Replies to post #232493 on NorthWest Biotherapeutics Inc (NWBO)

[biosectinvestor]

I’m not going to refute every point this time of morning... but...

You contradict yourself repeatedly in your reply... is, is not, so and so thinks it was ... no was is was not a safety issue...but we knew it wasn’t... but not really because...

Then back with the suppositions... they must’ve because if they didn’t how would they know about the “safety issue”... that wasn’t...

I did not say the FDA halted the trial for “efficacy”... that has yet to be proven, which is why the trial was not halted... nor was it a full hold... it was a partial halt... and press releases ...

Here it is:

https://nwbio.com/nw-bio-announces-lifting-clinical-hold-dcvax-l-phase-iii-trial-fda-progression-free-survival-events-reached-overall-survival-events-not-yet-reached/

“BETHESDA, Md., February 6, 2017 – Northwest Biotherapeutics (OTCQB: NWBO) (“NW Bio” or the “Company”), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, today provided a further update about the Company’s Phase III trial of DCVax®-L for Glioblastoma multiforme (“GBM”) brain cancer (the “Trial”). The Company announced that the partial clinical hold on the Trial has been lifted by the FDA, and that the Trial has accumulated a sufficient number of events toward the progression-free survival (“PFS”) endpoint, but not yet for the overall survival (“OS”) endpoint.

The Company remains blinded to all Trial data, and is only receiving and reporting updates on a blinded basis.

On February 3, the FDA lifted the partial clinical hold which had been in place on the Trial. As previously reported, the Company has been in an ongoing dialog with regulators. The dialog culminated in the FDA lifting the partial hold. As previously announced by the Company, and as the Company also informed the FDA, the Company has closed enrollment and is not going to enroll the last 17 of the planned 348 patients.

There are 331 patients enrolled in the Trial. The Trial endpoints involve thresholds of 248 “events” for PFS and 233 “events” for OS. PFS events are primarily tumor progression (i.e., recurrence), although they can occasionally be patient deaths which occur without prior evidence of tumor recurrence. OS events are patient deaths. The PFS and OS events are continuing to accumulate as the Trial continues. The PFS events have surpassed the 248-event threshold, but the OS events have not yet reached the 233-event threshold. Based upon the pace of OS events during the last six to eight months, the Company’s current anticipation is that it will be several months until the Trial reaches 233 OS events.

Dr. Linda Liau, Principal Investigator of the DCVax®-L Trial commented: “It is gratifying to have the hold removed from the Trial and exciting to see this Trial now moving towards completion, although of course the longer it takes for PFS and OS events to accrue, the better the patients in the Trial are doing.””

Partial hold... for enrollment...not treatment... and the 331 was still enrolled... just not the larger number they were going to add at that point...

There are plenty of indicators suggesting what I’m saying. I just don’t want to reiterate it for the nth time, and I don’t honestly care if you believe my theory. I don’t particularly want anyone to buy the shares... I just don’t like what looks like a disinformation campaign to go unchallenged.

https://nwbio.com/nw-bio-corrects-ongoing-false-claims-by-feuerstein-about-phase-iii-trail-of-dcvax-l-and-interim-analysis/

“Press Release

13
AUG
2014
NW Bio Corrects Ongoing False Claims By Feuerstein About Phase III Trial of DCVax®-L, And Interim Analysis
Posted By :
Comments : Off

Phase III Trial Is Alive And Well;  “Hint Of Failure” A Complete Fabrication;
No Interim Analysis of Efficacy Done;  55 Patients’ Positive Data Independently Collected.
BETHESDA, Md., August 13, 2014 – Northwest Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, today corrected ongoing false claims by Adam Feuerstein published on the TheStreet.com about the Company’s Phase III trial of DCVax-L for Glioblastoma multiforme (GBM) brain cancer:
* No interim analysis of efficacy in the Phase III trial has been done.
* The Company has had no access to any Phase III trial data at any time.
* The Phase III trial was and is solidly designed and progressing;  the enhancements just announced further de-risk it;  the “hint of failure” claimed by Feuerstein is a total fabrication.
* The highly encouraging survival data on 55 patients released by the Company was collected and maintained by an independent CRO, not the Company.
 
