Clinical trials in rheumatoid arthritis that have been done for drug approval fail to address numerous issues critically important to clinical care, according to an American College of Rheumatology task force report.
The group was critical of current clinical trial design and offered half a dozen recommendations for reforms aimed at boosting clinical relevance. The task force also drew up a ranked priority list for the next generation of RA clinical trials, i.e., studies needed to address current major knowledge gaps. Topping this must-have list are trials of induction therapy in early disease.
Dr. James R. O'Dell
• Induction therapy. The group recommended as an initial practical step a three-armed trial comparing current standard conventional methotrexate monotherapy to methotrexate plus a tumor necrosis factor (TNF) inhibitor versus methotrexate plus a non-TNF inhibitor biologic agent. This trial should be double-blind and consist of three phases: induction, maintenance therapy, and treatment withdrawal in patients whose disease goes into remission. It was the strong consensus of the task force that such a trial holds the greatest potential for advancing clinical care.
Biologic specimens should routinely be collected during this and all the other next-generation clinical trials in an intensive effort to identify biomarkers that will allow rational selection of medications and the tapering of treatment without triggering relapse. The urgent need for such biomarkers was "a recurrent theme that prominently permeated and at times dominated our discussions," according to the report of the task force chaired by Dr. James R. O’Dell, professor of medicine and chief of the section of rheumatology and immunology at the University of Nebraska, Omaha, who is also incoming president of the American College of Rheumatology.
In descending order of importance and urgency, the other topics on the task force’s clinical trials priority list are:
• Treatment of disease that remains active despite methotrexate and a first anti-TNF biologic. The group believed that in an ideal world, a clinical trial addressing this scenario would continue background methotrexate while randomizing patients to a different TNF inhibitor, the T-cell mediator abatacept, the CD20-directed cytolytic antibody rituximab, or the interleukin-6 receptor blocker tocilizumab. That may be too big an undertaking to be practical. At the very least, the next generation of studies in this patient population ought to compare two biologics having different mechanisms, according to the task force report (Arthritis Rheum. 2011;63:2151-6 [doi:10.1002/art.30402]).
• Patients in remission while on treatment. At present there are essentially no data to guide medication tapering and discontinuation decisions. The panel proposed piggybacking tapering trials – with liberal collection of biologic specimens – on the back of current trials and next-generation induction trials.
• Active disease despite methotrexate therapy. Roughly 70% of patients with early RA fail to achieve low disease activity on methotrexate monotherapy. There is a need for clinical trials aimed at defining optimal methotrexate dosing strategies, the panel agreed. Beyond that, however, the task force was split on the best way forward. Some argued that active comparator trials of various add-on therapies in suboptimal responders to methotrexate are badly needed now, while others said it makes more sense to hold off until biomarkers can be identified that will help in making individualized treatment decisions based on an agent’s mechanism of action.
The task force didn’t address the issue of how the proposed research agenda will be funded. Of note, however, of 25 experts invited to an ACR conference on clinical trial priorities and design that was held last year, most were from academia, four came from the National Institutes of Health, three were Food and Drug Administration officials, and none were from the pharmaceutical industry.
The task force proposed numerous changes in clinical trial design aimed at yielding results that are more meaningful to clinical rheumatology practice. For example, the group declared that in the current era of proven highly effective RA therapies, placebo-controlled clinical trials have become ethically questionable and should be greatly de-emphasized in favor of active comparator studies. The task force also raised ethical concerns about the current rule that an assigned therapy must be continued for a prolonged period of follow-up, often 1-2 years, even though modern therapies are expected to bring maximum clinical benefit in 3-6 months.
The panel expressed reservations about the generalizability of clinical trials in RA that are increasingly being conducted in developing countries. The group recommended that when these trials are reported, the investigators should fully describe the study population and assess the generalizability of the findings.
In addition to Dr. O’Dell, the members of the ACR Rheumatoid Arthritis Clinical Trial Investigators Ad Hoc Task Force were co-chair Dr. Michael E. Weinblatt of Brigham and Women’s Hospital, Boston; Dr. Ted R. Mikuls of the University of Nebraska, Omaha; and Dr. Robert A. Colbert of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md. Dr. Weinblatt has received consulting fees from Abbott, Amgen, Astellas, Astra-Zeneca, Biogen Idec, Bristol-Myers Squibb, Centocor, Crescendo, Lilly, Pfizer, and Roche.