The second dosing was originally intended as a rescue dosing or patients wouldn't participate in the trial. After progression (whether clinical or pseudo) triggered the second dose. That was the primary endpoint of the trial as defined in the original trial protocol, and reiterated in Dr. Liau's 2018 interim trial publication. NWBO reported the confounding repeatedly in their SEC filings:
"With the change in protocol, the double dosing became confounding of the naive OS endpoint as called out by NWBO in their 10K SEC filing. From the filing:
The statistical analysis plan that we submitted to regulators for the Phase III trial embodies a different primary endpoint and secondary endpoint than did the original Protocol for the trial. Under the Protocol the primary endpoint was progression free survival, or PFS, and the secondary endpoint was overall survival, or OS. Both of these endpoints were confounded: the PFS endpoint by pseudo-progression, and the OS endpoint by the “crossover” provision in the trial design, which allowed all of the patients in the trial to cross over to DCVax-L treatment after tumor recurrence (while remaining blinded as to which treatment they received before tumor recurrence). The statistical analysis plan uses external control patients rather than within-study controls. There can be no assurance that regulatory authorities will allow a product approval to be based upon this approach."
NWBO's statisticians performed statistical manipulations of the naive OS endpoint to attempt to compensate for the confounding. So the naive OS endpoint reporting is statistically manipulated. We'll see how regulators react to the double dosing bias of the trial as the external comparators were not screened for dosing.
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