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I hope all these arguments are silly. If the FDA would really hang on these things then they are truely a disfunctional organization.
The only thing I could think of that would be remotely worth worrying about would be orphan issues. And I'm pretty sure that orphan status excludes only similar therapies.
Beyond that if they would really have a problem with DCVax-L in any respect, due to Optune, then they should fire everyone, burn all the regulations, and start out with some finite number of central principals that cannot be violated.
Sounds like the US legal system, which has devolved into something that does not come close to supporting the principals of the constitution for about 90% of the population. Total disfunction out of excess complexity, due to the confusion that it generates and the corruption it invites.
"Did you know Cognate was given 8 million shares last October?"
AVII: You said yourself that the xfer of 8 million shares was to maintain LP's majority share stake. That seems like a pretty good reason to me. I want LP in charge, because I am willing to gamble that she is not a crook, or not primarily a crook. Ie, that bilking NWBO is not her primary intent.
Woodford is somewhat famous for his takeover of a large company in recent years. Why would LP not be concerned about that? Concerned enough to do whatever it takes to stay in charge.
"generally provides a meaningful advantage over available therapies"
There is a big difference between showing benefit over a therapy that you are going to replace and benefit "over" a therapy that you are going to augment. No distinction is made in the above statement, therefore the above statement is incomplete. As written, I don't believe that it applies here. I give the FDA more credit than you do AVII.
AVII: I have to agree that these lease details look totally damning for NWBO. But, as a long-time long, I also have to look for any potential explanation, as I await a response from Les on the question, that will likely never come. NWBO is currently in a hush-hush mode. Normally there would be some small chance of a reply from Les.
Are you certain that there was no sub-sub-leasing going on by Northwest, as you suggest might have been going on in the second, more reasonable contract? The square feet are not provided in the first contract.
Another point to possibly mitigate the issue: Look at the size of the spaces that LP rented at the last ASCO, the next ASCO, and at a recent conference in Europe. All huge spaces. Clearly intended to put NWBO on the map. And does she wear matching "Power Shoes"?
Back in 2006, funding tremendously expensive future trials was LP's primary task at NWBO. A task she was expert in. That was exactly her job at Enron. Perhaps she knew from experience that the very high cost of renting an impressive and large Suite in Manhattan would pay for itselt 10 fold in the ability to give investors a warm and fuzzy feeling that large investment sums are appropriate. Maybe she had investor parties there, and she knew that people's check writing skills improve with booze, or hookers. In the end, if she was funding a cure for brain cancer, the ethics would balance out well to the positive.
All that halo-ing rests on the assumption that the space really did demand the rent described. Maybe there was something special about it. The top floor? A spinning floor? A view of... something impressive?
But I do understand why you want to judge the issue more simply. Prima-Facia, that was gouging for rent by Toucan well beyond any reasonable level. Very suspect I agree. What concerns me further, is that such an appearance of impropriety in spending might spell caution to insurance companies, for example, and thus big pharma and even the FDA, regarding the potential abuse by LP in vaccine mfg charges by Cognate if DCVax-L gains approval.
"As you can see from the definition above, a biologic differs greatly from a device (e.g. constitution and mechanism of action). As such, the approval of a biologic is a separate and different process."
This actual response was pretty concise compared to the massive amount of ancillary material if you include the links. I guess I would agree that it appears to say that Optune's approval would not effect AA consideration for DCVax-L, but it doesn't quite say that.
That is worrisome that the FDA would be that indirect and pile on that much extraneous material in the reply. I don't think 2% of that extra material would be relevant. This is a very specific question.
But that game goes both ways. From what I have seen in the device industry, some submittals to the FDA contain divisivly worded, confounding, convoluted nonsense intended to put the reader on their heels, feeling inadequate to properly assess the issue which is clearly beyond them... if they can't even understand the submitted doc. And it works. The engineer that described it called it "wiggle words". I ended up locking horns with that engineer and ultimately quitting because the company scolded me for standing my ground when he tried to intimidate me into not correcting a long standing bogus test he had written for device validation. A validation protocol I had been assigned to update for a new version of the device. I was out of work for 4 years after quitting that job. I was blacklisted.
