Despite my planned reduction in posting, I wanted to present a further reason/theory this morning regarding why the surrogate trial requires 300 enrollment, and the confirmatory trial requires expansion to 348 (aka: 300 + 48). IMHO.
This first concept takes some distinction. I am talking about two things that often happen simultaneously, but there are some important differences, because this is two trials in one.
In the first portion of the trial, the surrogate primary endpoint for accelerated approval is progression free survival. Those patients are double-blinded until the entire trial is unblinded. Even if they event, they won't know if they received treatment or placebo in this portion of the trial unless this portion of the trial is unblinded.
The confirmatory endpoint, second portion of the trial, is overall survival. Those same patients are double-blinded from whether or not they are receiving placebo or treatment until they either: 1. Progress. In which case they will know anything they receive after progression is not a placebo. 2. The trial is unblinded.
As you may understand, there are some patients who progress that decided not to remain in the trial, (or they run out of maintenance therapy) -- therefore there are some patients who never receive therapy. While their survival would likely be monitored, the confirmatory trial trial would become relatively undersized in terms one or both post progression arms. It is for this reason that while the second/confirmatory trial is part of the first/surrogate trial, it must really be treated as its own statistical entity for purposes of powering it properly.
If my line of reasoning makes sense, the question became how many more patients would the confirmatory trial need to appropriately finish/power the confirmatory trial. It was 312 (aka 300 + 12), IMHO, but of course that was just a guess. After careful long term monitoring, the trial, without unblinding, determined that they would need 300 + 48 instead. Those patients being added after 300 enrollment was reached will likely be unblinded relatively quickly after they are enrolled, IMHO. And why not? The goal for the overall survival portion of the trial was not to have patients on placebo. Instead, once the placebo/surrogate/accelerated approval portion of the trial concludes, there is no reason to have anyone on placebo.
Still, the process of enrollment while the placebo trial is still in effect allows identical blind randomization methodology -- including that for subgroups -- even for patients really only being added to the confirmatory trial. This avoids any "cherry picking."
There is some thought, based upon Pyrr's prior reading of the old protocol, that the 32 (used to be 72) pseudo arm will actually ultimately be counted as part of the 348. Whether this is true or not, it would still leave 16 to enroll after the primary/surrogate endpoint enrollment of 300 was met. One can fuss back and forth with this quandary, but it does not change the overall theory.
But for now, let's keep it simple and say they needed to add 48 more patients after 300 enrollment was met. Why add anyone at all unless the primary/surrogate endpoint was met? Why only stop screening but continue enrollment? Why send documents to regulators unless the primary/surrogate endpoint was met? Remember, for accelerated approval, you have to show the next (second portion in this case) trial is well underway before they grant AA, and it really helps if you already have full enrollment. Why? Because historically, drug companies were dragging their feet on completing confirmatory trials, just in case their post approval therapies failed them. Hence the two in one trials we often see today.
How is any of this helpful? From my perspective, it means to me that completing enrollment ensures integrity of the trial for purposes of blinded randomization. If we are indeed submitting documents based upon the 1st IA, the results should be powerful enough to guarantee success. In other words, it's highly unlikely regulators will make NWBO go back and get more data from the surrogate portion of the trial. Completion of 348 enrollment, imho, will mean much more than what one might otherwise think.
Respect Risk. Conduct Your Own Due Diligence. Manage your assets wisely. Diversify.
