Phase III clinical trials of prophylactic HIV-1 vaccines, validation of efficacy measures and sample size

by Desai, Kamal

Given that interesting HIV vaccine candidates, including live preparations and DNA plasmids. exist and that testing for the first phase III vaccine (.IIDSLrAS) began in the US. in the summer of 1998, adequately addressing trial preparedness is a pressing issue. Despite double-blind randomized controlled clinical trial design. there may be difficulties wit h interpretation and use of the usual measures of vaccina1 efbcacy arid calculation of sample size. Difficulties arise froni vaccine characteristics (e.g. mode of action. time-lag, waning) and population heterogeneities (e.g. diferences in susceptibilit. sexual behaviour, niixirig preferences) causing frailty effects that can exacerbate bias and tinie-dependent eRects known already to erist in simple cases. Since vaccine properties. particularly mode of action. is unlikely to be known hefore onset of clinical trials. choosing an efficacy measure and the associateci arialyses and süniple size calculation d l be problematic. Interini arialyses designeci to decide whether a study will be prolonged may be tenuous if based on a tirrie-dependerit nieasure and will influence sample size determination. Despite shortcornings. general reconirriendations can be niade to minimise the pernicious effects. The objectives of this paper are priricipally to review the current state of knowledge of the different stages iri the preparation of large phase