"Feuerstein-Rutain Rule" The phrase makes me want to puke. I consider a reference to that offensive vehicle for manipulation to be a bad sign.
I am not all-in yet because I am not rolling in cash this year; so I don't post much. But hearing reference to that rule gets me out of my shell.
There is definitely foreshadowing of Ph 3 failure. There are the early statements by LL regarding both legs doing better being bad for the trial, and there is the recruitment hold, allegedly by the Germans. Those things are good cause for the SP to have dropped from $12 down to $2 maybe... but here we are at $.35/sh, I believe a gift if you do not bet the farm.
While the cheerleader in me wanted to believe that the Germans would be the last to let a trial detail interfere with a trial, what are the odds that something like that happened? The Germans are sticklers to rules and detail as well as being rational types. Would they hold up recruitment over a GMP detail if efficacy stats looked good? Of course they might. But more likely there was no look at efficacy. In the era where the screening hold occurred there was a worldwide hunt for any repetition of a problem seen at some other (not NWBO/Cognate) facility where mold grew on a patient sample or some such. So they found mold at a Cognate facility? Maybe, but more likely they came up with a specific strict inspection guide-line of mfg GMP details within the wiggle room of interpretation of existing rules, that would have prevented the case with the mold, and then scrutinized every facility from that perspective. Perhaps they found the vulnerability at a Cognate facility and reacted with the screening hold.
So... they did this in spite of the results of their look at efficacy for consideration of hospital exemption reimbursement????? Maybe there was no look for efficacy. The company says there wasn't. But if so, then why not?
Maybe at this point there is not a forced look for futility? Maybe the futility concern is more about the sponsor wasting time and money than about patients being provided a useless new drug. Or... maybe the FDA can step in if they see futility, but maybe they can't initiate the look at efficacy. So if the sponsor does not call for a look, maybe the FDA does not have the opportunity to intervene.
The company made statements along the lines of not wanting to waste alpha spend. I don't remember the exact statements, but clearly they got paranoid about their SS margins (if only within multiple ways to win fall-back subgroups) when they expanded the trial. So leaning as low as they can in their soap-box derby car, by avoiding the alpha spend of an efficacy look would fit what I know and what they said.
Restated:
Prima Facie, the Germans took an interim look at the data in consideration of futility and or early reimbursement evaluation and found futility, and in response put a hold on recruitment. But what are the other possibilities?
1) Aforementioned GMP detail that may or may not effect trial outcome in spite of a positive read on the data.
2) Aforementioned GMP detail that may or may not effect trial outcome (and no read on efficacy has yet occurred, as the company has stated.)
Why then the defensive posturing by LL, even in her most recent presentation? Same reason every company postures defensively as trials come to full data. The trial is blinded, so they do not know what the outcome will be, period. Sponsors have to take a defensive posture. UCLA, and LL herself have to do similar posturing. Take a look at some recently approved drug that was not open label and see what kind of statements were made by those companies before the final read on efficacy and or FDA decision. I doubt you will find a company that did not posture in a scary way to investors. (though I admit I have not done that DD.)
But maybe LL was more defensive than usual. If so, why... ? She seems to concede that the outstanding efficacy numbers stated for Phase 2 will probably not be reached in the phase 3. She must have good reason to suspect that such is true... with more than just the placebo efficacy effect on OS as the culprit. Maybe she feels that is a potential embarrassment and or exposure for liability. But what long investor would be shocked by a phase 3 showing less efficacy than a phase 2? None. Literally none. At least nobody that has been around the block at least once.
And LL did continue to claim that she and many others in the position to know as much as possible, believe that DCVax-L will prove out to be effective at least in some subgroups. She didn't say it would get approval... and the debate about subgroups is over my head, but the fact that with all the final posturing she feels comfortable continuing to claim efficacy in at least some subgroup(s) makes the fair price for this stock a lot higher than $.35 in my opinion, and the odds of some kind of approval much higher than AF and company would have you believe.
Why subgroups over my head? I don't know which subgroups were called in advance and whether a subgroup that was not called in advance can get approval after some alpha spend and or SS threshold hit penalty for not calling it in advance... or whether it is simply ineligible. I believe they called the methylation variable in advance, and I believe that gives them a pretty descent fallback for approval. Not sure about mesenchymal. The efficacy of that subgroup may have become apparent too late for them to have listed it as a subgroup. Not sure. I know they added subgroups pretty late in the game, and I believe that was legit... just don't remember mesenchymal being talked about. (In fact, adding subgroups late in the game, though prior to a read on efficacy, as they did, may have used up a lot of alpha spend and thus motivated them to do no further spending that would have resulted from any optional early looks at efficacy.)
Then there are the early progressors... (a separate trial...? I admit I don't remember.) If the combined real and pseudo's show efficacy as a group... then that would be very convenient, as they would be so easy to identify. My understanding is that the pseudo's are believed to benefit a great deal from DCVax-L, but I would think the opposite for true early progressors. If so, a distinction must be made and numbers are smaller than the combined group. And that distinction is problematic, though the methods have improved in recent years. But... do the true early progressors show unusual benefit for some strange reason????? I have read about this dozens of times and do not remember, I must admit. But I hope to spark a review of that issue.
Please excuse my lengthy post without full DD... but these days I do not post very often. So this is several months worth of babbling.
