Aug 23, 2021Liked by will-e

A correction on point 1 in your timeline:

Biogen's analysis, which showed a positive result in the first trial (EMERGE) in all of its primary and secondary cognitive endpoints, and a negative result in the second (ENGAGE), was done on the initial, pre-designated endpoints. It was only a "reanalysis" in the sense that it (rightly) used all of the data collected during the trial (through March 2019), as opposed to the futility analysis, which used data collected only up until December 2018, when that futility analysis began. Note that the futility analysis itself did not conclude that both trials were unlikely to reach positive results, merely that the second trial was (and as a result, both trials were terminated, since a positive result from both trials was the requirement for the standard FDA approval path).

Separate from this, Biogen *also* conducted a post-hoc analysis on a subgroup (participants enrolled after the fourth version of the trial protocol) which effectively received a higher dosage of the drug. In that post-hoc analysis, the reduction in the pace of cognitive decline was 30% (95% CI [1%, 60%]) in EMERGE and 27% (95% CI [-3%, 57%]) in ENGAGE. There are good reasons to be skeptical of doing this post-hoc analysis in the first place, but 1) it wasn't the analysis which led Biogen to claim a positive result in EMERGE, and 2) I would argue (to the extent we suspend our skepticism of its rationale) it's a more promising result than you've portrayed it as: the post-hoc analyses from both trials yielded very similar conclusions, both skirting the edge of statistical significance, and both with effect sizes of about a ~28.5% reduction in the pace of cognitive decline, which I'd consider more than a modest clinical benefit (that would buy 40% more time for someone).

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