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I'm not following all of the trial screening and trial group selection details. But from a distance it appears to me that it would have been better to not consider progression as part of screening. That would have removed all errors in identification of progression type. Whether someone is pseudo or real progressive, for example, is a lot easier to figure out in the post analysis.
And in the end, do they really want to limit DCVax-L use to patients that do not show some kind of progression. Why?
Is that how it looks, at this point, from your perspective?
"Is Neil Woodford implying Linda is a crook?"
Neil Woodford responded in a defensive manner to a laundry list of allegations against NWBO, written by an anonymous source. We don't know if his intent in asking for investigation was to nail NWBO, LP, or simply clear up the matter. In fact, the only statements by Woodford indicate that he felt this would likely prove to not be a large issue. He may have felt that the most likely outcome of the investigation would be to clear NWBO. He may still feel that way.
But feelings are secondary here in my opinion. The Phase V article was very pursuasive, if not accurate, and he responded in a normal manner, asking for investigation that might help protect his investment in the long run, and showed action rather than inaction, in the short run. LP decided to not trust his team after finding members that likely had unstated motives to get access to internal information that they definitely should not have access to. The assumption is that Niel Woodford is angry about LP rejecting his proposed team for investigation. We don't know that. The reveal of these improper people on Woodford or Ondra's team was real. He may fully understand LP's response. He may feel bad that he did not check these people out thoroughly enough.
"34k a month rent to Toucan for 4 nwbo employees."
This bothered me a great deal when I first learned about it. But in retrospect:
1) In addition to Toucan employees likely occupying the offices in that era, NWBO employs a large number of contract employees. Some of those employees would likely have taken up workday residence at NWBO headquarters. Hard to say how many employees were accommodated by the lease. Could be a very large number.
2) Bethesda may be pretty special in it's ease of access to DC. Some say that office space there can be very pricey.
3) Linda Powers has a great deal of experience financing. It is possible that she has learned that it is worth the money to have a large, nice space when it comes to making investors feel comfortable with their investment choice. The size of the booths at last year's ASCO, this year's upcoming ASCO, and one of the recent European conferences all lend some credibility to this possibility.
4) In that era they may have had such a small market cap that they were not required to have a dedicated accountant... indicating a relaxation, to some extent, of SEC formalities. Further, Linda Powers was essentially running several large businesses, which is a challenging situation, particularly if she had to deal with the accounting for each of the companies. At the end of the day, the books have to be balanced.
I wish I still drank. This reminds me of an old fashioned bar fight in a western. Ten different fights going on at the same time. Chaos.
Only once was I in a bar fight like that in real life.
Daryl, of Daryl, Daryl and Daryl... the tall one with the hat and long hair, and a missing a finger... was playing pool with someone, and somebody made a comment about his missing finger. All hell broke loose in the pool room. Everybody was swinging at somebody. I just stood and watched, not knowing at that point what had started it. Then tall lanky Daryl punched me square in the teeth. Luckily I was drunk enough that it didn't hurt. And... he either didn't have much of a punch, or he pulled it last minute when he recogized me. I don't think he pulled it. Anyway, I asked him why he did it; I was not an adversary of his. He wasn't sure why.
Bar fighting should never be done sober, and I don't drink any more, so... sorry guys, I have to stand this one out.
Is this what goes on at happy hour every day here?
"I think NWBO might still be sitting on a healthy war chest of funds, in part lots of money still left over from Woodford fundings. They might not need any more funding until late 2016 or into 2017."
I want to believe you Evaluate, but why would they fund at such a low valuation recently if they were sitting on a pile of money?
The only explanation I can think of would be if moneys from Woodford were constrained in their use in some way, and some new need arose (maybe a CI for sale? Or hiring her special investigator...), outside of those agreed or contracted constraints. Myself I don't know if those kind of constraints exist.
For example, the funds from Woodford might be constained to be used to fund the DCVax-L trial.
I shouldn't have stated my disinterest in reading the book that Flipper and Pyrrho and AVII were writing on Optune. The disinterest was a combination of not believing the topic could be relevant, not wanting to believe the topic could be relevant, and not understanding what they were talking about.
None of which are very good reasons to quash their enthusiasm. My apologies. Not my place anyway.
"I just read the translated version of the German Product Label again. It reminded me that product viability is 36 months."
Your post brings up several questions. One would be whether the Germans addressed only the viability of prepared vaccine, or also any leftover tumor tissue.
Or maybe the policy is to always continue electrophoresis until all the vaccine possible is made from the available tumor tissue. But that seems doubtful. What about huge tumors?
