Flipper, thanks for the DD on the crossovers. That confirms what I thought was the case, that the crossovers will have their own calculation for OS.
Great job on your analysis. I hadn't framed it that way before, that there is no control arm for OS. The independent variable for OS will be the timing of the DCVax-L treatment after SOC, not DCVax-L vs. SOC. DCVax-L is given either shortly after the initial SOC, or later after longer SOC, after the patient has crossed over.
I believe that your conclusion is correct that the crossovers can't hurt DCVax-L's odds, but could help.
But I don't think the crossovers have to have a dismal OS for the DMC to recommend unblinding. In the crossover group they will still measure the tumors. And they'll have a new baseline. The tumor size at the time of the crossover will be the starting point, not the tumor size at the start of the trial.
If the stats show that a significant percentage of the crossover patients now have shrinking tumors, even if the OS stats for the crossovers don't make a statistically significant case for unblinding, the DMC would have to see that as a strong argument for unblinding.
I raise this as a possibility because if the vaccine helps some or a lot of the crossovers, the death rate between the crossovers and the DCVax-L arm might not be statistically significant yet.
But if 30-60% of the crossovers either have shrinking or stable tumors, when prior to the crossover 100% had progressing tumors, the DMC wouldn't be able to ignore that data, regardless of the OS stats.
But it all starts with great PFS stats for DCVax-L vs. the control group. If those numbers are there, then the DMC will look at all the stats more carefully before they give NWBO their recommendation. Recommending an early halt isn't something to be taken lightly. The possibility exists that even if the DMC recommended that, that the FDA wouldn't grant early approval. Measure twice, cut once.
So if the DMC is taking their time, I think it's a positive sign. But without knowing when the events were reached and when the DMC started their analysis, it's just conjecture on my part.
