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Re: Doc logic post# 86142

Sunday, 12/04/2016 9:07:44 AM

Sunday, December 04, 2016 9:07:44 AM

Post# of 682063

"The problem with great treatment success and SOC expectations that are too low is that it puts too much pressure on the treatment arm events to end the trial." -- Doc Logic



And yet the length of the trial, now that we are past the approximate expected primary completion date, will make it possible to demonstrate the long tail -- which really, from a trial design point, should have been mostly absent.

The long tail, as LP liked to say, was somewhere around 30% of the patients.

However, by trial design, the majority of those expected types of patients were removed from the trial and placed in the psPD arm.

Depending on enrollment, we need somewhere around 71% to 75% of the entire group to event.

*Had there been no control group (everyone started on DCVax-L), and had the psPD been left in the main trial, as you probably agree, this trial might never reach 248 PFS events for a number of years.

* Had there been no control group, and as is the case, the psPD been removed, the trial may have taken yet another year or two to reach PFS 248 events.

*If we take the trial as it is, it still went beyond expectation, but as the FDA guidelines for immunotherapies suggest, sometimes enrollment and a higher number of predetermined events is needed to capture a true assessment of the sometimes delayed immunotherapeutic effect.

For the most part, the trial design appears to be correct. It was wise to remove most pseudoprogressors because the trial would have taken far too long (or it's possible the issues with potential misdiagnosis would have been more than a minor concern). It was wise to institute a 2 to 1 treatment/control ratio, because a one to one control would have ended the trial too quickly, and the long tail might have been minimized.

My point here is, well, we finally made it to the primary completion date, which is good for purposes of the trial; however, if all goes well and we get approval based upon that and that alone, what about the OS events? OS requires 233 events.

Look again at the paragraph in red up above. For purposes of OS, we've basically removed the control. True, it was done after each PFS event, but it was done nonetheless. It is my opinion that we are going to see a shorter placebo median than many suspect -- because most psPD were removed. That, to me means those early eventing placebo patients will get on DCVax-L much sooner on average than they otherwise would have if researchers left the psPD in.

Essentially, we've almost made it impossible to reach 233 OS events within any reasonable timeline. imho. Had there not been the crossover, we'd likely reach the secondary endpoint about a year or so after reaching 248 events -- imho. With the crossover, you might be talking 2 to 5 more years.

The designers, who included the FDA, must have thought they'd assured this wouldn't happen when they removed psPD, but guess what? It's happening -- imho. To me, the therapy appears more efficacious for everyone than researchers anticipated.

In other words, 233 OS events is not going to happen anytime soon. Maybe by the end of 2018 -- imho. However, by that time, the ability to help patients with an approved and improved DCVax-L plus CI might put that year much much further out.

Dr. Liau is right, that doesn't help the trial, but she meant that for the secondary endpoint. IMHO, for purposes of approval, the crossover will not slow down the approval timeline, because approval should be done with profound PFS improvement plus an OS trend. The spirit of the Cure's Act should make that even more probable. Safe and efficacious.





















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