paediatric rheumatology centres actively engaged in research and the clinical care of children with PRDs. It includes more than 300 centres from more than 50 countries and covers Europe as well as the rest of the world with the exception of North America (which is covered by the PRCSG). PRINTO has four main vertical structures: a Scientific Advisory Council; an International Coordinating Centre, whose main task is to facilitate the flow of logistic and scientific details needed to design, launch and manage multicentre, multinational, collaborative studies; the National Coordinating Centres (one per country), whose tasks are to facilitate the participation of as many as possible individual centres and to provide translations of all the forms to be completed by parents/patients; and finally the individual clinical sites, which constitute the main support structure to obtain a critical mass of data for on-going and future research.
In recent years PRINTO and the PRCSG have worked closely in various international collaborative projects (see below), whose general philosophy has been a bottom-up approach that has included the standardisation of measures to evaluate response to therapy in the major PRD, academic studies (table 1) and studies in collaboration with the pharmaceutical industry (table 2), training of young researchers, provision of the network facilities to members for the conduct of collaborative research projects and the creation of a website with health information for families.
Development of criteria for the assessment of clinical response in juvenile idiopathic arthritis
Until the late 1990s, the assessment of clinical response in juvenile idiopathic arthritis (JIA)6 was not standardised and multiple measures of outcome were in use and different trials had different end points. In 1997, the first combined effort conducted by the PRCSG and PRINTO, under the guidance of Dr EH Giannini, led to the development and publication of internationally accepted validated criteria to evaluate response to therapy in JIA, now known as the American College of Rheumatology (ACR) Paediatric criteria.7 According to the ACR Paediatric criteria, patients are considered responders to a given therapy if they demonstrate at least a 30% improvement from baseline in at least three of any six JIA core set variables, with no more than one of the remaining variables worsening by more than 30%. The ACR Paediatric criteria allow researchers and clinicians to dichotomise patients into responders and non-responders. Commonly, patients also are evaluated for ACR Paediatric 50, 70, 90 and 100 levels of response (at least 50–70% to 90–100% improvement, respectively, in at least three of any six JIA core set variables with no more than one of the remaining variables worsening by >30%).
The ACR Paediatric criteria are now accepted by both the FDA and the EMA for all phase III trials in JIA seeking drug registration.
Methotrexate in JIA
The use of methotrexate (MTX) in JIA is a successful paediatric story entirely written by academic researchers without any (or very minimal) support from industry.
After the pivotal trial published by Giannini et al,8 and the confirmatory trial by Woo et al,9 MTX, at the standard dose of 10 mg/m2/week, became the first choice disease-modifying agent in polyarticular course JIA. Later PRINTO, supported by the European Union (contract BMH4 983531), with a randomised, open-label standard-of-care trial demonstrated that the plateau of efficacy of MTX in JIA is reached with the parenteral administration of 15 mg/m2/week and that further increase in dosage is not associated with any additional therapeutic benefit.10
More recently, PRINTO was also able to complete another trial to show that in patients with JIA in remission, a 12- versus 6-month withdrawal of MTX did not reduce the relapse rate and that higher MRP8/14 concentrations, a marker of phagocyte activation, were associated with risk of relapse after discontinuing the drug.11 This trial also helped to demonstrate the feasibility of implementing a bio-bank by collecting biological samples from a large number of PRINTO centres.
Trials for the registration of new drugs
As a result of the paediatric legislation, several clinical trials supported entirely by pharmaceutical companies have been completed in children with JIA, others are in progress and some are in development, all in close collaboration with the PRCSG.
PRINTO and the PRCSG are involved at all levels, from writing the protocol, case report form development, centre selection, training and certification (eg, joint assessment in JIA), independent evaluation of study primary outcome,12 monitoring, analysis and data reporting. As a result, almost all trials in the past few years (meloxicam, infliximab, adalimumab, abatacept, canakinumab, tocilizumab and others to come)12,–,17 have been conducted or are under way through PRINTO and PRCSG membership (table 2).
In addition, PRINTO acts as a sort of central negotiator with pharmaceutical companies in order to establish a minimum per-patient fee to be offered to all participating centres, independently of the local socioeconomic situation. This is done on account of the peculiarities of childhood trials (eg, most centres have very limited human resources)18 and the difficulties for small centres to adequately deal with contract negotiation with the pharmaceutical industry. The rationale behind all this is to obtain additional financial resources, either locally for the centres or centrally at PRINTO level, to be reinvested for academic studies that will never be supported by the industry or other funding agencies.
