Replies to post #63729 on NorthWest Biotherapeutics Inc (NWBO)

[md1225]

Great post RK must read for anyone long!!!

Chris LaCoursiere

220k shares long

[Pyrrhonian]

The DMC may have recommended they halt the study for futility after seeing an excessive number of PFS events in DCVax-L group, and/or suggested they pause screening and submit info to regulators to engage them in dialogue about it, and perhaps request changes to the trial or say they want to continue despite what the DMC saw and recommended, as the blind has been maintained. And maybe they were able to use info outside the trial as well to explain immune response in GBM can cause false PD signals and try to use that to help their case. Would regulators agree to that? Revamping trial with OS co-primary or just primary with no crossover? Imo probably not, but I'm no expert.

But if a sponsor pauses screening they don't need regulators to allow them to screen again. Only if regulators placed a hold on an IND do they need them to remove that hold.

If you want to assert FDA has not placed a hold this is the best evidence (8-k from Dec):

"There is no pending, completed or, to the Company's knowledge, threatened, action (including any lawsuit, arbitration, or legal or administrative or regulatory proceeding, charge, complaint, or investigation) against the Company or any of its Subsidiaries, and none of the Company or any of its Subsidiaries has received any notice, warning letter or other communication from the FDA or any other governmental entity, which... imposes a clinical hold on any clinical investigation by the Company or any of its Subsidiaries."

https://www.sec.gov/Archives/edgar/data/1072379/000114420415073181/v427716_ex10-1.htm

Although the preamble "Except as set forth in the SEC reports," could disqualify that mention, it would be quite inflammatory for NWBO to have written that if one had really occurred, imo. But maybe...

So either

-NWBO initially paused screening, and has maintained this screening halt until today, without regulators issuing or maintaining any hold

-NWBO initially paused screening, and then submitted info to regulators, who after reviewing or after some time of dialogue then issued a partial clinical hold, thereby the 8-k that says they had no outright hold in Dec was true, but before March (10-k release) there was an actual partial hold placed, and so we have that language in the last 10-k.

-Regulators were all along the cause of initial pause in screening and current partial hold, being both one and the same

Take your pick I guess :) I think the second one sounds about right.

[longfellow95]

RK.

Thankyou for this very well-reasoned and well-argued post.

I think your conclusion, that the company probably initiated the hold in order to submit some protocol changes is most likely correct.

Although they probably initiated the hold, in doing so, they effectively lost control of timetables, and put themselves in the hands of the FDA, who could respond expeditiously, or more likely in a 'leisurely' fashion.

Possible protocol changes?

Well, elevating OS to co-primary endpoint is a possible. I think maybe unlikely though. As we know, OS is somewhat compromised because of crossover, and even if median OS proves to be totally unprecedented, as I'm sure it will, it can only be measured against historical norms, due to absence of control, hence of limited statistical value. Plus the issue of possible use of other post-crossover therapies. And the OS data will take several years to mature...
You could not estimate trial ending Sept 2016, if this was your co-primary endpoint.

Employment of immunotherapy imaging protocols?

More likely I would suggest.
From NWBO's point of view, they cannot allow the trial to fail on its primary endpoint, due to pseudo-progression being mistaken for disease progression. Use of iRano or irRC would ensure that that scenario does not happen. It's a tad unfortunate, that the original trial design goes back to a time when pseudo-progression had not been fully recognised, as a confounding factor. This would fit with the comment from Doc Bosch that the pseudo-progression issue was wreaking havoc with clinical trials.
Though quite how you go about retrospectively re-visiting progression decisions, using immunotherapy imaging criteria is not easy to see.

Subgroup identification?

Can they identify mesenchymal patients prior to commencement of L therapy? If so, how? What is the test? If they want approval for a subgroup, then there must be a routine test to identify a subtype prior to commencement of an approved therapy.

High TIL score? Same thing applies. Must be a simple test that can identify trial patients with this attribute, prior to commencement of therapy.

Heck, if they were submitting protocol changes, perhaps they took the opportunity to include patient-reported quality of life. An often forgotten major advantage of immunotherapy. Especially when compared to Keytruda, with its frequent serious and debilitating side-effects, and Optune, with its deleterious impact on patient life quality, when 'worn' for the recommended eighteen hours a day.

You only need to read a few of the patient forums to see how some of the treatments (excluding L) make life so very difficult. This is where L additionally scores.


If there is justice in this world (which I sometimes doubt..) then approval of L will be expedited some time, somehow, this year.