http://www.acponline.org/journals/annals/01oct96/surrogep.htm
Surrogate End Points in Clinical Trials: Are We Being Misled?
Annals of Internal Medicine, 1 October 1996. 125:605-613.
Thomas R. Fleming, PhD, and David L. DeMets, PhD

Phase 3 clinical trials, which evaluate the effect that new interventions have on the clinical outcomes of particular relevance to the patient (such as death, loss of vision, or other major symptomatic event), often require many participants to be followed for a long time. There has recently been great interest in using surrogate end points, such as tumor shrinkage or changes in cholesterol level, blood pressure, CD4 cell count, or other laboratory measures, to reduce the cost and duration of clinical trials. In theory, for a surrogate end point to be an effective substitute for the clinical outcome, effects of the intervention on the surrogate must reliably predict the overall effect on the clinical outcome. In practice, this requirement frequently fails. Among several explanations for this failure is the possibility that the disease process could affect the clinical outcome through several causal pathways that are not mediated through the surrogate, with the intervention's effect on these pathways differing from its effect on the surrogate. Even more likely, the intervention might also affect the clinical outcome by unintended, unanticipated, and unrecognized mechanisms of action that operate independently of the disease process.

We use examples from several disease areas to illustrate how surrogate end points have been misleading about the actual effects that treatments have on the health of patients.

• Arrhythmia Suppression: Use of reduction in ventricular ectopic contractions as a surrogate for decreased cardiovascular-related mortality.... Ventricular arrhythmia is associated with an almost fourfold increase in the risk for death related to cardiac complications  particularly sudden death.  Three new drugs (encainide, flecainide, and moricizine) were found to suppress arrhythmias effectively and were approved by the Food and Drug Administration (FDA) for use in patients with life-threatening or severely symptomatic arrhythmias. After the data were finalized, the sudden death comparison was 43 and 16 and the number of deaths was 63 in the encainide and flecainide group and 26 in the placebo group. Later results from CAST also established an increased risk for death in patients receiving moricizine .

 
• Lipid Lowering: Although lipid levels, especially those of total cholesterol or its subfractions and triglycerides, have long been known to be significant predictors of cardiovascular-related mortality, researchers have debated the relation between lipid lowering and reduction in overall mortality . As early as the Coronary Drug Project (CDP) in the 1970s, such drugs as clofibrate and niacin were known to decrease cholesterol levels. However, neither agent reduced total mortality in the highly powered 7-year CDP trial. (Similarly the HERS study for postmenopausal women with heart disease and HRT -Tishy)

 
• Osteoporosis in Postmenopausal Women: Postmenopausal women have loss of bone mass and develop osteoporosis, which ultimately leads to an increased risk for fractures of the hip and other bones....Sodium fluoride, which stimulates bone formation and increases bone mass, came into widespread use although it was not approved by the FDA....Riggs and colleagues conducted a placebo-controlled randomized trial of fluoride in 202 postmenopausal women who had osteoporosis and vertebral fractures. Patients were followed for 4 years. Treatment increased bone mineral density in the lumbar spine by 35% (P < 0.001). However, new vertebral fractures occurred more frequently in patients treated with fluoride than in those who received placebo (163 compared with 136 fractures), and nonvertebral fractures also occurred more frequently in patients treated with fluoride (72 compared with 24 fractures; P = 0.01). Riggs and colleagues concluded that the form of fluoride treatment used in their study increased some aspects of bone mineral density but caused bones to become brittle, thereby increasing skeletal fragility.