Outcome Assessments in Clinical Trials of Cryptococcal Meningitis: Considerations on Use of Early Fungicidal Activity as a Potential Surrogate Endpoint for All-Cause Mortality.

Cryptococcal meningitis (CM) is a common disease in resource-challenged settings, with a high mortality within weeks of disease onset. Mortality remains high with current treatments, so more effective interventions are needed to decrease mortality. There has been interest in using the outcome assessment of quantification of fungus from cerebrospinal fluid as a replacement (surrogate) endpoint for all-cause mortality (ACM) as a means of decreasing sample size in randomized clinical trials in CM. To evaluate a biomarker as a potential surrogate endpoint to replace ACM requires several steps. This paper discusses the issues of determining whether the context of a disease is one where a potential surrogate endpoint is rational, the types of outcome assessments that might qualify as potential surrogates, and the process for evaluation of the evidence that a chosen biomarker is a valid replacement for ACM in the given context of use. We then apply those principles to the context of randomized clinical trials of CM.