Clinical trials in AD: are current formats and outcome measures adequate?

Great strides have been made in the measurement of outcomes and treatment efficacy in clinical trials of Alzheimer disease (AD) drugs during the past 25 years. Several sensitive, reliable, and valid clinical outcome measures have been developed. The methodology, trial design, and outcome measures for demonstrating symptomatic benefits of an AD drug are now established. However, a greater challenge lies ahead. Major advances in fundamental knowledge about the pathophysiology of the disease and in animal models have transformed the focus of current efforts to developing and testing therapies that may actually slow disease progression, delay the onset of symptoms, and even ultimately prevent the disease. The long-duration trials that will likely be necessary to demonstrate an effect on disease progression will be costly and difficult. Proof-of-concept trials and subsequent long-term trials could gain power and efficiency from use of biologic markers of underlying disease severity, but currently available biologic markers are not ideal. A major barrier to such trials is their size and cost. One approach to reducing the cost would be to recruit "enriched" samples of subjects who are at greater risk of developing AD during the trial than the general, elderly population. The major effort required to screen and recruit large numbers of subjects for such trials also contributes to the cost. Probably the biggest problem currently is the enormous effort and cost of conducting periodic clinical evaluations to determine if subjects have declined or developed dementia. Research to develop more efficient assessment methods is clearly needed. Data acquisition over the Internet is potentially efficient and attractive and may become practical as Internet accessibility increases.