Another question would be regarding the (low dose) comment. Many will remember all of your previous discussions about multiple low dosing. I only remember some of the discussions. I assume this dosing change was intended to avoid some kind of bottle-necks in the lymph passages / DC travel tubes or some such that I have heard you and Pyrr talk about. Or was the reason they tried low dosing just so they could dose more often, but it turned out that lower doses worked better due to the bottleneck issue, even when they did not dose more often...? ie, did they find this by accident? Which patient population did they vary these things for? The main trial patient population? Or did they learn these things elsewhere, and then petition to use what they learned in the main population?
This 36 month expiration in the German Product Label is what AVII believes pushed Pyrrho over the edge?
But is there a difference, in terms of alpha spend, between a 1st interim look where only futility can be reported/(stop-recommeded) by the DMC, and a 1st interim look where the DMC is also allowed to come back with some other statement related to efficacy... such as, "go for it" with it being, for example, some form of early or accelerated approval for the entire patient population or some subgroup(s)?
Would it be correct to say that if they did use the 1st interim as an efficacy look beyond the DMC, that it would be an un-planned alpha-spend, and would thus lower the chance of approval both at the second interim and at full planned trial length, if such proved necessary? ...Thus it would be a gamble.
Back to the basics for me: Hope it is some value to somebody else.
(Blame it on Mapman. The slightest encouragement, and some people just won't shut-up).
These issues very much old-hat I realize, but I need to review:
Someone please correct me if I am wrong about the following things:
1) LP says no 1st interim was done.
2) While LP may or may not be required to announce the 1st interim, she is certainly not allowed to lie about it. Therefore, I am comfortable with believing that the 1st interim had, in fact, not been reached back when she made the statement.
3) That allows that the current hold might be related to a look at data at the 1st interim. It might be simultaneously many other things, including a look for the benefit of Celldex, but it might very well be a planned look at the data at the 1st interim.
4) While it may seem inconcieveable that the 1st interim is only now being reached, we would be talking about the new and improved 1st interim, which would be a larger number of events than the original trial 1st interim. Maybe that makes it feasible. I know people have addressed it a hundred times.
5) LP may not be required to announce that they are at the 1st interim review. This is where I am feeling unsure. I know people here know. Or did she actually say that they are not currently in an interim review? I don't think so. I think she said that before this hold. I know you guys know.
6) Can you decide things like the early approval that we all dream about at a 1st interim review? The second interim is usually deemed the efficacy review. But I would think any reveal that is planned can be a period for such decisions, just that it would be unusual. But multiplicity category constraints might say no; that a look at efficacy for consideration of any kind of approval must not only be at a planned interim, but that it must be at a planned interim for efficacy. Sounds like the kind of debate that at least four of you are tired of hearing. But any input there?
You meant patents, right, not patients?
If so, I would agree. Many of the 200 patents might be relatively useless to NWBO. Particularly if many are improvements on their previous patents.
But among other things, the large number of patents shows that an enormous amount of R&D has likely gone on. Something important to note as you look at the number of employees, which is therefore deceptive. And secondly, there is no reason to assume that most of the patents are useless.
Thirdly, the very large number of patents does suggest that some could be improvements on their earlier patents. The older patents then would be ideal for use as collateral on loans. Valuable to some other companies, but of no value to NWBO. This has great potential relevance to the patent controversy brought up by Phase V.
(Correction: 7 currently in Toucan's hands, and 19 in Mehiel's hands, out of about 200 patents generated by "NWBO")
Ok, I will try to stay away for a while. My feelings are not hurt. I have noticed that when the noise settles down, and or outsiders move away, many high quality, but non-confrontational posters reveal themselves and the party continues.
Even sentiment dissappeard recently. That is a bad sign.
If DCVax-L is shooting for all the marbles, then it is possible that they will have to show greater efficacy than Celldex, within Celldex's subgroup, to win. They may not have to be powered for that, but mean efficacy for that subgroup may have to be greater than that of Celldex.
What are the chances of that? AF would have you believe that the greater concentration on that subgroup, in terms of antigen focus, would favor Celldex. He would have you believe that such is common sense. Maybe it is for someone somewhere, but he expected his simple analogy concerning shotguns and elephant-guns and elephants to be some kind of proof.
The fact is, from slightly above lay-mans level it looks like this: There are probably immune bloom path's that can be bottle-necks. There are a finite number of T-Cells hanging around waiting for DC's to present their antigens. Rather, while there are an enormous number of such T-Cells waiting in the lymph nodes, there are a very finite number of each kind. Thus each antigen type may not need to be presented in large numbers to saturate that particular antigen->T-Cell path. If that is the case than presenting smaller numbers of many different kinds of antigens wins... by a very large margin.