I said I think Optune might be synergistic with DCVax-L or other immunotherapies. I say that because the immunotherapies seem to be on the edge of efficacy, ie needing temador to put them over the top. A non-linear escalation in efficacy with any added support. More specifically, if Optune really does slow the cancer as advertised, that would give an immunotherapy critical extra time to ramp up. Maybe. That would certainly make wearing the funny gear worth the effort. But I think if there is measureable efficacy... people might feel it is worth it anyway. I think that believing otherwise may not be properly imagining the emotions that likely come with being told you have a fatal brain tumor.
I didn't read everything you included Sentiment, but I can't imagine that the FDA would weigh the release of this device when considering AA or any other issue in a pharma trial for GBM. There would be no reason to expect anything other than simple added benefit or synergistic benefit in using the two. in fact, good reason to expect synergistic benefit.
The chance that some side effect for either gets enhanced seems so close to nill that it would not be worth debating or slowing any trial.
Then again, I am not familiar with the FDA, and AVII definitely is. Perhaps they do irrational things. I know a lot of other governmental agencies do.
AVII (who is out of posts) commented that he didn't think that pseudoprogression was an issue for DCVax-Direct.
I may be the one that brought that issue into the confusion a few days ago while trying to explain / defend the high rate of progression in the Direct trial. I suggested it might be possible that some of the progressors will ultimately prove to be pseudos.
The Direct patients have been under care for some time, having gone through a large number of other treatments in most cases, so that pseudoprogression that late in the game would seem unlikely. So I agree with AVII. Further, regardless of why, this has not been an issue discussed for whatever reason. He is right about that.
However, being the die-hard long that I still am, in spite of still digesting the disturbing record of rent gouging by LP, I think there is a small possibility that some of these patients' immune systems did not kick-in early-on for whatever reason, and finally did kick-in after being stimulated by DCVax-Direct. Early in the patients treatment the immune system may have been so supressed that it never got a chance to generate pseudoprogression.
I'm not sure I believe that Direct can restore a destroyed immune system, but it probably can restore a depressed immune system. Not just through the DC's, but the adjuncts, which are in fact immune system stimulators. So... maybe it will ultimately prove that some of the DCVax-Direct progressors are pseudoprogressors...
If that is your opionion AVII, and it appears to be with no embedded device, then any offense is neither here nor there. But no offense taken.
"The reason for the no on AA is that the trial isn't fully enrolled."
But aren't they fully enrolled for the old efficacy bar of 6 months improvement in PFS?
I think you read me backwards. Just agreeing that those rule would be innappropriate for immunotherapies. Glad to hear that they are not being enforced for DCVax-L or Direct.
I should have limited my statement to DCVax-L and Direct, since there are immunotherpies with side effects.
Having touched that subject, the idea of using Checkpoint Inhibitors for GBM, as AGEN is planning, kind of scares me. If runaway inflammation is the common side effect, isn't the captive brain the last place you would want that to happen?
On the other hand, any checkpoint inhibitor that crosses the blood brain barrier could have the same effect. I wonder if the approved ones do cross the blood brain barrier? If so... maybe this issue is not as large an issue as I would fear.
If OS is a co-primary endpoint at this point, along with PFS, then would NWBO have the option of either early full approval based on PFS or AA based on PFS if there was a look at the data?
If an agency, rather than Northwest or it's DMC, called for a look at all the data for some reason, including everything related to efficacy, would that count as an alpha spend by NWBO? Could Northwest cease that opportunity to ask for consideration of AA or early approval based on the data the agency requested, without suffering an alpha spend? Note that the trial recruitment was halted at a conspicous level of full recruitment, and trial enrollment was halted at a conspicous level of full enrollment for the previous efficacy bar / trial design. Or very close to those two numbers.
