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Rheumatology Advance Access originally published online on March 11, 2008
Rheumatology 2008 47(5):563-566; doi:10.1093/rheumatology/ken055
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

Improving the evidence base for treatment of juvenile idiopathic arthritis: the challenge and opportunity facing the MCRN/ARC Paediatric Rheumatology Clinical Studies Group

J. Thornton1, M. W. Beresford2 and P. Clayton1,3

1Greater Manchester, Lancashire and South Cumbria Medicines for Children Research Network, Royal Manchester Children's Hospital, Pendlebury, Manchester M27 4HA, 2Medicines for Children Research Network/Arthritis Research Campaign Paediatric Rheumatology Clinical Studies Group, University of Liverpool Division of Child Health, Royal Liverpool Children's Hospital, Alder Hey, Liverpool L12 2AP and 3Department of Child Health and Paediatric Endocrinology, University of Manchester, Manchester, UK.

Correspondence to: J. Thornton, Greater Manchester, Lancashire and South Cumbria Medicines for Children Research Network, 2nd floor, Colwyn House, Royal Manchester Children's Hospital, Pendlebury, Manchester M27 4HA, UK. E-mail: judith.thornton{at}cmmc.nhs.uk

One of the greatest challenges facing paediatric rheumatologists in the care of children with complex, unusual, chronic, auto-immune, often multi-system diseases is the striking paucity of a rigorous evidence base for their treatment. Juvenile idiopathic arthritis (JIA) is the commonest among such conditions and has been the predominant focus of clinical research to-date. In the past decade, there have been significant advances in therapy with the development of new treatments including biologic disease-modifying agents, which have resulted in significant changes in its management. Despite this, there is very little evidence upon which therapy of children with JIA can be based [1].

A recent systematic review of controlled studies in JIA identified only 34 relevant studies conducted across all JIA subtypes and all pharmacological interventions, but excluded management of uveitis [2]. There were 14 studies of all non-steroidal anti-inflammatory drugs (NSAIDs) 13 studies of DMARDs with only three examining methotrexate, one study of intravenous corticosteroids, three studies of intra-articular corticosteroid injections, two of intravenous immunoglobulin and just one using anti-cytokine biologic therapy (etanercept). The various subtypes of JIA differ considerably in symptoms and response to treatment. For children with polyarthritis, NSAIDS were found to be effective in fewer than 25% of children, intra-articular corticosteroids in 25–50%, and methotrexate and etanercept in more than 50% [2]. For children with oligoarthritis, NSAIDs were effective in up to 50% of children, intra-articular corticosteroids in more than 50%, but effectiveness of DMARDS and biologic agents remained unclear or unknown [2]. The review emphasized the minimal level of evidence available for the management of children with systemic and enthesitis-related subtypes [2]. In the paper published in this issue of Rheumatology, Abrahamyam et al. [3] have continued exploring these issues and have evaluated the quality of studies in JIA published between 1996 and 2005. They identified 52 randomized controlled trials (RCTs) of pharmacological and non-pharmacological interventions, and also included management of complications such as uveitis. They applied pre-defined quality indicators including how the allocation sequence for randomization was generated and implemented, how participants and investigators were masked to allocation, whether an intention-to-treat (ITT) analysis was undertaken, whether the primary outcome was clearly defined and the dropout rate from the study was determined. Generation and reporting of allocation sequence and masking were mostly unclear and/or inadequate, only 48% of studies specified the primary outcome, only 37% of studies employed an ITT analysis and dropout rates were high (15%). They concluded that despite some positive improvements over time, the quality of RCTs in JIA was poor and that significant improvements in methodology and study design are needed.

The management of rheumatic disease has been revolutionized with the recent advent of biologic therapies such as monoclonal antibodies and fusion proteins [4]. Despite more specific therapeutic targeting, these agents can be associated with rare but severe adverse events. This underlines the importance of determining their efficacy, toxicity and pharmacodynamics [4]. Increasing off-label use of biologic therapies in paediatric rheumatological diseases has recently been outlined by a systematic review of their use in the treatment of JIA [5]. The authors identified just one RCT and six uncontrolled prospective studies supporting the general efficacy of etanercept for the treatment of polyarticular JIA. They highlighted major gaps in the evidence for other biological therapy in JIA as well as significant methodological issues with published series.

Results of a recently published randomized placebo-controlled, double-blind study of 122 children with persistent polyarticular JIA despite previous methotrexate treatment [6], illustrated some of the major challenges faced by the paediatric rheumatology community in establishing an evidence base for the use of biologic therapies in JIA and other rheumatic disease. Despite international, multicentre collaboration, the studies failed to demonstrate a statistically significant difference between infliximab-treated and placebo-treated patients although they provided evidence of durable efficacy at 1 year. Data for the use of abatacept [7, 8] and adalimumab [9, 10] in JIA have been reported (in abstract form to date) as a result of significant international collaborative efforts.

