Impact of diagnostic methods on efficacy estimation – a proof-of-principle based on historical examples

Abstract

Introduction: Accurate diagnostic methods are essential for evaluating treatment efficacy in clinical trials, including vaccine trials. Although a plethora of studies assessing novel or modified treatment options is available, clinical trials evaluating the sensitivity and specificity of diagnostic methods in compliance with the demands of drug registration trials are scarce. We assessed the accuracy of diagnostic methods in two vaccine trials conducted in 1995 and 2009 to demonstrate the impact of sensitivity and specificity on efficacy estimations. Methods: We applied the sensitivity- and specificity-adjusted vaccine efficacy estimator of Lachenbruch for modelling the impact of test characteristics on the outcome of the two vaccine trials by varying diagnostic specificity. Results: Because of non-ideal diagnostic sensitivity and specificity, the estimation of vaccine efficacy is compromised. We demonstrate the impact of diagnostic accuracy on efficacy estimations with increasing confidence limits. Conclusions: Because sensitivity and specificity less than one have a direct impact on efficacy estimations in clinical trials, evaluation of diagnostic methods should lead to a level of evidence comparable with the efficacy assessment of novel treatment options. Furthermore, statistical methods adjusted for sensitivity and specificity of diagnostic methods should be applied for efficacy estimations, or this lack of confidence has to be taken into account when interpreting the results of trials.