Composite cognitive and functional measures for early stage Alzheimer's disease trials

INTRODUCTION: Composite scales have been advanced as primary outcomes in early stage Alzheimer's disease trials, and endorsed by the U.S. Food and Drug Administration (FDA) for pivotal trials. They are generally composed of several neurocognitive subscales and may include clinical and functional activity scales. METHODS: We summarized the development of 12 composite scales intended as outcomes for clinical trials and assessed their characteristics. RESULTS: Composite scales have been constructed from past observational and clinical trial databases by selecting components of individual neuropsychological tests previously used in clinical trials. The atheoretical approaches to combining scales into a composite scale that have often been used risk omitting clinically important measures and so may include redundant, irrelevant, or noncontributory tests. The deliberate combining of neurocognitive scales with functional activity scales provides arbitrary weightings that also may be clinically irrelevant or obscure change in a particular domain. Basic psychometric information is lacking for most of the composites. DISCUSSION: Although composite scales are desirable for pivotal clinical trials because they, in principle, provide for a single, primary outcome combining neurocognitive and/or functional domains, they have substantial limitations, including their common derivations, inattention to basic psychometric principles, redundancy, absence of alternate forms, and, arguably, the inclusion of functional measures in some. In effect, any currently used composite is undergoing validation through its use in a trial. The assumption that a composite, by its construction alone, is more likely than an individual measure to detect an effect from any particular drug and that the effect is more clinically relevant or valid has not been demonstrated.