The Company confirmed, yet again, that no interim analysis of efficacy relating to the Phase III trial has been conducted at any time.  The only analyses to date have been analyses solely about safety (not efficacy), and those safety analyses have been conducted solely by the independent Data Monitoring Committee (DMC), with no involvement of the Company and no communication by the DMC to the Company except to direct that the trial should continue.  The Company has had no access to any information about either safety or efficacy in the trial at any time.
“As the Company has stated clearly and specifically in its public announcements, the DMC has not conducted any efficacy analyses and the DMC has not provided any access for the Company to any clinical trial data,” commented Dr. Curt Furberg, Chairman of the DMC.  “The DMC adheres to established clinical trial monitoring procedures and does not release any data while the trial is ongoing.  This is an important issue, and it is surprising and troubling to see inaccurate claims being made by commentators who seem to lack a fundamental understanding of clinical trial monitoring.  I have been on the DMCs for more than 60 clinical trials, and I have never experienced this type of attack.”
Since the Company has had no access to any data about the trial at any time, it was impossible for the Company to have been motivated or shaped by any such information or any “hint of failure” about the trial in seeking regulatory approvals for the enhancements of the trial announced on Monday.  Feuerstein’s assertion of such “hint of failure” lacks any basis and is a total fabrication.
The fact that the Company has had no access to any trial information was also a key factor in obtaining approval from the regulatory authorities in the US, UK and Germany for the enhancements to the trial.  Regulatory authorities do not allow changes to be made in an ongoing randomized, blinded trial if the changes are, or might be, based upon any knowledge about clinical data in the trial.
“The fact that there has been no interim analysis for efficacy and that the Company has had no access to trial data, is very clear and very simple,” commented Linda Powers, CEO of NW Bio.  “There is no room for any honest confusion.  Feuerstein’s ongoing false claims about these points are either deliberate falsehoods or reckless disregard of the truth.”
The Company reiterated that its Phase III trial was already solidly designed prior to the enhancements just announced, with a conservative assumption that the extension of Progression Free Survival (PFS) in patients treated with DCVax-L in the Phase III trial would be only 1/3 as long as the extension of PFS (compared to PFS with standard of care) that was seen in patients treated with DCVax-L in the Phase I/II trials.  This conservative assumption in the Phase III trial design was and is also combined with strong statistical powering in the trial design (with an anticipated “p value” of 0.02).
The enhancements of the Phase III trial do not in any way seek to “rescue” a trial that is already strong and solidly designed.  The changes seek to prevent external variables from potentially distorting the results of the trial, while also having the added benefit of further lowering the threshold for the primary endpoint to be met from 6 months’ difference in PFS to 4 months’ difference in PFS between patients treated with DCVax-L and the control arm.  This is a further de-risking of the trial, and as such is a valuable enhancement.
The Company also reaffirmed the encouraging survival data in 55 compassionate use “Information Arm” patients that was released by the Company.  All of the data was collected and maintained by an independent contract research organization (CRO), not the Company.  The Company reported clearly that the data were gathered in a compassionate use “Information Arm” outside the Phase III clinical trial.  The Company simply reported the factual results gathered by the independent CRO.  Even Feuerstein acknowledges that the data are strikingly positive.
Feuerstein’s questions about why those 55 patients were handled separately from the Phase III trial are once again baseless and reflect a lack of understanding of clinical trial design.  As the Company explained in its announcement, it is well established in the medical and research communities that “rapid progressor” GBM brain cancer patients have a significantly different version of the disease than regular GBM patients.  It is fundamental to clinical trial design that the patients included in a trial must be as homogeneous as possible, in order for the data to be as comparable as possible among the patients in the trial.  The Company has followed these fundamental principles in its Phase III trial design.
The Company re-confirmed that the Phase III trial has, in fact, expanded to multiple sites in the UK and Germany as the Company has previously stated.  Feuerstein’s false claim that “none of the European sites have materialized” is directly contradicted by the Phase III trial profile on www.clinicaltrials.gov that he himself cites.  At the bottom of the trial profile there, both the first UK site and the first German site in operation are clearly listed. The listed UK site has been in operation for well over a year.  The listed German site was the first among several German sites to which the trial has expanded.”

