Figure 6.

Potential Reasons for Surrogate Endpoint Failure

(A) The surrogate endpoint is not in the causal pathway of the disease state. (B) There are several causal pathways of the disease state, but the intervention only impacts the pathway mediated by the surrogate endpoint. (C) There are several causal pathways of the disease state, but the pathway mediated by the surrogate endpoint is not impacted by the intervention. (D) The intervention acts on a pathway separate from the disease process.

Reproduced with permission from Fleming and DeMets (88).