It is noteworthy that there are no published RCTs in other important paediatric rheumatological conditions such as juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM) and childhood scleroderma. All of these conditions are debilitating chronic diseases with significant effects on function and health-related quality of life of children. Even with remission, the effects of the disease can persist into adulthood [11–13]. Early intensive, multi-disciplinary management is needed to reduce damage and achieve the best outcomes. Improved understanding of the pathogenesis of JIA has been a driving force for the development of targeted therapies. The same is true for many of the other paediatric rheumatic diseases such as JSLE in which many new therapeutic regimens such as B-cell depletion are already in use in many centres without a robust evidence base for their efficacy, safety and toxicity [14].

The lack of a strong evidence base for treating JIA, JSLE and other paediatric rheumatic diseases including JDM and childhood scleroderma undermines significantly the clinician's confidence in managing children often with life-long conditions and significant associated morbidity and morbidity. Clinicians are often reliant on translating adult data to childhood diseases with additional confounding factors including growth and puberty and longer life expectancy where side effects of medications are of particular relevance [1]. Patients, parents and clinicians are therefore faced with making important therapeutic decisions based on a striking paucity of evidence.

To study uncommon diseases such as JIA, multi-centre collaborations are needed to increase the acceptability of study protocols, to increase enrolment and to increase study numbers [1]. Several such well-established groups have been developed internationally including the Paediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO) [15]. The aim of these groups is to facilitate the conduct of trials in children with rheumatic diseases [1]. Other organizations including the British Society Paediatric and Adolescent Rheumatology, the UK JSLE Study Group [16], the Paediatric Rheumatology European Society, the North American Collaborative Study Group and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) promote and facilitate an active collaborative research agenda [1]. The creation of international trial networks have facilitated the development of internationally recognized and standardized outcome measures and definitions of improvement in JIA and allowed the conduct of some pioneering RCTs in JIA. Such collaborations form the basis of ensuring children with paediatric rheumatic diseases have the same opportunities as adults to be treated with medications whose safety and efficacy have been assessed through appropriate scientific means [15].

The problem of poor evidence is not unique to JIA and is endemic throughout the management of paediatric disease. Of 4897 RCTs published in general medical journals, 14% were classified as paediatric compared with 68% as adult and 18% in both age groups [17]. Campbell reviewed 249 RCTs among children published in Archives of Diseases in Childhood [18]. Most studies recruited only small numbers of children and many reports gave insufficient information to allow quality to be assessed. Of 1496 Cochrane Database Systematic Reviews investigating an intervention for a condition occurring in both children and adults, only 52% included data from children and many studies failed to report sufficient data for quality to be assessed [19].

Evidence-based treatment is compromised by the lack of clinical trials across the spectrum of medicines for children. More than 50% of medicines used by children are not tested and authorized specifically for their use [20–23]. Consequently, children are denied innovation and their health is harmed because of lack of information, lack of quality, unknown safety profiles, unknown efficacy [24] and lack of appropriate pharmaceutical formulations [25, 26]. The problems of conducting studies in paediatrics and particularly JIA include: small numbers of subjects and patient accrual to trials, individualized treatment approaches needed in complex diseases, the length of time taken for objective outcomes to develop, trial costs and ethical concerns about randomizing children to placebo. There are many case series but few rigorous treatment studies [1, 3]. Because of the smaller market, there have been few financial rewards for pharmaceutical companies to study their medicines on children.

The challenge faced by clinicians and allied health providers looking after children with JIA and other paediatric rheumatic diseases of childhood is to strategically collaborate with all disciplines of relevant expertise. In this way, all diagnosed children will be given an opportunity to participate in a research protocol of the highest scientific and ethical standard in order to advance safe treatment and cure of their disease.

Thankfully, new European legislation may have an enormous impact on how paediatric medicines are studied [27]. The US Food and Drugs Administration (FDA) set the scene by increasing the numbers of paediatric clinical trials through the "paediatric exclusivity’ provision in the FDA Act 1997 with incentives for studies in children through patent protection [28]. Subsequent European Union legislation was implemented in January 2007 [29]. The objective of the legislation is to improve the health of children in Europe by increasing high quality, ethical research into medicines for children, increasing availability of authorized medicines for children and increasing information on medicines. All applications to the regulatory authorities for licensing of new medicines must now contain a Paediatric Investigation Plan (PIP). The PIP describes how the medicine will be developed for use in children and must include details of the measures proposed to demonstrate quality, safety and efficacy as well as any measures needed to adapt the formulation for administration to children. Companies are given incentives to encourage them to test medicines in children through patent protection.

In parallel with the European legislation, the UK Department of Health launched ‘Best Research for Best Health’ [30]. One component of this initiative was the formation of research networks in priority health areas. This led to the establishment of the National Institute for Health Research (NIHR) Medicines for Children Research Network (MCRN) (http://mcrn.org.uk/) [31]. The MCRN has been created to improve the co-ordination, speed and quality of RCTs and other well-designed studies of medicines for children and adolescents, including those for prevention, diagnosis and treatment. The goal is to produce high-quality research findings so that children receive new and better treatments and clinicians have real evidence on what to base their decisions [31]. The network has extensive knowledge and experience of paediatric research, and supports non-commercial, pharmaceutical/biotech-sponsored and investigator-led partnership studies through six regionally based local research networks (LRNs).