[jammyjames]

I do think lf's theory of an issue with the placebo is the closest to being correct... Exactly what that issue is who knows. But I think it fits best with what we know.

We know they fully enrolled treatment arm. This wasn't just random chance as that is extremely unlikely and more importantly there's a slide from liau or bosch stating 'original randomization - 2:1'. They wouldn't have put that if the randomization hadn't changed.

The theory also semi explains the silence over the reason for the hold as it was needed to maintain the integrity of the trial. Otherwise all the last patients enrolled and their physicians would have known they are in the treatment arm.

It's also "not necessarily a bad thing" as I guess those patients who would have ended up in the control arm could get dcvaxl compassionately.

The idea that they put all the patients on treatment after a futility rec is a bit hard to swallow. If it's looking like you're not going to hit stat sig difference between the arms why would you go and make life even harder for yourself to hit stat sig difference by doing that?

[longfellow95]

First, it is a clinical hold (at least in the US). Not a halt or partial halt. The FDA issued hold was only partial, that is true. But still a hold. Straight from NWBO:

Quote:NW Bio Announces Lifting of Clinical Hold on DCVax®-L Phase III Trial By FDA; Progression-Free Survival Events Reached; Overall Survival Events Not Yet Reached

It was a partial clinical hold. You've clearly forgotten it's been lifted!
Even 'clinical hold' is a bit of a misnomer. All randomised patients receiving treatment as per protocol. But seeing as FDA use the term, we're stuck with it.

Most all agree it was not a safety issue (though longfellow has suggested the possibility that the actual placebo caused damage as it is active).

Did I?
I've made a few guesses (and haven't controlled for multiplicity) in the past couple of years, but don't recall making that one. I have speculated about possible dose mix up for a control patient, seeing as they will have two sets of doses.
So, a DCVax vial being shipped instead of a placebo vial (or vice-versa). Or even a deliberate tampering of labels. Unlikely it may be, but not impossible.
Other possibilities include an FDA inspection to Memphis perhaps identifying a manufacturing issue or labelling issue or storage issue, or drug trail auditing issue.
FDA conducts hundreds if not thousands of such site inspections each year. And I bet they did one on this trial.

Shelf-life issue? A late progressing control patient might require a treatment dose that was produced more than 3yrs previously, when shelf-life had been previously stated on German documentation as 3yrs, creating a possible conflict with what may have been stated on a consent form.
FDA maybe required real time testing of extended shelf-life.
Still my favorite theory, even though it is probably wrong.

From FDA document on hold reasons:-

Product Quality:

Product has an impurity profile indicative of a potential health hazard or an impurity profile insufficiently defined to assess health hazard

Product cannot remain chemically stable throughout the testing program

There is no proof of the futility theory, that is true. But we do have these facts:
. A still unexplained FDA Clinical Hold
. An IA gone MIA
. Trial running years past the primary and secondary endpoints
. Changing the trial SAP, including redefining the primary endpoint

The fact that the partial hold remains unexplained, doesn't specifically point to futility in any way.
Same goes for an IA not being reported.
Trial running on since the Cretaceous in no way points to futility. The hold itself effectively depowered the trial significantly, by forcing NWBO to accept a 5% smaller trial size, and could be seen as a factor necessitating extending the trial.
Changing the SAP. Happens all the time. Pseudo-progression issue may have required that.
Redefining the primary endpoint? Certainly not a fact.
No evidence that they have changed the PE.
Added a layer of EP adjudication, yes; redefined it, no.

Yes, of course a lot has gone wrong over the years with this trial. Starting way back when, with the FDA reportedly requiring the crossover..
Thereby muddying OS.
Why didn't they do the same in Checkmate-548?

In fact none of your facts (term used loosely), point a finger at futility any more than they do at any other type of DMC recommendation.