Surrogate markers in AIDS clinical trials: conceptual basis, validation, and uncertainties.

The identification of surrogate markers for clinical end points has important implications for the conduct of AIDS clinical trials, the approval of drugs for the treatment of infection with human immunodeficiency virus (HIV), and the management of HIV infection. In this paper, the concept of a surrogate marker and the properties of an ideal marker are discussed. The steps required for the empirical verification of a potential marker are then addressed, and current information on surrogate markers for AIDS is reviewed. Studies conducted to date indicate that the effects of a new drug on numbers of CD4 lymphocytes account only partly for its ultimate impact on the clinical progression of HIV infection. Consequently, the potential benefits of early approval of a drug based on its effect on CD4 lymphocytes must be weighed against the uncertainty about its ability to actually delay clinical progression.