The CDR‐SB and other clinical trial mistakes made due to regulatory momentum

In 2013 the FDA released a draft guidance for developing drugs for the treatment of early stage Alzheimer’s disease (AD) with the CDR‐SB suggested as a suitable scale for a primary outcome. Since that time, this suggestion has been treated as a regulatory requirement, but a single endpoint is preferable to the co‐primary endpoints necessary in mild‐to‐moderate populations or when using an outcome besides the CDR‐SB. Although it is true that AD progression is mostly represented by a single dimension, the FDA incorrectly claimed that CDR‐SB represents this dimension, when this would be true only for an empirically‐derived composite outcome, like ADCOMS. Years of damaging regulatory momentum surrounding clinical trial outcomes has resulted in equivocal results in nearly all development programs. The only major approval in almost two decades (aducanumab) was granted without definitive success in the primary outcome (CDR‐SB) partially because of this.