The quality of life project for PRD
A particular issue for the conduct of international studies was the absence of parent/patient reported outcome for functional ability and quality of life assessment. Thanks to the European Union (contract BMH4 983531), PRINTO has been able to cross-culturally adapt and validate two questionnaires: the Childhood Health Assessment Questionnaire (CHAQ) for functional ability assessment in JIA, juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE) and the Child Health Questionnaire (CHQ) for health-related quality of life (HRQL) evaluation for all PRDs. A total of 6644 subjects (3235 patients with JIA and 3409 healthy children) were enrolled in the project and 32 validated versions of the CHAQ and CHQ are now available.19 20
More recently, PRINTO has decided to develop a more user-friendly multidimensional questionnaire for the assessment of children with JIA in standard clinical care, which incorporates the traditional parent and patient reported outcomes (functional ability, HRQL, overall well-being, pain) and some parent and patient reported outcomes not assessed by conventional measures (morning stiffness, rating of disease course over time, proxy or self-assessment of joint involvement, description of side effects of medications and assessment of therapeutic compliance and satisfaction with the outcome of the illness).21 22
Disease activity and damage assessment in JSLE and JDM and related trials
Once the problem of a standardised approach for the evaluation of response to therapy in JIA was resolved, the logical follow-up was to conduct a similar project for two other chronic PRDs, JSLE and JDM. With a second grant from the European Union (contract no. QLG1-CT-2000-00514), PRINTO has been able to propose validated core sets for the evaluation of disease activity and damage23,–,25 and also definitions of improvement to be used in future clinical trials in JSLE26 and JDM.25 27 Data on 294 patients with JDM and 557 patients with JSLE were collected from 41 countries. These projects have been officially endorsed by the ACR and the European League Against Rheumatism (EULAR) and are now known as the PRINTO core set24 and PRINTO/ACR definition of improvement for JSLE26 and the PRINTO/ACR/EULAR core set for JDM25 and PRINTO definition of improvement for JDM.27
Because of the availability of response to therapy criteria in JDM and thanks to a grant from the Italian Agency of Drug Evaluation (AIFA), PRINTO is now conducting the first interventional trial in untreated children with JDM, where subjects are randomised to three different treatment strategies: prednisone alone versus prednisone plus cyclosporine A versus prednisone plus MTX. The overall goal is to establish if combination therapy is superior to treatment with steroids alone in preventing flares once patients have reached clinical remission. As of today, the trial has enrolled 135 patients from 24 countries.
Research training in paediatric rheumatology
Good collaborative clinical research requires qualified people around the world able to conduct studies in a standardised fashion. PRINTO, with another grant from the European Union (contract no. AML/B7-311/97/0666/II-0246-FI), and more recently with funding from EULAR, PRINTO internal funding and other sources, has set up a research training programme in paediatric rheumatology to support medical research (since the beginning, more than 80 fellows from 24 different countries have been involved). The goal is to provide the basis for setting up research projects and to harmonise outcome assessment of patients participating in common collaborative studies as demonstrated by the many resulting publications (available at http://www.printo.it).
PRINTO as a research service tool
In the last few years, principal investigators from different countries belonging to the network have been allowed use the central PRINTO research facilities to implement collaborative research projects. The underlying rationale is that once a researcher has an idea for a project and this is endorsed by the network, PRINTO will help, through the central facilities of the international coordinating centres located in Genoa, to formalise the study protocol and related case report forms, develop a web-based data collection system, and assist in the practical implementation of the data collection (including liaison with ethics committees), as well as in the data analysis and related reporting. The projects so far concluded or still to be implemented include the above-mentioned study on MTX withdrawal,11 the validation of new classification criteria for childhood vasculitides,28 29 a Paediatric Rheumatology European Society (PRES) registry for autoinflammatory syndromes (EU funding) and a PRES pharmacovigilance registry (EU funding) to evaluate the long-term safety and efficacy of biological agents in JIA.
A website for families of children with PRDs
The widespread availability of internet access allows families retrieve medical information quickly and easily, but this information is often not standardised, inaccurate and unreliable. To address this problem, PRINTO in collaboration with PRES, and again supported by the European Union (contract 2001CVG4-808), set up a website directed to families containing consensus-defined information about PRDs (in the format of Frequently Asked Questions) as well as the list of paediatric rheumatology centres and family help associations in each country. All information is available in more than 50 languages (http://www.printo.it/pediatric-rheumatology/).18 The website has been very successful, with more than 11 000 people connecting everyday from over 130 countries.
How to deal with difficulties associated with obtaining approvals to conduct studies in multiple countries
One of the advantages of the PRINTO network is the worldwide in-house experience gained from the implementation of not-for-profit and profit trials in the past few years. Table 3 has been prepared by PRINTO based on experience from past collaborative study (see tables 1 and 2). It shows the diverse requirements of regulatory authorities in different countries participating in previous PRINTO studies for undertaking an interventional study with medicinal products in children. The table is the result of the knowledge acquired by PRINTO while implementing the not-for-profit trial conducted in children with JDM with the support of AIFA (briefly described below). In this regard, it is worthwhile noting that it took PRINTO more than 2 years to obtain approval from 102 different ethics committees, with only four ethics committees which refused the approval. It took approximately 2 years to enroll 135 patients from 24 different countries. Such a huge administrative burden highlights the difficulties of conducting paediatric studies without the support of pharmaceutical companies and the ‘ethicity’ of discussing the same protocol more than 100 different times. Similar concern can be expressed regarding other requirements that sometimes are demanded, such as proper insurance coverage or the need for local monitoring, that often hampers the practical implementation of paediatric studies. Simplification of this large administrative burden will surely help the implementation of trials in children. An example of such simplification would be the adoption of adequate simplified legislation binding all countries of the European Union (eg, by requesting a single qualified ethics committee approval valid for all participating centres such as is now the case in France), instead of the current non-binding ethical recommendation.30
In addition to the adoption of adequate legislative measures, the presence of very large international trial networks such as PRINTO and the PRCSG has played a key role in the implementation of successful controlled studies on the safety and efficacy of new and old drugs in PRDs. These networks have provided a central research facility with specific competences, allowed for the rapid collection of suitable sample sizes, defined internationally recognised and standardised outcome measures and provided definitions of improvement for JIA, JSLE and JDM, cross-cultural adapted and validated functional and quality of life instruments, research training in clinical trials for paediatric rheumatologists as well as information on PRDs for families all over the world. This has resulted in the rapid and effective implementation of several profit as well as not-for-profit controlled trials in childhood rheumatic diseases. The PRINTO and PRCSG networks can be seen as a model for international collaboration in other paediatric subspecialties.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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