AVII Quote:
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That's what efficacy interims are for.
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Both Linda Powers and Linda Liau lost parents to brain cancer and dumped their hearts and soles into this effort. Just like many of the longs on this board, they are very personally involved.
LP originally claimed to be hopeful that DCVax-L, would become part of SOC for all GBM patients. She funded and piloted a moon-shot for GBM. Maybe she worried that even the second interim might not be reached in a reasonable length of time if they went with OS as the primary endpoint.
I know the first interim is primarily to look for adverse effects of the drug. I don't remember if efficacy is even looked at during the first interim to judge futility. Is it? Or do they wait for the second interim even to judge just futility?
Wow! Written with the assumption that there is a race to see if the medicine kills you or the cancer first, so if the cancer comes back, best to stop taking the poison and just try to give the patient comfort in their remaining time.
Completely innappropriate for immunotherapies. Unbelievable that the protocols could be lagging that far behind.
Or did I miss something here?
I had worried that TapImmune wasn't moving on some of the products in their arsenal. This patent explains this one.
And even a week ago when Glyn spoke about PolyStart he got very sheepish all of a sudden. That worried me. Now I understand. He felt uncomfortable bragging up a product that they did not yet have a patent on. That is a good sign about Glyn. Many CEO's have no hesitation bragging about products that they don't really own.
If the Germans wanted a look at the data to determine reimbursement level for the HE patients, would they have asked for a hold?
Ie, if that was the only thing going on. (There could be multiple things going on.)
I wonder if the PEI and the British and the FDA were not all in agreement on exact details of the trial approval criterion, so that Northwest had to choose who to satisfy completely up front.
Yes Koman. I didn't know there was any other path for early approval than AA. AVII pointed that out again in his last post, and I already aknowledged that I finally understood in my last post, while you were writing the post I am responding to.
I almost asked early on in this effort if there was some other mode of early approval other than AA. I thought that might be my confusion. I didn't know what that other mode would be.
I should have asked. (If I didn't.).
Thank you AVII,
So you can get full approval early based on the primary metric, rather than AA, which much be based on a surrogate metric.
In retrospect, your examples did contain those situations. Thanks for your patience and persistance. I do understand now.
If you are pointing to the requirement that AA be based on a surrogate; please note that I aknowledged that in my original post and in related posts over the past couple of days. The question would be what rational is there for such an arbitrary rule. I provided a very simple example to put this question to test. Orders of magnitude simpler than dozens of posts that fill this board daily, and you respond with a statement of the rule that I aknowledged in the first place. Bazaar.
But if you are pointing to "or an intermediate clinical endpoint" then I would have to say that is an absurdly meaningless line. AA is by definition intermediate, so any threshold / metric used to consider AA would be an intermediate clinical endpoint.
As much respect as I have for AVII, and as tremendously knowlegeable, and useful to us as I recognize that he is, I must say that his extremely informative post also completely skirted the single issue that I brought up.
Some of that seemed inconsistend AVII, though I only understood about 80% of it. I need to learn a little more about alpha spend. I do understand the idea.
But;
You say the criteria are the same for AA and regular approval... yet you say OS can't be used as a metric for AA. I realize that OS is not a surrogate, I just don't understand why there is a hard and fast rule that AA has to be based on a surrogate.
For example: If a trial with 250 control and 250 experimental patients had an agreed threshold for approval for the primary endpoint OS at 12 months improvent in median OS, measured at 350 events, then why couldn't the trial be considered for AA if it reached 24 months median OS (or some other number much higher than 12 months) at an interim look at only 250 events? Is it only the arbitrary rule that the metric for AA must be surrogate that prevents consideration of AA in the above hypothetical case?
