Randomized Controlled Trials of Biologics for Rheumatoid Arthritis
Disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis (RA) have been considered effective treatments that can reduce or prevent joint damage, thus preserving joint integrity and function.
This report [Arch Intern Med. 2012;172(3):237-244], compiled by 2 French physicians, aimed to answer whether there were inadequate head-to-head trials and fair control arms in recently conducted or ongoing randomized controlled trials of biologic DMARDs for RA. The authors wished to determine whether some patients had possibly not received correct therapies for their RA due to lack of trial data. To gather information for the study, the authors identified all protocols of randomized controlled trials of biologic DMARDs for RA, reported in ClinicalTrials.gov, that ended after 2002 and were dated as late as October 1, 2009.
They searched ClinicalTrials.gov with the terms interventional [study types] AND rheumatoid arthritis [disease] AND adult OR senior [age group] AND phase 3 OR phase 4 [phase]. Sulfasalazine, hydroxychloroquine sulfate, minocycline hydrochloride, and methotrexate were considered conventional DMARDs. Anti–tumor necrosis factors (TNFs; certolizumab pegol, etanercept, adalimumab, infliximab, and golimumab), anti-CD4 (zanolimumab), anti-CD20 (rituximab, ocrelizumab, and ofatumumab), fusion proteins (abatacept), anti–interleukin-1 (anakinra), anti–interleukin-1β (ACZ 885), anti–interleukin-6 (tocilizumab), P2X7 receptor antagonist (CE-224535), calcineurin inhibitors (cyclosporine), JAK-3 inhibitors (CP-690550), and T-614 were considered biologic DMARDs. Of 306 trials identified, 154 were screened; of these, 63 were eliminated, leaving 91 selected for analysis. Of the 91 trials, 15 were DMARD-naive trials with 6010 patients enrolled, 63 were biologic-naive trials with 28,322 patients enrolled, and 13 were biologic second-line trials with 5133 patients enrolled. A total of 18,554 patients were enrolled in control arms (3059 DMARD-naive, 13,095 biologic-naive, and 2400 biologic–second-line patients). Sixty trials (66%) are ongoing; 50 trials started before 2007 and 41 after. In total, 53 trials (58%) investigated anti-TNF agents and 41 trials investigated other biologic DMARDs.
Three trials investigated anti-TNF agents head-to-head against other biologic DMARDs (2 a fusion protein and 1 a JAK-3 inhibitor). Five of the 91 trials (5%) were head-to-head trials, including 3 biologic-naive trials (commercially funded) and 2 biologic–second-line trials (noncommercially funded). Two head-to-head trials began in 2005, 1 in 2008, and 2 in 2009. Among the 60 ongoing trials, 4 (7%) are head-to-head trials. Networks of treatment comparisons reflect a predominant use of placebo as a comparator (81 of 102 comparisons among the 91 trials). In all 15 DMARD-naive trials, all control patients received a new treatment. In 54 of the 63 biologic-naive trials, 9224 of the 13,095 control patients received their previously ineffective treatment, 3848 for >6 months, despite high levels of disease activity and contrary to guidelines. In biologic–second-line trials, 851 of the 2400 control patients received treatment comparable to their previously ineffective one.
Despite recommendations to give biologic DMARDs to patients with an inadequate response to conventional DMARDs, 9879 patients were randomized to control arms to receive no treatment or their previously ineffective treatment. Patients with an inadequate response to conventional DMARDs should receive biologic DMARDs.
