Replies to post #47417 on NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

It's called a resizing, and it can be done without unblinding the trial and without conducting an interim analysis. Which it was. Therefore no DMC analysis was conducted. Therefore the trial was not resized because the results were meh, instead, they don't know the efficacy results.

Instead it was resized to account for a new variable, as a precautionary measure.

The Company has been blinded at all times, with no access to any data in the Phase III trial, and will remain fully blinded until the trial is completed. The changes relate to the statistical analyses that will be done at the end of the trial, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects. The changes were driven solely by external factors — particularly research reports about a newly discovered variable which has been found to significantly affect GBM patients’ survival times, and which the Company recognized could significantly skew the clinical trial results if the trial’s statistical analyses did not control for it. The Company’s Phase III trial design and statistical analyses already controlled for key variables known at the time when the trial was designed, such as a particular genetic factor (referred to as MGMT methylation), the extent of tumor removal, and others.

The new variable involves the level of certain white blood cells in GBM patients when they finish the 6 weeks of daily radiation to the brain which is part of the current standard of care treatment. Important recent research has found that as many as 40% of GBM patients have such severely depressed white blood cell counts following radiation that their level is comparable to the level at which AIDs patients are put on continuous antibiotic treatments, prophylactically. Further, this research has found that these GBM patients’ white blood cell counts do not recover with the passage of time. See, for example: Grossman et al., 2011: Clin Cancer Res 17(16):5473-80; Ellsworth et al. 2014: Oncoimmunology 3(1):e27357. Epub 2014 Jan 3.

Most importantly, the recent research has identified a major impact on these GBM patients’ Overall Survival (OS): the variable relating to severe depression of white blood cell counts can make a difference of 6 months in OS. As a comparison, the standard of care drug for GBM, Temodar, only makes a difference of 10 weeks in OS. If the statistical analysis of GBM trial results does not take account of such a major variable, the overall trial results could be significantly skewed.

Under the enhancements to NW Bio’s Phase III trial, the statistical analyses of the trial results will be modified to take account of, and control for, this important new variable.

Also under the enhancements, the threshold for satisfying the primary endpoint of the Phase III trial (which is Progression Free Survival, or PFS) will be lowered from requiring a 6-month difference to requiring only a 4-month difference between the PFS of the patients treated with DCVax-L and the PFS of patients in the control arm of the trial.

....And the regulatory agencies approved the changes.

We are grateful to the regulatory agencies for allowing us to take account of important new research findings in our ongoing Phase III trial, to control for a variable that could have significantly and artificially distorted the trial results, and we are grateful to be able to maximize the number of “events” to be counted from the patients in our trial,” commented Linda Powers, CEO of NW Bio. “Although it has been a long process to obtain approvals from three different regulators for these enhancements of our trial, we believe that achieving approval for these changes will be of great value to the ultimate results of the trial and to the building of shareholder value.”

[sentiment_stocks]

Adam, the DMC have the power and authority to recommend to the sponsor that the trial be altered or enlarged, even while the sponsor is blinded. Remember, the sponsor is blinded to ALL PATIENT EFFICACY DATA during the trial.

Now note, a sample size re-evaluation was designed into the trial… once the trial hit 80% enrollment *** that means those patients were through the pipeline and randomized INTO the trial *** and note, the previous main arm enrollment number was 240. What do you bet they hit that 80% main trial enrollment number in the time frame, and that’s when the DMC recommended enlarging the trial.

So that means that by around the time the DMC (not the sponsor) were reviewing the data on the 66 patients (December 2013 through February 2014), the trial reached 192 patients. (240 x 80% = 192). And as we know, around that same time, they had reached 66 events. Now, they went quiet in June 2015, and no first interim analysis for efficacy had occurred prior to that because Linda was still telling us it was still coming in the May presentation. So perhaps by June 2015, they reached the NEW 1st IA number of 149 events. And I say perhaps. We really don’t know. Maybe they didn’t, and that would even be more remarkable.

But say they did… and let’s pretend for a moment that they never enrolled another patient after February 2014 and thus, had only had 192 patients enrolled. So by a full 12 months later, we still haven’t reached 149 PFS events. Huh.

And we still have to go another 4 months, or 16 total months, to reach 149 PFS events. So that means that if the trial never increased past 192 from Feb 2014, it took a full 16 months for 83 more patients from 192 “pretend enrollment” to reach the required 149 events.

Gosh, and there were even 64 of them that were placebo patients. 16 months is an awfully long time for 83 more (from 192) newly diagnosed GBM patients to just event. Maybe they actually had to add more patients just to get some more placebo patients into the mix.

Yet you think the DMC recommended Linda halt the trial for futility, and she said no way, let’s not only move forward, let’s increase the size! Well, it seems a good thing she did because it took a long time for this trial to reach just 149 events.

[Tony888]

The only reason for the changes made was because the interim efficacy analysis was conducted and came back showing DCVax to be futile, or at best, just barely maintaining a difference from placebo above the O'Brien-Fleming boundary for the PFS primary endpoint.

Then are you saying that the chairman of the DMC is lying and committing fraud?

[spartex]

Hahahaha. Needed a good laugh today after reading this old post of yours. How about you?