Sources of variability on the estimate of treatment effect in the PROWESS trial: Implications for the design and conduct of future studies in severe sepsis*

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Abstract
To elucidate sources of variability in the estimate of treatment effects in a successful phase 3 trial in severe sepsis and to assess their implications on the design of future clinical trials. Retrospective evaluation of prospectively defined subgroups from a large phase 3, placebo-controlled clinical trial (PROWESS). The study involved 164 medical centers. Patients were 1,690 patients with severe sepsis. Drotrecogin alfa (activated) (Xigris) 24 μg/kg/hr for 96 hrs, or placebo. All prospectively defined subgroups were examined to identify treatment effects that potentially differed across subgroup strata (assessed by Breslow-Day p p A learning curve appeared to be present within the PROWESS trial such that the ability to demonstrate efficacy improved with increasing site experience. This potential learning curve may have implications for design of future trials. Investigational sites may need to require a minimum level of protocol-specific experience to appropriately implement a given trial. This experience should be an important consideration in designing trials and analysis plans. Diligence by coordinating centers, site investigators, study coordinators, and sponsors is necessary to ensure that the protocol is executed as designed such that a treatment benefit, if present, will be evident.