ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 10, October 2015, pp 2555–2556 DOI 10.1002/art.39258 C 2015, American College of Rheumatology V
EDITORIAL
The Vital Role of Randomized Controlled Trials in Arthritis & Rheumatology Daniel H. Solomon,1 Michael E. Weinblatt,1 and Richard J. Bucala2 In this issue of Arthritis & Rheumatology (A&R), Sieper and colleagues report the results of an important trial demonstrating the benefits of a tumor necrosis factor (TNF) antagonist for the treatment of nonradiographic spondyloarthritis (1). As optimal treatment for this condition evolves, well-designed randomized controlled trials (RCTs) will play a pivotal role in defining the standard of care for one of the more common inflammatory arthritides. We highlight this study not only because of its importance to rheumatology but also because of the vital role of RCTs in A&R. Throughout the 57-year history of A&R, RCTs have always played a prominent role. Major advances in our understanding of treatment, pathobiology, the mechanisms of action of a treatment, and new avenues of scientific investigation are facilitated by RCTs. Some of the major RCTs published in A&R throughout the many dec-
ades document the roles of TNF antagonists in rheumatoid arthritis (2,3), cyclophosphamide and belimumab in systemic lupus erythematosus (4,5), nonpharmacologic therapies in osteoarthritis (6,7), novel therapies in gout (8,9), and various treatments in vasculitis (10,11) With this issue, which begins the tenure of the new editorial team, we rededicate Arthritis & Rheumatology to the goal of publishing the most important RCTs in our field. The importance of RCTs in A&R is reflected by a new section of the journal that is dedicated to RCTs, with one of us (MEW), a senior clinical trials investigator, as the section advisor. As with the RCT published in the current issue (1), A&R will now offer fast-track reviews. For example, the total review time for the article by Sieper and colleagues (1), from submission to acceptance, was 20 days. Authors of RCTs desiring a fast-track review need to contact the Editor in Chief (RJB) or Deputy Editor (DHS) at least 14 days prior to submission to facilitate such a review. The new section will focus on phase I, phase II, and phase III RCTs. A phase III RCT using approved drugs for new indications, such as that reported by Sieper and colleagues, will also be considered for this section and for fast-track review. Nonrandomized phase IV studies will be published in other sections of the journal, and phase I and phase II studies will typically not receive fast-track status, except under circumstances in which the findings are exceptionally noteworthy. In addition, A&R embraces the important role of effectiveness studies in the current research milieu. Efficacy studies (how interventions work in idealized settings, such as an RCT) and effectiveness studies (how interventions work in typical settings, such as registries and pragmatic controlled clinical trials) contribute complementary and critical information for determining best practice. RCTs with negative results also provide important information for drug developers, providers, and patients that will be embraced by this journal.
Dr. Solomon’s work was supported in part by research grants to Brigham and Women’s Hospital from Amgen, Lilly, Pfizer, AstraZeneca, and CORRONA. 1 Daniel H. Solomon, MD, MPH (Deputy Editor, A&R), Michael E. Weinblatt, MD (Clinical Trials Advisor, A&R): Brigham and Women’s Hospital, Boston, Massachusetts; 2Richard J. Bucala, MD, PhD (Editor in Chief, A&R): Yale University School of Medicine, New Haven, Connecticut. Dr. Weinblatt has received consulting fees from AbbVie, Ablynx, Amgen, AstraZeneca, Bristol-Myers Squibb, Can-Fite BioPharma, Catabasis, Compugen, CORRONA, Crescendo Bioscience, Ensemble Therapeutics, Exagen Diagnostics, Five Prime Therapeutics, Genentech/Roche, Idera, Infinity, Lycera, Lilly, MedImmune, Merck, Novartis, Pfizer, Principia Biopharma, Receptos, Regeneron, Samsung, Sanofi, and UCB (less than $10,000 each) and grants from Bristol-Myers Squibb, Crescendo Bioscience, and UCB. Dr. Bucala is a named inventor on, and has received royalties from, licensed patents in the area of macrophage migration inhibitory factor therapeutics and owns equity in Promedior and MIFCOR. Address correspondence to Daniel H. Solomon, MD, MPH, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, 75 Francis Street, PBB-B3, Boston, MA 02115. E-mail: [email protected]. Submitted for publication June 15, 2015; accepted in revised form June 18, 2015. 2555
2556
SOLOMON ET AL
An analysis of the RCT presented in the current issue highlights why such studies are important to our field (1). First, the authors defined a study question with great clinical relevance: whether anticytokine therapy would increase attainment of 20% improvement according to the criteria of the Assessment of SpondyloArthritis international Society among patients with ankylosing spondylitis who have not developed changes apparent on plain radiographs. Second, they selected a study sample reflecting typical patients with AS that was sufficiently large to obtain a clear answer. Third, the conduct of the trial involved the use of rigorous clinical trial methods, with adequate masking, successful randomization, appropriate safety monitoring, and clear prespecified analyses (https:// www.clinicaltrials.gov/ct2/show/NCT01453725?term5 NCT01453725&rank51). Finally, the interpretation of the results does not reach beyond the data. The authors let the data speak. Pragmatic trials—reflecting conditions closer to typical practice than many double-blind RCTs—will take on a greater prominence (12). The design of relevant RCTs for some rheumatic diseases requires innovative approaches, using adaptive designs in which strategies (not drugs) need to be tested or in which only specific subgroups of patients are likely to respond (13). In some adaptive and nonadaptive trial designs, biomarkers will be used to identify relevant subgroups of patients who are likely or unlikely to respond to a given treatment. Arthritis & Rheumatology aspires to leadership in the delivery of high-quality and timely information that is useful to clinicians, scientists, and policy makers. This will include a broad range of clinical, basic, and population science publications dealing with common rheumatic diseases as well as those that are rare. RCTs often reflect the culmination of years of basic science studies, the translation of mechanistic studies into therapeutic options, and proof (or disproof) of clinical relevance. The ultimate goal of A&R continues to be advancement of the scientific basis of rheumatology and to improve clinical practice. We look forward to publishing more high-quality RCTs in A&R. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.
