FUTILITY ANALYSES IN ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: A RISKY BUSINESS

Abstract

In the standard, orderly progression of drug development trials, a moderately-sized Phase 2 trial demonstrates safety and efficacy of one or more doses of the investigational product, followed by large confirmatory Phase 3 trials of one or two doses leading to regulatory approval. The large and lengthy Phase 3 trials often include interim futility analyses using statistical methods to assess lack of benefit, so that programs “fail early” by identifying ineffective treatments early if evidence points toward lack of efficacy, in part to limit financial loss and redirect resources. For disease-modifying drug development programs in Alzheimer’s disease (AD), finding an optimal strategy is particularly challenging. A slowing of decline rather than symptomatic improvement indicates disease-modification, and primary outcomes for such trials are noisy and sometimes subjective. As a result, very large, lengthy trials are required to see efficacy signals, so Phase 2 trials may look like Phase 3 programs or Phase 3 trials may directly follow Phase 1 trials. In other words, enormous trials may be launched without sufficient evidence of preliminary efficacy of the doses studied, dramatically increasing the financial risk to sponsors. In such instances, futility analyses embedded in trials would seem to be particularly important.