De Gruttola V, Fleming T, Lin D Y, Coombs R
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
J Infect Dis. 1997 Feb;175(2):237-46. doi: 10.1093/infdis/175.2.237.
Because of the difficulties in conducting studies of clinical efficacy of new therapies for human immunodeficiency virus infection and other diseases, there is increasing interest in using measures of biologic activity as surrogates for clinical end points. A widely used criterion for evaluating whether such measures are reliable as surrogates requires that the putative surrogate fully captures the "net effect"-the effect aggregated over all mechanisms of action-of the treatment on the clinical end point. The variety of proposed metrics for evaluating the degree to which this criterion is met are subject to misinterpretation because of the multiplicity of mechanisms by which drugs operate. Without detailed understanding of these mechanisms, metrics of "surrogacy" are not directly interpretable. Even when all of the mechanisms are understood, these metrics are associated with a high degree of uncertainty unless either treatment effects are large in moderate-size studies or sample sizes are large in studies of moderately effective treatments.
由于开展人类免疫缺陷病毒感染及其他疾病新疗法临床疗效研究存在困难，人们越来越倾向于使用生物活性指标作为临床终点的替代指标。评估此类指标作为替代指标是否可靠的一个广泛使用的标准要求，假定的替代指标要充分体现治疗对临床终点的“净效应”——即所有作用机制综合产生的效应。由于药物作用机制的多样性，用于评估该标准满足程度的各种指标容易被误解。如果不详细了解这些机制，“替代指标”的指标就无法直接解读。即使了解了所有机制，除非在中等规模研究中治疗效果显著，或者在疗效中等的治疗研究中样本量足够大，否则这些指标仍存在高度不确定性。