REFERENCES 1. Sieper J, van der Heijde D, Dougados M, Maksymowych WP, Scott BB, Boice JA, et al. A randomized, double-blind, placebocontrolled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2015;67:2702–12. 2. Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2004;50:353–63. 3. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti–tumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:35–45. 4. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46:2121–31. 5. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al, for the BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918–30. 6. Messier SP, Loeser RF, Miller GD, Morgan TM, Rejeski WJ, Sevick MA, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum 2004;50:1501–10. 7. Baker K, Goggins J, Xie H, Szumowski K, LaValley M, Hunter DJ, et al. A randomized crossover trial of a wedged insole for treatment of knee osteoarthritis. Arthritis Rheum 2007;56:1198–203. 8. Schumacher HR Jr, Sundy JS, Terkeltaub R, Knapp HR, Mellis SJ, Stahl N, et al, on behalf of the 0619 Study Group. Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2012;64:876–84. 9. Sundy JS, Becker MA, Baraf HS, Barkhuizen A, Moreland LW, Huang W, et al, for the Pegloticase Phase 2 Study Investigators. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol–conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum 2008;58:2882–91. 10. Hoffman GS, Cid MC, Hellmann DB, Guillevin L, Stone JH, Schousboe J, et al, for the International Network for the Study of Systematic Vasculitides (INSSYS). A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46:1309–18. 11. Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum 1997;40:2187–98. 12. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624–32. 13. Buch MH, Pavitt S, Parmar M, Emery P. Creative trial design in RA: optimizing patient outcomes. Nat Rev Rheumatol 2013;9: 183–94.
EDITORIAL
The Vital Role of Randomized Controlled Trials in Arthritis & Rheumatology Daniel H. Solomon,1 Michael E. Weinblatt,1 and Richard J. Bucala2 In this issue of Arthritis & Rheumatology (A&R), Sieper and colleagues report the results of an important trial demonstrating the benefits of a tumor necrosis factor (TNF) antagonist for the treatment of nonradiographic spondyloarthritis (1). As optimal treatment for this condition evolves, well-designed randomized controlled trials (RCTs) will play a pivotal role in defining the standard of care for one of the more common inflammatory arthritides. We highlight this study not only because of its importance to rheumatology but also because of the vital role of RCTs in A&R. Throughout the 57-year history of A&R, RCTs have always played a prominent role. Major advances in our understanding of treatment, pathobiology, the mechanisms of action of a treatment, and new avenues of scientific investigation are facilitated by RCTs. Some of the major RCTs published in A&R throughout the many dec-
ades document the roles of TNF antagonists in rheumatoid arthritis (2,3), cyclophosphamide and belimumab in systemic lupus erythematosus (4,5), nonpharmacologic therapies in osteoarthritis (6,7), novel therapies in gout (8,9), and various treatments in vasculitis (10,11) With this issue, which begins the tenure of the new editorial team, we rededicate Arthritis & Rheumatology to the goal of publishing the most important RCTs in our field. The importance of RCTs in A&R is reflected by a new section of the journal that is dedicated to RCTs, with one of us (MEW), a senior clinical trials investigator, as the section advisor. As with the RCT published in the current issue (1), A&R will now offer fast-track reviews. For example, the total review time for the article by Sieper and colleagues (1), from submission to acceptance, was 20 days. Authors of RCTs desiring a fast-track review need to contact the Editor in Chief (RJB) or Deputy Editor (DHS) at least 14 days prior to submission to facilitate such a review. The new section will focus on phase I, phase II, and phase III RCTs. A phase III RCT using approved drugs for new indications, such as that reported by Sieper and colleagues, will also be considered for this section and for fast-track review. Nonrandomized phase IV studies will be published in other sections of the journal, and phase I and phase II studies will typically not receive fast-track status, except under circumstances in which the findings are exceptionally noteworthy. In addition, A&R embraces the important role of effectiveness studies in the current research milieu. Efficacy studies (how interventions work in idealized settings, such as an RCT) and effectiveness studies (how interventions work in typical settings, such as registries and pragmatic controlled clinical trials) contribute complementary and critical information for determining best practice. RCTs with negative results also provide important information for drug developers, providers, and patients that will be embraced by this journal.
