The primary systemic vasculitides (PSV) are clinically distinct diseases usually characterised by inflammation of the wall of the blood vessel without identifiable cause.
Owing to the rarity of PSV and the inherent diagnostic difficulties in these complex diseases, clinical research in the past was limited to single‐centre cohort studies or open‐label case series. However, substantial progress has been made in the past decade; firstly by the development of new diagnostic tools—for example, antineutrophil cytoplasm antibody (ANCA) serology—and secondly by the formation of collaborative research groups like the European Vasculitis Study (EUVAS) Group, the International Network for the Study of Systemic Vasculitis, the French Vasculitis Study Group and the Vasculitis Clinical Research Consortium (VCRC). Independently, these groups have conducted a number of randomised controlled clinical trials (RCTs) using standardised clinical measurement scores. The results of these trials have had a significant effect on patient care in clinical practice.1,2,3,4
Despite these improvements, there are still enough variations among these trials to make cross‐study comparisons difficult, and these variations impair extrapolations of results to treatment in everyday clinical practice. Among the most controversial differences between the respective studies were variations in the following: definitions of disease, disease stages, activity stages, outcome measures, duration of treatment, duration of observation and use of concomitant drugs.
Based on a proposal by EUVAS to the European Standing Committee for International clinical studies including therapeutics, a group of experts was formed, including members of EUVAS and VCRC. The aim of this working group was to formulate recommendations for conducting clinical trials in PSV. For the process of developing these recommendations, we used the European League Against Rheumatism (EULAR) standardised operating procedures for the elaboration, evaluation, dissemination and implementation of recommendations.5,6
Published evidence in the form of high‐quality RCTs was found primarily for vasculitides associated with ANCA. We therefore focused the recommendations on the ANCA‐associated vasculitides (AAV): Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CSS). However, many of the issues dealt with in these recommendations are likely to be relevant to other types of vasculitis, and these generic issues are outlined in the beginning of each section.
The aim of these recommendations is not to cover all general aspects related to planning and conducting a clinical trial, but rather to address critical issues that are specific for vasculitis. The general aspects of trial methodology are beyond the scope of these recommendations, and recommendations for good clinical practice and updates regarding legal requirements for conducting clinical trials should be closely followed. Requirements for the conduct of clinical trials in Europe, including good clinical practice, have been implemented in the European Clinical Trial Directive.7
Web pages of the health agencies contain further helpful advice (http://emea.eu.int;http://fda.gov;http://eudract.emea.eu.int
). Recommendations for standardised assessment of adverse events in rheumatology have been elaborated by the Outcome Measures in Rheumatology Drug Safety group.8
The European Commission recently published a regulation on the conditional approval of drugs for the treatment, prevention and diagnosis of seriously debilitating or life‐threatening diseases where there is an unmet clinical need.9
The PSV clearly fall within the scope of this document.
It is recommended that biostatisticians should be involved in the earliest stages of planning a clinical trial in PSV. The recommendations on design and outcomes in clinical trials in systemic sclerosis by the American College of Rheumatology (ACR) cover many relevant issues related to statistical analyses and sample‐size calculations in rare systemic autoimmune diseases, and should be considered in planning a trial in PSV.10
We would strongly recommend that trials in vasculitis, with the exception of pilot studies, should be undertaken only if sufficient number of patients can be recruited to satisfy the sample‐size requirements; this effectively means that almost all studies will need to be multicentred, thus further emphasising the need for standardisation of protocols and assessments.
This working group concentrated on the most controversial issues, including (1) definitions of disease and activity stages, (2) primary and secondary outcome measures, (3) eligibility criteria including a definition of clinically meaningful end points, (4) trial design and (5) use of biomarkers.