So that is possibly the current pending question being answered. Which may be what many have said a hundred times in recent posts. If so... sorry. But I know Turtle and others are hanging on my every word. So while many of you may be hoping that if you just don't reply, I will go away, I feel I have a duty to ramble on.
So what happens if NWBO decides to go for approval for the entire GBM population ("Win Big or Go Home"?), avoiding the handicaps of multiplicity and small subgroup sizes, while Celldex would clearly be shooting for only a subgroup, and would be fully powered in that sub-group?
I would think that NWBO would be allowed to change their minds about whether they want to shoot for the entire GBM population or some or all subgroups (all-subroups not being the same thing as the entire GBM population due to multiplicity and or powering issues) up until the point that they have efficacy data or feedback of any kind. So that; if that feedback was relative efficacy to Celldex within a subgroup, for example, NWBO would have to commit prior to that reveal.
Even though they had to define subgroups in advance, just in case they choose to use that later, they may not have been required to commit in advance to whether efficacy will be evaluated subgroup by subgroup, or as just one big GBM population.
Good point. Further along those lines, NWBO relies heavily on contract services. While many such services would operate physically outside of NWBO's office, others might take up residence in the office. The duration could be nearly continous for years on end for some functions, such as accounting. Maby there are many such functions.
Further, with LP running three different large businesses; while this introduces pathways for improper deals, it would also make it very difficult to keep as tidy an accounting ship compared to having three different CEO's. Some slop back and forth, and creative means to balance books might be something to be expected.
Such an argument could cover anything and everything suspicious, so it is a dangerous argument. But I have recently begun to appreciate the enormous advantages for NWBO to have LP in charge of all three companies. That appreciation was not suggested by Flipper or BearTrap or anyone else. Just a result of watching the ups and downs, and aggression that the company has faced. (Though not sure she is still fully in charge of Toucan. I know she is in charge of Cognate). Without the appreciation of the true need for the head of NWBO to have control of as much finance and mfg as possible, the relationships lack explanation, and default to the facilitation of fraud. I think that may be part of the problem. The appearance of convenience for improper reasons due to a lack of appreciation of the true legitimate value of the relationships.
That makes sense Flipper. Smith may or may not predict the outcome of trials well, but he certainly knows the trial formalities well... ie whether it is possible that an efficacy look of consequence to NWBO is currently in progress, and other issues of concern recenty addressed.
Thanks for the box of cracker jacks by the way. There was a magic decoder ring inside! I thought it was all paper prizes these days.
"Wasn't the patent issue something that was done long before the screening hold? Is protecting the patents and hence the company, a bad thing? I rather like the fact that they are not dangling like cheese in front of the aggressive mice."
Your right that the patent positioning was many years ago. I didn't know that. The only reason it recently got attention was because it was a section of Phase V.
According to Phase V there were 32 patents that got shuffled around, some in 2004, and some in 2012, with 26 that remain outside of NWBO, in the hands of Dennis Mehiel.
To me it looks like the patents may have been used as collateral in loans. There was speculation on the board that these may have been key patents, but I do not remember anyone studying which patents were involved to verify that. Maybe the patents are collateral and they deliberately used patents that might be valuable to some, but not to NWBO.
What Phase V fails to mention is that NWBO owns on the order of 200 patents. So these 26 may or may not be of importance. They do not support the idea that they are important. Most smallcap biotech stocks have only a handfull of patents. This is not exactly a weak area for NWBO, yet Phase V paints the picture that it is in shambles. Again, it is possible this is an issue, if these are key patents, but there is no reason to assume that, and there is no support for that view provided by Phase V.
Maybe you are right about the delay of Direct being so disturbing, but I don't see the L Phase 3 as being in a shambles.
Aside: I should not be talking about whether anybody should be invested right now or not. Easy enough to keep strictly to why I am invested, or not.
Further, the imminent catalyst that I think LP is planning on, in retrospect, is very likely the lifting of the screening hold. Fancier stuff could be in the works, but I am influenced by AVII's discussion about unplanned looks at efficacy. That they can't lead to any action by a company. The company / sponsor can't know the results of those looks. If there is a look right now it is probably to make a decision about Celldex and will likely have no effect on NWBO. That doesn't mean they won't have a scheduled look soon, or that somebody might do something out of the norm because efficacy is so fantastic... but in the normal scheme of things, I believe AVII, that any look now would not be allowed to benefit NWBO. Flipper knows so much more than I do that I will continue to listen to his perspective on the question, but I am influenced by AVII's recent discussion.
Oh... I left out the screening hold as one of the reasons for the recent SP decline. That is a big one to leave out.
