Have you ever been jolted wide awake by—biostatistics? That’s what happened on the last morning of the Clinical Trials on Alzheimer’s Disease conference held November 5-7 in Barcelona, Spain. At 8 a.m., as sleepy CTADeers slowly shuffled in, Suzanne Hendrix of Pentara Corporation, Salt Lake City, Utah, delivered a triple espresso in the form of a keynote calling on trialists to move beyond the scales they currently use to measure drug effects in early Alzheimer’s disease trials. In language that made statistics accessible well beyond the small geekdom of biostatisticians, Hendrix laid out how current power and regulatory factors conspire to prevent trials from showing cleanly in Phase 2 whether a drug works. In effect, the status quo overprotects the null hypothesis that the drug does not work, Hendrix said. For their part, outcome measures are weighed down by items that add noise without reflecting disease progression, and the CDR-sb is clinically meaningful but not granular enough to be a good trials outcome. Hendrix’s solution: build lean composites with items that, in math lingo, add up to a “summed vector” that basically is the direction of the disease getting worse. Hendrix showed examples of how composites developed by different groups compared in a given study population to more-established measures such as the ADAS cog or CDR-sb. Hendrix argued for separating the measurement of a cognitive drug effect in early AD from the assessment of whether that effect is clinically meaningful for early stage patients, who are not impaired or barely functionally impaired. Optimizing tools and statistical requirements for a stepwise process, rather than trying to do both in one go, would open the way to more successful therapy development in early Alzheimer’s. Senior clinicians in the United States and Europe praised the talk.
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