Preventive HIV type 1 vaccine clinical trials: a regulatory perspective.

The clinical development of a human immunodeficiency virus (HIV) vaccine should be planned so that adequate safety and efficacy data can be obtained in an efficient manner to permit a risk/benefit assessment. Phase 1 and 2 studies should support the selection of an appropriate vaccine formulation, dose and schedule for evaluation in efficacy trials. Evaluation of the immune response(s) elicited by an HIV vaccine has an important role, even early in clinical development. Immune assay results and viral detection/quantitation technology may be used to identify and characterize HIV infections occurring during the trials. Thus, information about the performance parameters of these assays is important. Considerable research and development may be needed in this regard, especially when multiple endemic HIV-1 subtypes (clades) are expected. Prior to initiating an efficacy trial, background epidemiological information (e.g., recent seroincidence, endemic clades), as well as safety and immunogenicity data with the candidate vaccine, should be obtained in the intended efficacy trial population. The effects of antiretroviral therapy use and sensitive viral detection assays on the evaluation of the primary efficacy end point (as well as secondary end points) are important considerations. The detailed statistical plan for an efficacy trial should consider the 95% confidence limits on the estimate of vaccine efficacy; this may be of exceptional importance when relatively low point estimates of efficacy are expected.