Challenges to demonstrating disease-modifying effects in Alzheimer's disease clinical trials.

Progress in understanding the molecular biology of Alzheimer's disease (AD) has provided a number of plausible therapeutic targets for disease-modifying interventions. To advance these agents toward eventual US Food and Drug Administration (FDA) approval and incorporation into clinical practice by physicians and acceptance by patients and caregivers it is necessary to reach consensus on the meaning of disease modification and on what information is needed to provide a compelling factual basis for distinguishing disease modification from symptomatic treatment effects. Disease modification requires that the intervention have an impact of underlying pathology and pathophysiology of AD; disease course modification, illness modification or disability sparing are alternate terminologies that could be applied to symptomatic agents that do not affect the underlying neurobiology of AD. A variety of trial designs have been proposed to provide information supporting disease modification including change from baseline designs, survival type designs, staggered start designs, and staggered withdrawal designs. Each of these has shortcomings, and by themselves trial designs are not likely to provide sufficient information to conclusively prove that disease modification has occurred. Incorporation of a biomarker into clinical trials will support the claim for disease modification. Such a surrogate marker ideally should respond to the intervention, predict the clinical response to the intervention, and be compellingly related to the neurobiology of AD in the pathway affected by the intervention. A third axis of information supportive of disease modification is derived from observation of the effect of treatment in animal models of AD. The triad of a clinical outcome consistent with disease modification, support from a surrogate marker incorporated into the clinical trial, and basic science information indicating the effect of the therapy on a model of AD would combine to make a convincing case for disease modification.