Re: SE "robustness" issue. Discussions on the board recently have commented on the order of statistical testing for SEs (components of MACE) described in the design paper and the p values required for significance of these. JL and others have noted that R-It might continue to the end of the trial simply to maximize numbers of events for more rare SEs (like CV death) so that they achieve significance. Makes sense, but...
An FDA guidance I posted quotes from a while back made very clear that the only reason you would need statistical significance for SEs using ordered testing on the MACE components was IF FDA labeling was being sought for those specific components ("V reduces CV deaths"). It would obviously be terrific to be able to say this.
The company, on the other hand, in a conference call when they revealed the revised SPA said quite specifically that statistical significance was not required for the SEs, but rather they just needed to be "robust." They know the FDA rules, so this says to me that they are simply going for expanded labeling to a wider TG range, rather than worrying about (i.e., instructing the DMC via rules provided) getting labeling for "death" or "MI" specifically. If it all works out perfectly using sequential testing, I am sure they will go for this more detailed labeling. But if not, I think they will be quite happy with just an expanded TG indication.
Bottom line is that if we can trust what the company said, there is no reason they have to delay results for a year on the chance that individual MACE components might become significant solely for the purposes of getting a very specific labeling that is more "gravy" (death) than meat (TGs).
The composite PE is made up of the 5 MACE components. To have a good RRR for the composite measure, these components largely have to agree at least in their trends ("be robust"). I predict a stop at 80%, and if there isn't one, I think the final RRR is going to be (hopefully) close the originally targeted 15% RRR. They would be continuing in this case because the PE is not strong enough to stop and they are seeing trends that it may be improving a bit (e.g., slowing of events hence the new guidance on final event in 2018, changes in slope of events between 60% and 80%). Just my opinion obviously.
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