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Challenges in Treatment Development for Lupus: is it the Targets or the Trials?

Joan T Merrill, MD1, and Paul G Brunetta, MD2

In the past two decades, a number of investigational treatments for lupus have entered Phase II/III clinical trials but primary or secondary endpoints have not been met. Recently, successful outcomes were reported for two Phase III trials of belimumab, a human monoclonal antibody that targets the B cell survival factor BLyS (BAFF). However, this success in Phase III was preceded by a negative Phase II trial, and the statistical outcome was obtained at the cost of conducting two large-scale, international trials involving 865 and 816 patients, respectively. There are legitimate concerns that trials of this size would be difficult to run simultaneously by too many of the programs that are currently contemplating Phase III studies for lupus. The clinical trials community continues to struggle with formidable problems in how to design efficient but ethical trials for lupus patients. It remains uncertain how to minimize confounding background treatments while providing adequate treatment for patients, how to assess disease activity in a clear and reproducible manner, and how to design interpretable and clinically meaningful endpoints for this heterogeneous and unpredictable disease. Efforts have been further complicated by scientific guidelines proposed by the regulatory agencies that set standards; these guidelines are appropriate for diseases with safe and effective, approved treatments, but become perceived impediments to progress when the standard of care is unapproved therapy. Int J Adv Rheumatol 2010;8(4):137–43.

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