Surrogate End Points and FDA Approval

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Abstract
Risk factors such as high blood pressure, elevated low-density lipoprotein (LDL) cholesterol levels, and high blood glucose levels are strongly, consistently, and directly associated with the risk of major cardiovascular events, including myocardial infarction, stroke, and heart failure. Over the last several decades, the development and widespread use of drugs to reduce the level of these risk factors have been a mainstay of cardiovascular disease prevention efforts. For new drugs designed to treat these conditions, the US Food and Drug Administration (FDA) generally uses their treatment effects on the level of the risk factor to evaluate them for approval. Risk-factor levels serve as surrogate end points for the outcomes of primary interest—the incidence of cardiovascular disease. According to the FDA guidance on lipid-lowering therapy, “The objective of lipid-altering therapy is not merely to alter serum lipids but to diminish the morbidity and mortality from cardiovascular disease and/or pancreatitis that is associated with abnormal serum lipid levels.” Because the “ability to extrapolate the value of any particular lipid-altering drug in accomplishing either of these objectives is limited . . . lipid altering agents should be shown to have a relatively low incidence of adverse effects prior to approval for marketing.”1