The catalysts in the cue are substantial Pete. This time, the movement should have staying power. I mean, I don't want to see a pop. I'm sure nobody wants to see a pop...
?Why surrogate for AA always instead of simply showing statistical significance of primary metric with less patients than full enrollment but higher efficacy than the bar set for approval at full enrollment?
"Who knows, maybe Optune's MOA wasn't the TTF electric fields but just the heat given off from that device that heated the head and disrupted the BBB. Pretty far fetched, huh."
That might help explain the better survival rate for young GBM patients; the non-stop use of cell phones.
Thank you AVII. I'm not sure what you said, but I am confident that it is very meaningfull, and if I study enough to interprit it, I will have arrived at a much higher level of understanding of these trial technicals.
Does DCVax-L increase psPD %? If it works, wouldn't it generate pseudoprogressives out of regular patients with some unknown rate of occurence? Does that change all your stats?
I don't know. I can't yet follow you guys in these discussions.
Flipper: This thread started with me commenting on the issue of AA possibly being judged on PFS data when the DCVax-L Ph 3 has a primary endpoint of PFS.
I asked, "But can the surrogate endpoint for AA be PFS when the primary endpoint is PFS?".
I was asking. I wasn't saying that I didn't think that could happen. It is confusing because it is not the more common situation where the primary endpoint for the Phase III is OS, and AA is judged using PFS data. So I was trying to get your thoughts on that.
I don't think your equation / reply was very helpful in clarifying that issue. I think it just confused things.
As for my last post about AA and surrogate and primary endpoints etc., I want to back peddle on a couple of things.
First of all I realize I might not be talking about AA correctly. I think of it as an interim analysis of existing trial data based on a surrogate for the primary endpoint. The primary endpoint usually being OS and the surrogate usually being PFS in oncology. In fact that pair is the example used in almost every discussion of the topic that you will find online.
Whether it is proper to call PFS in the above common example the surrogate endpoint for the AA, I don't know; I think you are saying that is not how it is stated. I think it might be easier to speak in terms of the overall effort rather than the AA. For the overall effort in that example OS is the primary endpoint and PFS is the surrogate to OS, used to judge early marketing approval, or not, after a request for AA.
But maybe AA is not what I think it is to begin with.
As far as the confirmatory being a continuation of the phase 3... I should not have said that. If crossover of all patients is part of the granted AA, then that would be a large change in the trial. The Phase IV confirmatory, then would not be simply finishing out the Phase 3. Not sure how they then measure success... but apparently many or most companies just blow it off, and get away with that.
But the original question / comment remains. Semantics aside, can they judge AA on PFS when the phase 3 primary endpoint is PFS? I would think that if PFS was good enough to judge AA in a trial with OS as the primary endpoint then surely it would be good enough to judge AA for a trial with PFS as a primary endpoint (for the phase 3). I think that is logical. Yet every description of AA that I can find says that it has to be based on a surrogate to the primary endpoint, and technically, PFS cannot be a surrogate to PFS. I think the requirement that AA must be judged on a surrogate to the primary endpoint doesn't make sense... but that is what I see stated in every write-up on the issue.
"You can't have OS as the primary endpoint in an AA trial."
I think this is semantics. Important semantics, but semantics.
I know what a confirmatory trial is. Although they call it a phase IV, it's really just finishing out the previous phase III with it's original primary endpoint and efficacy bar based on that primary endpoint.
If you start a phase III with a primary endpoint of OS, then after the second interim, the interim for efficacy, you decide to apply for AA, you do so based on a surrogate endpoint such as PFS. You can call that an AA trial with a primary endpoint of PFS, but I would call it an AA trial with a surrogate endpoint of PFS. PFS in the AA trial is surrogate to OS in the confirmatory trial, which is really just finishing out the original Phase III.
20% of 51 is 10.2 or approx 10, not 11 Pyrrhonian. Probably doesn't matter, but just in case.
No information in there about AA and surrogate endpoints.
