New and different approaches needed for the design and execution of Alzheimer's clinical trials

Results of recent Alzheimer’s disease (AD) clinical trials have been mixed. Both the bapineuzumab and solanezumab trials did not reach planned end points, although prespecified subgroup and pooled analyses of results in participants with mild AD given solanezumab demonstrated signs of efficacy. Despite these results, there is much to learn from both research programs that will inform the design of future trials. Thus, an international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met inMonteCarlo,Monaco, onOctober 31, 2012, during the Clinical Trials in Alzheimer’s Disease conference to review lessons learned from these trials and to incorporate insights gained into future clinical studies [1]. The task force affirmed the emerging consensus that prevention of dementia by treating people in the earliest stages of ADmay be the best way to avert a public health disaster as the population ages and the number of people with AD increases exponentially [2]. Moreover, the task force identified a number of trial design changes suggested by the bapineuzumab and solanezumab programs that may increase the likelihood of success in future trials. Both target engagement and a sign of clinical efficacy or downstream effects on relevant biomarkers should be demonstrated before proceeding to very large phase 3 studies, and this could be accomplished with larger phase 2 or combined phase 2 and phase 3 studies. In addition, for trials of drugs that target amyloid, amyloid positivity should be a requirement, although amyloid-negative subjects should also be studied to learn more about the natural history of dementia across a more representative, heterogeneous population. The task force also recommended embedding biomarker studies in all clinical trials to gather more information about the utility of biomarkers and to inform future trials, even though these studies may be invasive and not approved for clinical use. Even multidomain prevention trials such as those currently underway in Europe would benefit from the incorporation of biomarker studies. A biomarker of preclinical AD has not yet been standardized or validated. However, even with a validated biomarker of preclinical AD, more sensitive cognitivemeasures are needed andmay be the best indicators of efficacy. In addition, trial designers should consider including the oldest old in their cohorts despite the fact that biomarkers tend to be less predictive in those older