Clinical trials during early anti-HIV (human immunodeficiency virus) drug development were designed as large-scale studies, using mortality and progression to AIDS (acquired immunodeficiency syndrome) as end points. Representing the only end points of relevance at the time, clinical end points defined "clinical efficacy" for new drug approvals but necessitated cumbersome, prolonged, and costly trials, often requiring years to initiate and complete. Resulting delays in defining useful therapies had real and implied impact on the ever-widening AIDS epidemic and led to a concerted effort to accelerate new drug development through identification of surrogate end points, that is, biomarkers that could be used to substitute for clinical end points in trials of antiretroviral drug efficacy. With the advent of highly sensitive molecular tools for the detection and quantitation of circulating HIV-1 RNA in all infected individuals, a key advance was made. The quantitation of HIV-1 RNA together with the CD4 cell count (the end organ of HIV attack) were validated as useful biomarkers in that they were shown to predict clinical outcome in longitudinal studies of untreated HIV infection (type 0 marker). Each of these markers responded to effective antiretroviral therapy (type 1 marker) and together they accounted for a substantial proportion of the clinical benefit mediated by therapy (type 2 marker; Mildvan, et al. Clin Infect Dis. 1997;24:764-774). These findings have been so consistent across trials and populations that they resulted in a paradigm shift for new drug approvals based on "antiretroviral efficacy." This has translated into an accelerated drug development/approval process for anti-HIV therapies, which ultimately resulted in dramatically improved patient outcomes. The extent to which the AIDS model may be extrapolated to other disciplines was discussed.
Mildvan D. Surrogate Markers: The AIDS Clinical Trials. Arch Neurol. 2000;57(8):1233-1234. doi: