Termination of a clinical trial with no treatment group difference: the Lupus Nephritis Collaborative Study

The Lupus Nephritis Collaborative Study (LNCS) was a multicenter randomized clinical trial designed to assess the effects of standard drug therapy alone versus drug therapy plus plasmapheresis (plasma exchange) on the incidence of fatal or nonfatal renal failure associated with lupus nephritis. After 86 patients had been entered, with a mean of 97 weeks of follow-up, the trial was terminated partly due to lack of a beneficial effect of plasmapheresis. Although there are numerous methods for the statistical analysis of emerging results in a clinical trial, there have been relatively few descriptions of the application of these methods to the termination of a clinical trial when no favorable difference exists between groups. This report presents a review of the statistical methods employed for the pivotal interim analyses of the LNCS that were performed in order to help reach the decision to terminate the trial. These included the assessment of unconditional power post-hoc and the assessment of conditional power using an exact method appropriate for small sample sizes. Conditional power was used to assess the likelihood of detecting a significant treatment effect in the future given the data thus far observed and given reasonable hypotheses regarding the nature of the possible differences between the treatment groups. In addition, weighted-likelihood ratios (Bayes odds ratios) were computed to assess the likelihood of various alternative hypotheses given the present data. We show how such analyses can be useful in reaching a decision to terminate a trial that fails to show a treatment effect.