After a reflective Thanksgiving, please settle any uneasiness, preoccupation and most of all confusion resulted from the question: what on earth is "the reason behind the long delayed" TLD/publication. Today it has been well known about the phenomena of pseudo-progression and cross-over associated with most immunotherapeutic clinical trials.
As a result, the trials today can follow related regulatory guidance in design to circumvent the potential unfavorable effects of pseudo-progression and cross-over. But for a 15-year old trial which was data locked on 5 October 2020, its sponsor NWBio had no luxury back then. In light of the endless confusion still existing today, please allow me for a quick rehashing on what has been going on:
About in 2014-2015, the company finally realized its initial endpoints might be compromised due to recently known pseudo-progression phenomenon. Despite pseudo-progression in and by itself may actually indicate stronger than expected immunogenicity, i.e., it's inherently a good thing, it may wreak havoc with PFS as the primary endpoint.
Evidently, FDA halted the trial prohibiting the company from screening new patients in order to protect new patients from being harmed. Note any regulatory agency would not wait for the company to prove otherwise if they deem patients may experience harm. To get the trial halt lifted, the burden obviously fell upon NWBio to prove. NWBio's opinion obviously is there is no harm to any participated patients for the reason of pseudo-progression. Evidently in Feb 2017, FDA agreed with the company. As a result, it lifted the halt.
Concurrently with pseudo-progression, by the time the company also realized its initial overall survival secondary endpoint might also be compromised because by design patients in the trial would switch (cross over) to receiving DCVax-L vaccine at disease progression so that about 90% of all the patients enrolled have received DCVax-L. That may make accurately measuring the efficacy of vaccine problematic between both the control and treatment arms of patients.
In order to solve the two potential problems (pseudo-progression and crossover) above, it became natural and necessary for the company to revise its initial SAP in which trial endpoints are significant parts. Today we know both UK and Germany have accepted the changes, evidenced with their respective government responsible update in their clinical trial registries:
"The primary endpoint of this study is overall survival (OS) compared between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma.
Secondary end point(s)
The first secondary endpoint is overall survival (OS) compared between patients randomized to placebo who received DCVax-L treatment following disease recurrence, and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.
The second secondary endpoint, confirmed progression-free survival (cPFS), is confirmed disease progression (cPD) compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study.
The third secondary endpoint, PFS, is progression-free survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study.
The fourth secondary objective, OS, is overall survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study.
The fifth secondary objective is tumor response compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study."
Please note the initial primary and secondary endpoints are still part of the revised endpoints. It just now they are ranked the third and fourth endpoints (see above above).
So obviously NWBio will have plenty of explanation work to do to persuade and convince those who have doubts due to a variety of reasons. As a commercial company with only one product in the late stage development, it may not be rational and reasonable for the company to proceed in the direction of what seems familiar for most people: release TLD shortly after data lock, followed by publication/conference presentation, months if not years thereafter, considering the potential relentless malicious attacks the company had received in the past, because the trial results upon and after published will be most likely diced and spun in any negative way possible regardless how good the results will be.
This I think is the fundamental reason why we have been heading in this direction of making the trial data go through the multi-step reviews by "the Company, the Principal Investigator, the Steering Committee of the Trial, the Scientific Advisory Board, and a panel of independent brain cancer experts, who will analyze the data with the statisticians in preparation for public announcement and scientific publication"
Obviously the well analyzed and reviewed trial results published in a peer reviewed journal will be hard to rebuff; In terms of getting the vaccine approved, it may, by carefully making the preparation of data now, save time in the end.
Recently we have known the publication is in the stage of journal peer reviews. Hopefully it will not take long to get the publication out to the public.
Personally, I have been a buyer, even recently having taken a loan since I don't see any other reason not doing so for myself of course. I can accept delayed rewards from my investment after carefully reviewing what we are at and the share price which I consider it close to the price if the trial would fail its primary endpoint. As I have stated many times on this board, it's highly probable the trial will readily meet its primary and key secondary endpoints significantly based on what have been known to the public.
All the above are just my humble opinions. Good luck and be happy everyone!