The MCRN does not fund studies but may adopt studies that are awarded funding in open, national competition and are peer-reviewed. Current examples of paediatric rheumatology studies adopted by the MCRN include: Prevention and Treatment of Steroid-induced Osteopenia in Children and Adolescents with Rheumatic Diseases (POPS Study); the Study of the Immunological and Genetic Mechanisms of Response, and Psychological Response to, Standard Disease Management in JIA (SPARKS CHARMS Study); and the UK JSLE Cohort Study and Repository (http://public.ukcrn.org.uk/search/Portfolio.aspx?Level1=4). Adopted studies are eligible for LRN support that provides practical assistance to researchers such as streamlined set up and management of studies, helps with recruitment and data collection, support of LRN research nurses, and provides training and education for all staff involved (Table 1). The MCRN Clinical Trials Unit has specific expertise in paediatric trials and can provide expertise in trial design, data management and approval processes. Of particular importance is the fact that any study adopted by the MCRN will be automatically eligible for service support costs. It should be noted that in areas of the UK not covered by the MCRN LRNs, support for clinical trials is available from the NIHR Comprehensive Clinical Research Network (CCRN) (http://www.ukcrn.org.uk/index/networks.html).


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  		TABLE 1. Support available from local research networks of the UK Clinical Research Network (http://www.ukcrn.org.uk/index/networks.html)

 
Because of the relative paucity of clinical trials involving children, the task of developing a portfolio of trials of medicines for children presents challenges but also exciting opportunities to develop a new research agenda where previously little has existed. The MCRN Clinical Studies Groups (CSGs) across specific disease areas were established to facilitate this process. The CSGs bring together multi-disciplinary expertise including research nurses, allied health professionals, consumers and representatives from the pharmaceutical industry. However, the MCRN CSGs have limited core funding support [31]. They were conceived in the hope of forging close links with academic and clinical communities and in particular medical research charities, patients and the public in order to help drive a research portfolio in disease areas including musculoskeletal disease.

Recently, the UK Arthritis Research Campaign (ARC) has launched a new paradigm for its support of clinical trials and related studies in the UK including paediatrics [32]. In establishing and supporting seven CSGs (including one specifically for paediatric rheumatology) and in partnership with industry and consumers, ARC aims to optimize its efforts through the enhanced support offered by the CCRN.

This close collaboration is illustrated by the model of partnership between the MCRN and ARC in forming the unique MCRN/ARC Paediatric Rheumatology CSG (http://www.arc-research.org.uk/med_director/clintrialsinit.asp; http://www.mcrn.org.uk) (Fig. 1). This CSG will have a dual role of both advising the MCRN and ARC of research priorities in paediatric rheumatology and developing a comprehensive, integrated, long-lasting research programme for paediatric rheumatology in the UK. The remit of the MCRN/ARC Paediatric Rheumatology CSG includes:

  • To be responsible for developing and overseeing a comprehensive portfolio for clinical trials and related studies covering the spectrum of major disease areas in paediatric rheumatology.
  • To propose and develop protocols for trials and related studies.
  • To provide robust scientific evaluation, expert advice and support to investigators.
  • To ensure consumer involvement in all activities.
  • To uphold the highest standards of Research Governance and Good Clinical Practice.


Figure 1
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  		FIG. 1. The MCRN/ARC Paediatric Rheumatology CSG: the partnership, role and collaborative links. UKCRN, UK Clinical Research Network; CTU, clinical trials unit; BSPAR, British Society for Paediatric and Adolescent Rheumatologists; ARC, Arthritis Research Campaign.

 
The priority for the new CSG and the significant opportunity it offers to improving the evidence base for JIA and related disorders is the development of a comprehensive, nationally agreed and scientifically robust research strategy for clinical trials and related studies in paediatric rheumatology through wide-ranging consultation with relevant stakeholders. This will lead to testing of both new and existing interventions across the major rheumatological diseases affecting children. Topic-specific groups will be established and supported for the task of developing of key research themes. These groups will gather under disease-specific groupings (e.g. JIA) or themes of intervention. In these environments, multi-disciplinary expertise will inform project development including access to clinical research infrastructure support such as experts in statistics, trial design and data management, pharmacy and formulations, basic science and genetics, as well as consumer representation. The CSG therefore has the opportunity to respond proactively towards the paucity of robust evidence for the treatment of JIA and other paediatric rheumatological diseases, and ensure the highest quality of clinical trials that is highlighted so clearly by Abrahamyam et al. [3] in this edition.

Partnership between a committed research charity funder closely integrated with the MCRN and UK CCRN will enable the CSG to define, develop and access the research support needed for both commercial and non-commercial studies in JIA and other related paediatric diseases. As an integrated national research network it will be in an excellent position to collaborate closely with international trial networks (e.g. PRINTO, PRCSG) while fostering its unique contribution to the transformation of clinical practice by driving both knowledge advance and quality of care of patients with JIA.

Disclosure statement: The authors have declared no conflicts of interest.

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Accepted 23 January 2008


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