But I thought the most common situation was to have OS as the primary endpoint with PFS as the surrogate endpoint because PFS happens sooner yet is predictive of OS?
It is an issue of proportion AVII.
But can the surrogate endpoint for AA be PFS when the primary endpoint is PFS?
NWBO started out with the hope of becoming SOC for all GBM and possibly all gliomas. I don't think that is going to happen, but it is possible they consider the magnitude and simplicity of that situation worth shooting for, and to shoot for that they may be extending the trial farther than I would like or you would like, starting with keeping the phase 2 blinded. Keeping the phase 2 blinded extends it backwards in time which is a mixed blessing.
I think that the drop to a 4 months PFS benefit was to have a chance at pulling in the un-methylated in general, or possibly just the unmethylated in the mesenchymal subgroup. That doesn't mean the over-use of SOC damaging the immune system was not a legitimate rationale...
Otherwise stated: I think they could get AA on the methylated mesenchymals or possibly all the mesenchymals or all the mesenchymals and the methylated everything else right now... but want all the marbles, or more marbles.
That said, they seem to think there is a finite chance of failure, otherwise "Win or Go Home" and positioning patents into trusted independant parties hands would not make any sense.
I have seen a very wide range of estimates of mesenchymal percentage in GBM.
One study states 48.8% (which would be really nice!).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995672/figure/pone-0094871-g004/
Another, study, or another part of the same study shows 32.4%
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995672/figure/pone-0094871-g001/
This is the main link for the study(ies):
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995672/
I didn't see results on page 238 nor starting on page 238. I saw the trial description starting on page 260, and the questions and answers about PSF as a primary endpoint. Interstint the FDA was ok about using PFS as a primary endpoint with some loosely stated caviats, but warned specifically against using PFS as an interim measure. Seemed kind of backwards to me.
But I didn't find the conclusions or mentions of crossover for that specific trial. Looked like they were talking about more than one trial to me.
I found the doc very difficult to navigate. I am sure it is much easier for you.
So what was the result? I take it they failed.
"Please elaborate when you say "something is wrong here"."
I need to read AVII's link; but so far he seems to think that the FDA will not be considering PFS advantage for approval as a primary endpoint. More important, everything he says and how he says it strongly suggests that the FDA knew from the beginning that they would not ultimately be considering PFS advantage as a primary endpoint for approval.
If the FDA knew full well that they would not be accepting PFS advantage as a primary endpoint for approval, and at the same time insisted on a crossover that they certainly new would spoil the OS differential, then the FDA was setting up Northwest to fail.
That is totally obvious and would be totally obvious to a judge or jury or congress or the general US population if it ever came to light. Period.
This is not a complicated situation.
At least, that is how this looks to me. Maybe I am missing something here, but I don't think so. I don't think there is any way it is going to go down that way. I think AVII must be wrong and the FDA will in fact consider PFS advantage for approval. If not... this is a big deal. This is a legal matter, and I don't mean civil.
It will not go down that way... so do not worry. Not gonna happen.
Good to know that the FDA insisted on crossover.
"Dr. Liau told you why. She said it was because patients were asked to undergo the somewhat invasive leukerpheresis procedure."
Maybe Dr. Liau said that... but it doesn't make it any more rational. These people are going to have the top of their skulls cut off, brains cut into as they cut out the tumor, radiation, chemo... and the argument for crossover that would spoil the OS differential is that the patients have to face the horrors of leukophoresis? That's ridiculous!
Perhaps Dr. Liau recounted the rationale that the FDA used when deeming the crossover. If so, glad there is further record that they had no reason. That is no reason. Something is wrong here, and you aren't making any sense. Quite bazaar. I guess I will have to read/listen to your link and hope I understand you thereafter.
AVII77: "Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions."
You were quoting some FDA guidline, in response to my saying,
"Allowing that the FDA insisted on crossover after progression in the DCVax-L trial is aknowledging that they accepted PFS as a primary endpoint, period."
