Freedman L S, Schatzkin A, Schiffman M H
Biometry Branch, National Cancer Institute, Bethesda, Maryland 20892.
J Cell Biochem Suppl. 1992;16G:27-32. doi: 10.1002/jcb.240501105.
Using an intermediate marker of precancer as an endpoint for evaluating agents that may prevent cancer involves a presumption that the modification of the marker will be accompanied by a modification of cancer incidence. This presumption can hold only if the marker is on or very closely linked to a causal pathway. Epidemiologists have discussed the nature of evidence required to infer causal relationships, and we briefly survey their work. Studies relating exposure (E) to marker (M) provide only indirect evidence for causality. Those relating marker (M) to disease (D) are more relevant. We propose a new validation criterion based on an analysis of the three-way relationship of exposure (E), marker (M) and disease (D). We discuss the level of evidence required for using intermediate markers as endpoints for Phase II and Phase III trials, and propose very stringent criteria for Phase III trials. For Phase II trials, we propose less stringent criteria, but still recommend that the marker (M) should have been shown to have a strong association with disease (D).
使用癌前病变的中间标志物作为评估可能预防癌症的药物的终点，涉及到一种假设，即标志物的改变将伴随着癌症发病率的改变。只有当标志物位于因果路径上或与之紧密相连时，这一假设才成立。流行病学家已经讨论了推断因果关系所需证据的性质，我们简要概述一下他们的工作。将暴露（E）与标志物（M）相关联的研究仅提供因果关系的间接证据。那些将标志物（M）与疾病（D）相关联的研究更具相关性。我们基于对暴露（E）、标志物（M）和疾病（D）三者关系的分析，提出了一种新的验证标准。我们讨论了将中间标志物用作II期和III期试验终点所需的证据水平，并为III期试验提出了非常严格的标准。对于II期试验，我们提出了不太严格的标准，但仍然建议标志物（M）应已被证明与疾病（D）有很强的关联。
