Challenges of systemic lupus clinical trials

Due to the complex and unpredictable nature of lupus, clinical trials have been problematic to design, conduct, analyze, and interpret. Despite more than 30 treatments entering human development since the early 1990s, only one, belimumab, has been approved by regulatory agencies. This chapter addresses major impediments to lupus trials, including substantial disease heterogeneity, implications of standard of care polypharmacy, and difficulties in trial design and management. Also reviewed is evidence suggesting that current understanding may be yielding better trial outcomes. More clarity in results has been observed under conditions ensuring active enough disease at baseline, tapering of background medications, and use of more robust endpoints. Additional strategies that may facilitate identification of effective treatments include improved statistical approaches to address “between-subject” and “within-subject” heterogeneity, valid ways of handling protocol deviations and missing data, and novel trial designs that can offer greater flexibility and efficiency in lupus drug development.