Editorial: The Enduring Value of Reporting Randomized Controlled Clinical Trials in <i>Arthritis &amp; Rheumatology</i>: 2016 and Beyond
Authors: Daniel H. Solomon, Richard J. Bucala
Journal: Arthritis & Rheumatology (2016)

One year ago, we discussed the continued importance of reporting randomized controlled clinical trials in Arthritis & Rheumatology (A&R) 1. The journal encouraged submissions through a fast-track option and consultation with a senior clinical trialist (Dr. Michael Weinblatt) to help facilitate submissions and reviews. The process appears to be working. In 2016, A&R published results of 14 randomized clinical trials (RCTs), whereas during 2014–2015 the number was 7. Perhaps more important, of the RCTs published during the past year, 8 were accepted for fast-track review, and the mean turnaround time for fast-track review was 17 days. The current issue of A&R reports 2 important parallel phase IIb RCTs of the same selective JAK-1 inhibitor, ABT-494 2, 3. These 2 trials evaluated this new JAK-1 inhibitor in 2 populations of patients with rheumatoid arthritis (RA). The study by Genovese et al 2 focuses on patients with moderate-to-severe RA and an inadequate response to methotrexate (MTX), and the study by Kremer et al 3 examines a similar population of patients who have had an inadequate response to a tumor necrosis factor antagonist. These are both highly clinically relevant populations to study for this agent. The investigators tested ABT-494 using a range of dosages, and after 12 weeks of treatment, both studies demonstrated positive outcomes for both the primary end point, i.e., the proportion of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) 4, and the secondary end points, i.e., the proportions of patients achieving ACR50 and ACR70 responses and the proportion of patients achieving a score of ≤3.2 or <2.6 on the 28-joint Disease Activity Score using the C-reactive protein level (5). As phase IIb studies, there are several aspects of both trials that are worth discussing. Phase II trials are intended to test the effectiveness of treatments in patients with the targeted clinical condition, typically after phase I trials have demonstrated an acceptable safety profile. Different dosages of a drug are often tested against placebo, and trials are often brief but allow for planning of more definitive phase III trials. The 2 trials reported in this issue have led to an active phase III trials program that will likely be reported in the ensuing few years. The emphasis on RCTs by the journal speaks to several issues. First, RCTs provide a very high level of evidence for clinical practice. Determining the value of any new treatment in medicine requires adequately powered and well-conducted RCTs. While an intervention's safety often can be best determined from phase IV postmarketing surveillance, RCTs provide information to determine the most efficacious treatments that clinicians can offer to patients. Second, our focus on RCTs flows from the journal's interest in serving its readers, many of whom are practicing rheumatologists looking to offer the best therapies to their patients. Increasingly, patients come to the clinic with information from journals and other sources for providers to consider. Publishing high-quality evidence through RCTs ensures that provider–patient discussions are informed and timely. Finally, RCTs play a vital role in establishing standards of care and defining the future therapeutic armamentarium for rheumatology. Advances in immunology continue to offer insights into next-generation therapeutics, but the potential benefits of these targeted therapies cannot be determined without appropriate RCTs. Indeed, such trials provide ultimate validation for a new therapeutic concept and can establish novel paradigms for experimental investigation. The readership of A&R, a broad mixture of basic scientists and clinicians united in advancing the practice of rheumatology, is the ideal audience to critique and consume the RCTs of today's cutting-edge therapies. In addition to these core values, several trends in RCTs warrant discussion. Adaptive trial designs are becoming more commonplace. These designs allow investigators to adjust treatments and re-randomize subjects based on interim treatment results. For example, in recent trials assessing the benefits of discontinuing biologic disease-modifying antirheumatic drugs (DMARDs), investigators have re-randomized subjects achieving remission of their disease. We anticipate more creative adaptive trial designs in the future that will help define subgroups of rheumatic disease patients based on biomarker responses and re-randomize these subgroups to different treatment options. Such designs better mirror clinical practice, help define relevant patient subsets for targeted therapy, and can increase the cost effectiveness of new drug development. There is continued strong interest in large pragmatic controlled trials. These trials involve less intensive follow-up and often can be conducted in more typical practice settings. Sometimes randomization occurs at the level of the practice, avoiding individual patient randomization. These trials are often appropriate for comparative effectiveness settings in which several treatments may be considered similar enough that there is clinical equipoise. In the US, funders such as the Patient-Centered Outcomes Research Institute have developed networks of providers to consider conducting pragmatic controlled trials. We anticipate that the pragmatic controlled trials would have appropriate designs for a range of issues in rheumatology, such as selecting the first (or second) biologic DMARD after inadequate response to MTX in RA, comparing different glucocorticoid regimens in the initial treatment of polymyalgia rheumatica, testing bisphosphonate withdrawal patterns among patients with osteoporosis, identifying the most effective nonpharmacologic interventions for osteoarthritis, and determining optimal treatment regimens in children with polyarticular juvenile idiopathic arthritis. Two broad issues in drug development and surveillance are also relevant to the journal's focus on RCTs. First, there is great interest worldwide in the development of biosimilar products. To date, 3 biosimilar products relevant for rheumatology have been approved by the Food and Drug Administration, and others are on the horizon 6. Biosimilars offer the promise of greater accessibility to biologic DMARDs, but there are concerns about potential induction of immunogenicity when patients start and stop treatment with different products that are molecularly similar but not identical. In addition, there are concerns about the extrapolation of data from one clinical indication to another. A&R recognizes that the rheumatology community has great interest in these details and invites submissions from investigators conducting RCTs of biosimilars. The International Committee of Medical Journal Editors (ICMJE) has recently developed a framework for sharing clinical trial data that requires authors to share deidentified data as a condition of publishing trial results 7. While the potential benefits of greater data sharing are self-evident, the proposal has engendered controversy. The devil is in the details about how the data are shared, when the data become available, how to protect intellectual property, and how best to govern access to and utilization of the data. As Editors of A&R, we support the ICMJE initiative for sharing trial data and are encouraged by the ongoing debate. A&R will develop a balanced policy taking into consideration our belief that data sharing and data transparency will generate new information more quickly. At the same time, these efforts must not inadvertently stymie innovation or reduce research progress. Throughout A&R's 58-year history, the ACR has strived for the most robust educational and scientific forum. RCTs will play an increasing role in the journal's content. Drs. Solomon and Bucala drafted the article, revised it critically for important intellectual content, and approved the final version to be published.