Dr. Solomon’s work was supported in part by research grants to Brigham and Women’s Hospital from Amgen, Lilly, Pfizer, AstraZeneca, and CORRONA. 1 Daniel H. Solomon, MD, MPH (Deputy Editor, A&R), Michael E. Weinblatt, MD (Clinical Trials Advisor, A&R): Brigham and Women’s Hospital, Boston, Massachusetts; 2Richard J. Bucala, MD, PhD (Editor in Chief, A&R): Yale University School of Medicine, New Haven, Connecticut. Dr. Weinblatt has received consulting fees from AbbVie, Ablynx, Amgen, AstraZeneca, Bristol-Myers Squibb, Can-Fite BioPharma, Catabasis, Compugen, CORRONA, Crescendo Bioscience, Ensemble Therapeutics, Exagen Diagnostics, Five Prime Therapeutics, Genentech/Roche, Idera, Infinity, Lycera, Lilly, MedImmune, Merck, Novartis, Pfizer, Principia Biopharma, Receptos, Regeneron, Samsung, Sanofi, and UCB (less than $10,000 each) and grants from Bristol-Myers Squibb, Crescendo Bioscience, and UCB. Dr. Bucala is a named inventor on, and has received royalties from, licensed patents in the area of macrophage migration inhibitory factor therapeutics and owns equity in Promedior and MIFCOR. Address correspondence to Daniel H. Solomon, MD, MPH, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, 75 Francis Street, PBB-B3, Boston, MA 02115. E-mail: [email protected]. Submitted for publication June 15, 2015; accepted in revised form June 18, 2015. 2555
2556
SOLOMON ET AL
An analysis of the RCT presented in the current issue highlights why such studies are important to our field (1). First, the authors defined a study question with great clinical relevance: whether anticytokine therapy would increase attainment of 20% improvement according to the criteria of the Assessment of SpondyloArthritis international Society among patients with ankylosing spondylitis who have not developed changes apparent on plain radiographs. Second, they selected a study sample reflecting typical patients with AS that was sufficiently large to obtain a clear answer. Third, the conduct of the trial involved the use of rigorous clinical trial methods, with adequate masking, successful randomization, appropriate safety monitoring, and clear prespecified analyses (https:// www.clinicaltrials.gov/ct2/show/NCT01453725?term5 NCT01453725&rank51). Finally, the interpretation of the results does not reach beyond the data. The authors let the data speak. Pragmatic trials—reflecting conditions closer to typical practice than many double-blind RCTs—will take on a greater prominence (12). The design of relevant RCTs for some rheumatic diseases requires innovative approaches, using adaptive designs in which strategies (not drugs) need to be tested or in which only specific subgroups of patients are likely to respond (13). In some adaptive and nonadaptive trial designs, biomarkers will be used to identify relevant subgroups of patients who are likely or unlikely to respond to a given treatment. Arthritis & Rheumatology aspires to leadership in the delivery of high-quality and timely information that is useful to clinicians, scientists, and policy makers. This will include a broad range of clinical, basic, and population science publications dealing with common rheumatic diseases as well as those that are rare. RCTs often reflect the culmination of years of basic science studies, the translation of mechanistic studies into therapeutic options, and proof (or disproof) of clinical relevance. The ultimate goal of A&R continues to be advancement of the scientific basis of rheumatology and to improve clinical practice. We look forward to publishing more high-quality RCTs in A&R. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.
REFERENCES 1. Sieper J, van der Heijde D, Dougados M, Maksymowych WP, Scott BB, Boice JA, et al. A randomized, double-blind, placebocontrolled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2015;67:2702–12. 2. Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2004;50:353–63. 3. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti–tumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:35–45. 4. Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46:2121–31. 5. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al, for the BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918–30. 6. Messier SP, Loeser RF, Miller GD, Morgan TM, Rejeski WJ, Sevick MA, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum 2004;50:1501–10. 7. Baker K, Goggins J, Xie H, Szumowski K, LaValley M, Hunter DJ, et al. A randomized crossover trial of a wedged insole for treatment of knee osteoarthritis. Arthritis Rheum 2007;56:1198–203. 8. Schumacher HR Jr, Sundy JS, Terkeltaub R, Knapp HR, Mellis SJ, Stahl N, et al, on behalf of the 0619 Study Group. Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2012;64:876–84. 9. Sundy JS, Becker MA, Baraf HS, Barkhuizen A, Moreland LW, Huang W, et al, for the Pegloticase Phase 2 Study Investigators. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol–conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum 2008;58:2882–91. 10. Hoffman GS, Cid MC, Hellmann DB, Guillevin L, Stone JH, Schousboe J, et al, for the International Network for the Study of Systematic Vasculitides (INSSYS). A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46:1309–18. 11. Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum 1997;40:2187–98. 12. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624–32. 13. Buch MH, Pavitt S, Parmar M, Emery P. Creative trial design in RA: optimizing patient outcomes. Nat Rev Rheumatol 2013;9: 183–94.
