Some important issues in the planning of phase III HIV vaccine efficacy trials

Given that interesting HIV vaccine candidates, including live preparations and DNA plasmids, exist and that the first phase III vaccine (AIDSVAX) test ing is due to begin this summer, 1998, in the U.S., adequately addressing t rial preparedness is a pressing issue. Despite double-blind randomized cont rolled clinical trial design, there may be difficulties with interpretation and use of the usual measures of vaccinal efficacy and calculation of samp le size. Difficulties arise from vaccine characteristics (e.g. mode of acti on, time-lag, waning) and population heterogeneities (e.g. differences in s usceptibility, sexual behaviour, mixing preferences) causing frailty effect s that can exacerbate bias and time-dependent effects already known to exis t in simple cases. Since vaccine properties, particularly mode of action, a re unlikely to be known before the onset of clinical trials, choosing an ef ficacy measure and the associated analyses and sample size calculations wil l be problematic. Interim analyses designed to decide whether a study will be prolonged may be tenuous if based on a time-dependent measure and will i nfluence sample size determination. Despite shortcomings, general recommend ations can be made to minimise pernicious effects. The objectives of this p aper are principally to review the current state of knowledge of the differ ent stages in the preparation of large phase III HIV vaccine efficacy trial s, the methodological difficulties related to their design, and the analysi s of data collected from them. Mathematical models and trial simulations ar e used to demonstrate that further research is necessary to study the behav iour of vaccine efficacy measures under heterogeneous conditions of populat ion, vaccine action, and trial design and identify a time-independent effic acy measure. Alternative methods to validate sample size calculations have to be developed in order to reduce the chances of unnecessary economic and human cost in phase III HIV vaccine trials. (C) 1999 Elsevier Science Ltd. All rights reserved.