Competing demands for scarce healthcare resources have accentuated the requirement for routine clinical practice to be evidence-based. One of the benchmarks for evidence-based medicine is the appropriately conducted randomized controlled trial (RCT). Although epidemiological studies, whether casecontrol or cohort in design, have contributed enormously to the generation of hypotheses and permit the controlled evaluation of therapeutic interventions, they are susceptible to biases through selection, information ascertainment and confounding. While RCTs are also susceptible to such biases, the process of randomization and of blinded evaluation of outcomes permits the closest approximation in clinical research to the conduct of a hypothesis-testing laboratory experiment. Historically, there have been several obstacles to the execution of high-quality RCTs to address important rheumatological questions. One of the most important of these has been the practical difficulty entailed in prioritizing ideas for such trials, and in moving these through the design, execution, analysis and publication stages necessary for completion; this task becomes all the more daunting when busy practitioners are limited in their time, resources and supporting infrastructure.
In order to address this issue, the Arthritis Research Campaign (ARC) and British Society for Rheumatology (BSR) established a Clinical Trials Collaboration (CTC) in 1997. This utilized strategies previously employed by other disciplines, most notably cancer care, to: (i) solicit ideas and evaluate proposals for multicentre clinical trials in rheumatology and relevant related disciplines; (ii) monitor trial progress and provide a central database of participants and funding streams; (iii) supervise the Trial Steering Committee (TSC) and Data Monitoring and Ethics Committee (DMEC) for each trial; (iv) provide advice on protocol design for any individual seeking support from the Arthritis Research Campaign for clinical trials; and (v) provide educational support in clinical trial methodology. Trials were evaluated which were either based in a single centre and lasted 5 years or longer; or were multicentre and lasted between 3 and 5 years. The committee consists of a Chair and Vice-Chair with representatives from the British Society for Rheumatology, Medical Research Council (MRC), British Orthopaedics Association (BOA), NHS Research & Development Directorate, and Arthritis Research Campaign, as well as including 12 ordinary members. The work is supported by an executive secretary and Mrs Caroline Doré, the Arthritis Research Campaign's statistician, based at the MRC Clinical Trials Unit.
The CTC issues an annual call for outline proposals. These are scored by members of the Committee for originality, feasibility and importance to rheumatology. Successful outline applications are assigned mentors (who often progress to the chair of the Trial Steering Committee), and the investigators are invited to submit a full application. This is peer reviewed by four external assessors and, based on the results of these reviews, a recommendation regarding support is made. Once approved, a DMEC subgroup is assigned to each trial and the TSC is formally constituted.
The remit of the TSC is to monitor and supervise trial progress on behalf of the CTC. It reviews and approves any protocol amendments and considers recommendations of the DMEC subgroup. It provides overall supervision for the trial; protecting the rights, safety and well-being of trial participants is its primary concern. The TSC should consist of an independent chair (often the mentor), two or more independent members, the principal investigator, main collaborators, trial statistician, lay/consumer representative if possible and the Arthritis Research Campaign's CTC statistician as an observer. Ideally, it should meet before the commencement of the trial to approve the trial protocol and patient information sheet, set targets for recruitment and review the plan of data collection. Thereafter, it meets annually to review trial progress.
The DMEC provides essential independent monitoring of all the trials funded by the Arthritis Research Campaign's CTC. Its main function is to protect patients by regularly monitoring safety and, if appropriate, efficacy data. In RCTs where mortality or severe morbidity is a major outcome measure, unblinded analysis of the safety and efficacy data may be necessary to safeguard the interests of trial participants; if one treatment arm is clearly superior to another, it is unethical to continue treating patients with an inferior treatment. Only the DMEC has access to the unblinded data analysis. The Arthritis Research Campaign's CTC has established a central DMEC (the first such initiative in the UK) to monitor trials funded by the CTC. For each trial, the central DMEC will select three members of its committee to form a DMEC subgroup. Members of this subgroup must be independent from the trial management team, and take the responsibility for monitoring individual trials.
To date, 10 trials have been supported (Table 1), at a total cost of around £4m. It is imperative for the continuing success of this initiative that all British rheumatologists consider the entry of their patients into such studies. In many instances, the trials address the management of relatively infrequent rheumatological disorders, so that the sample size required mandates recruitment from a large number of clinical practitioners. It would be a sad indictment of our specialty if such important studies were to flounder as a consequence of failure to refer our own patients to the investigating centres. The CTC represents a key platform in the Arthritis Research Campaign's 5-year strategy, which aims to increase the funding for translational research. Its research portfolio already covers a broad range of musculoskeletal disorders, and has provided the necessary supporting infrastructure and financial resource. It represents an opportunity for us to prove that rheumatology as a specialty is as capable of delivering high-quality randomized controlled trials as any other within medicine. Not only will such studies increase our scientific credentials, but they will also form the basis for improving the management of patients with rheumatic disease. We owe it to ourselves to ensure its success.
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Notes
Correspondence to: C. Cooper, MRC Environmental Epidemiology Unit, Southampton General Hospital, Southampton SO16 6YD, UK. E-mail: cc{at}mrc.soton.ac.uk
* Prof. C. Cooper, Chairman; Dr E. Choy, Vice-Chairman; Dr J. Camilleri, ARC Clinical Advisor, ARC; Dr J. Dacre, ARC Chairman of the Education Sub-Committee, ARC; Dr M. E. Devey, ARC Scientific Secretary, ARC; Mrs C. J. Doré, ARC Statistician, MRC CTU; Mr M. Patnick, ARC Head of Research and Education Funding, ARC; Miss S. Watkinson, ARC Executive Officer, ARC; Dr E. M. Hay, BSR Chairman Training and Research Committee, BSR; Dr T. Palferman, BSR Chairman Clinical Affairs, BSR; Prof. D. G. I. Scott, BSR President, BSR; Mr G. Giddins, British Orthopaedic Association, BOA; Prof. P. J. Gregg, British Orthopaedic Association, BOA; Prof. J. Darbyshire, Medical Research Council, MRC CTU; Prof. A. Nunn, Medical Research Council, MRC CTU; Prof. P. R. Croft, DMEC Chairman, DMEC; Dr M. Byron, DMEC Vice-Chairman, DMEC; Prof. D. Symmons, DMEC Member, DMEC; Prof. M. Boers, European Representative, General; Dr B. L. Hazleman, Vice-ChairmanFacilitative Network Groups, General; Dr M. Rooney, Paediatric Rheumatology, General; Dr R. Watts, EditorRheumatology, General; Dr G. Kingsley, Trust NHS R&D Director, General; Prof. C. Bailey, NHS R&D, General; Ms J. Taylor, BHPR, General; Dr H. A. Capell, Mentor, Ordinary; Dr V. Dhillon Mentor, Ordinary; Prof. D. O. Haskard, Mentor, Ordinary; Prof. D. A. Isenberg, Mentor, Ordinary; Dr M. E. Shipley, Mentor, Ordinary; Prof. D. R. Blake, Mentor, Ordinary