--------------------------
Perhaps Linda Liau mispoke, and the crossover was really just a suggestion by the FDA, but that is not the situation I was commenting on. I was clearly commenting on the reported situation that the FDA insisted on a crossover. Not the same thing. You may argue it is the same thing. The FDA may argue it is the same thing... but no reasonable person would buy that argument.
You go on to state that the FDA only insisted on a crossover group because NWBO wanted PFS as the primary endpoint. You say that like it obviously follows. Why? It doesn't follow. There is no reason in the world for the FDA to have either suggested or insisted on a crossover of patients at progression. The secondary endpoint in any trial matters too, and the crossover obviously poisons the stats for the secondary endpoint which was OS.
To any reasonable person... for the FDA to insist on NWBO having a crossover in the DCVax-L trial and to subsequently disallow PFS as a primary endpoint would be premeditated sabotage.
Among the reasonable people that would see that as sabotage would be a very sad and angry Vice President of the United States, and thousands of furious GBM patients and family members. And me.
Quote: "It is course impossible for the DCVAX-L trial to show CR's."...
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It is course impossible for the DCVAX-L trial to show CR's. And I never heard Linda L describe such in the P1.
And what exactly would be the mesenchymal subgroup in the the Direct trial? They sure as hell were not sticking needles into the brain.
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I was talking about phase 1 data or phase 1/2. Early unblinded data that Dr. Liau recently presented with long term follow-up. Being phase 1 data without a control you are free to ignore it. But if you choose to give it any weight; it showed 25% of patients living past 5 years and she stated that most were still alive now, which is another 3 or 5 or 7 years... I don't remember exactly, but these patients are staggard. All were mesenchymal. What is the correct term for this longevity, rather than complete response? Maybe cured, or fkn cured. Is that better?
Regarding mesenchymal patients in the direct trial. Mesenchymal turns out to mean connective tissue. The brain has connective tissue to hold it's shape, as do all organs. Even cartilidge is mesenchymal. So, there is the potential for a mesenchymal malignancy in all organs. How often such malignancies occur in other organs is another question, as is whether they would also be highly treatable with DCVax-L, but they might be. It would certainly be something you should be curious about.
I had done just a quick search and found that there is a mesenchymal subgroup for melanoma. Then again there are DC therapies or at least one DC therapy already for melanoma. That is where Dr. Liau got the idea of testing a DC therapy for GBM.
Why would a mesenchymal malignancy be more treatable with DCVax-L than other subgroups? I don't know, but I like to speculate. When people get excited immune systems during a bout with a cold or flu, their joints often ache... why? The most common forms of auto-immune problems are with the joints, why? Maybe connective tissue cells do not have blockade/checkpoint function. The primary function of the checkpoints is to prevent auto-immune problems. They aren't there to protect cancer.
It hadn't occured to me that the large $ movement to Cognate could be a defensive stance like the positioning of patents in trusted private parties hands. I just hope that is not the case. It makes total sense, except that I don't think they could get away with that, so I don't think they would risk it.
I'm not trying to talk anyone else into ignoring the questionable looking dealings with Cognate, I am just saying that I don't know enough to say anything is really out of order. I feel I do know enough at this point to feel ok about the general idea of LP being in charge of both companies. It actually makes total sense to me at this point. And I know that there are possible explanations for some of the big $ movement. Why that wouldn't be more above board... that is hard to explain. Many write such things off as the need to be secretive to not effect the trial. I think there is more truth in that than many others allow... but big $ movement to Cognate... I do have some trouble understanding why infastructure spending would need to be secretive.
Maybe your right about them protecting the $. Or maybe they don't want to get into a discussion about why they would spend so much money on mfg development and or facilities acquisitions and development because the key reasons have to do with their perceived odds of success, which includes things they are not supposed to talk about. But that is reaching, I admit.