NorthWest Biotherapeutics Inc (NWBO)

[AVII77]

AV. You keep trying to relate the hold to a prior IA, to support your theory of a futility finding.
If you believe the two things are connected (and there is no good evidence that they are), then how do you explain that patients joined the trial right up until Nov?

Because they were consented at surgery (prior to the hold).

BTW, I was the one who showed randomization continued after the Aug 2015 hold (by pointing out the patient accounts of jefeGBM and Dudeknee).

An alternative plausible theory would be that an IA found that the interim data was right on the margin for stopping early for efficacy, such that the FDA, after being consulted, felt that further recruitment to placebo was not warranted, but that the trial should continue, in order to statistically confirm the signs of PFS efficacy seen at interim, to further reduce the possibility of a Type 1 error, and to elucidate OS benefit. That would fit the scenario better than your hypothesis, I would suggest.

If the interim analysis showed the data was "right on the margin for stopping early for efficacy" the DSMB rec should be "continue".

This situation is like a Ulysses Contract; the role of the DSMB is to resist the sirens song. "Right on the margin" may tempt a PI, but the DSMB should be mature and unbiased to rec a continue.

Some trials continue even after crossing the "margin" to collect additional data.
See my post from a couple years ago exploring this.

There the SPRINT trial DSMB continued after crossing an efficacy stopping boundary.

Similarly the JUPITER trial continued after crossing an efficacy stopping boundary.

The Zytiga 301 trial continued after crossing a stopping boundary (though this is debatable).

The DCVax trial primary is a surrogate endpoint (PFS). Even if it crosses the interim threshold there are valid questions on if you should stop (and this relates to LP's comments at the 2014 ASM conducted in early 2015, prior to the planned first interim). If a surrogate EP were "right on the margin" at an interim I can't think of any reason whatsoever to stop enrollment.

Another alternative might be that an IA gave a simple 'continue' recommendation. If so, NWBO might have been majorly disappointed, because they may well have been hoping to stop early for efficacy, based on interim findings. And such a 'continue' rec may have been enough to alert them to the possibility that pseudoprogression after DCVax, may be depressing the PFS delta somewhat.
In this scenario, the hold would likely be unrelated to a prior IA.

OK, then why not simply say :the IA was conducted and the DSMB rec'd a continue?

Rather,they are silent on the summer 2015 interim.

And again, I believe the silence is to protect from 10b5 fraud claims. They are permitted to stay silent. What they can not do is say something positive about the interim but, at the same time, withhold negative information.

"It is unlawful .....To make any untrue statement of a material fact or to omit to state a material fact necessary in order to make the statements made, in the light of the circumstances under which they were made, not misleading,"

So, imo, your theory is one of only half a dozen that could be advanced as plausible.

And it just doesn't fit well, with what we might construe about the nature of the hold.

I haven't seen a better theory.

Nor a good refutation of my theory.