I don't remember the order of these major events. I should sit down and try to draw that up, for my own sake. Wish I was an iHub member. It would make such research much easier. But it can be done. And of course many will know the sequence of such major things off the top of their heads. Not me though.
Maybe Direct-I results are the alleged imminent catalyst, but I think it is more likely related to the recruitment hold. And while LP seems to be planning for good news, she also appears to have planned in case it is bad news by protecting some patents.
Unless... regarding the patents: The share price has plummetted steadily over the last 6 months, I believe starting with the Phase V article, then Woodfords reaction. The share price drop alone may have worried her enough to worry about being able to finance the company in the future. That alone may have driven her to protect the patents.
Or: There was speculation that she was protecting against takeover, and dismissal of that idea by some due to her very large ownership percentage. But in retrospect... people were not considering Woodford as a potential aggressor at that time. But given his history, it is reasonable for her to worry about him. Maybe not acting alone, but him going along with any others that want the power out of LP's hands. So the idea of her posturing against takeover becomes very reasonable. I like that explanation for her actions with the patents much more than a concern about an imminent binary event going the wrong way.
Not saying that you think Direct Phase-I results are an imminent event.
I remember ultimately speculating that recent large expenditures could be for large scale and automated mfg development and build. That is an assumption I am willing to make. Of course it could be wrong. I know that such expenditures can be huge... Of course such loose rationalizations add risk.
I think I will seperate out these recent expenditures, and just review the expenditures prior to that ramp-up in spending. The difficulty is knowing enrollment at any point in time. People have spent a lot of time trying to guess such things. Is there a logical point, back just before Woodford when expenditures accelerated, where someone felt they had a good guess as to the number of patients that had been treated?
Again... whether or not there has been too much spending, I think something big is imminent, and I think Linda Powers believes there is at least some chance that it will be a good big thing.
Fundamental positive: AVII's perspective does dampen my enthusiasm. Not sure in the long run if it will effect me or not. I do want to look back again at the gross expenses through the trial and compare them to other companies. If they are off by a factor of 10, then I will worry a great deal, if they are high by 30%, then I really don't care. I did look at that stuff a couple of months ago with Pyrrho and RK providing some input, but to be honest, I don't remember what conclusion I came to. Doing such a look a second time is usually more accurate anyway.
For now however, the reason I returned here was because I felt I had run out of time to gamble elswhere so that I could buy more $NWBO. I don't think Celldex's schedule for the annual meeting next week is a tell because it is almost the same day as last year. I do think LP could probably have found more financing 6 weeks ago, but she chose to finance only about 2 months worth. Why? I think she may have said that she expected a catalyst of some sort about now. If not, I inferred it. Something is about to give, one way or the other. I think AF's presence affirms that.
I could say that something big is in the air 20 times a year with NWBO and be wrong almost every time, but I didn't return 20 times this last year. I returned once about 2 months ago, then left, and now I am back.
Something is about to give in my opinion... so if you are over-playing your hand I think you should back off a little, and if you are waiting for the next dip, I think the risk that something will happen sooner is too large. Too large for me anyway.
Read em and weep! IMO (I am hoping the weep part is for the shorts!)
"I guess Pyrrho came up with some alter scenario to flat out needing to redo the trials if Optune is an issue. Some change to OS as the primary endpoint or something. I'm not following, but thought I had short-circuited the complex discussion in the Celldex feedback scenario... but maybe not."
I didn't say that quite right. Maybe I shouldn't have tried since there is a large book's worth of discussion between you and Pyrrho on the topic of Optune. A book I chose not to read. Not sure if you debated the Optune-Celldex dimension yet. If not, it does seem worth debating if Optune is worth debating.
Celldex is probably already using OS as the primary endpoint, so if that somehow makes Optune a non-issue, then I guess Celldex becomes irrelevant. But you guys must be awfully deep in the details to reach an argument that Optune would effect DCVax-L but not Celldex's vaccine.
It has to be the same issue or non-issue in my opinion. Non-issue for both IMO.
Just saying that if Optune has any effect on NWBO's path to approvals then it would have to also effect Celldex. My understanding is that Celldex may currently be in efficacy review for their vaccine for new GBM. Their trials didn't include Optune in the control group as far as I know, so any decision in the direction of an early approval would verify that Optune is a non-issue.
Of course Celldex may not be in efficacy review... and even if so, the most likely outcome will be a very low-key "continue" with no other information. In that case there would be no reveal concerning Optune or anything else...
??? but maybe even a continue, if in fact there is a review for efficacy, would indicate that Optune is a non-issue. Why continue the trial with no Optune in your control group if such would be required ultimately for approval? Wouldn't all that get hashed out now if an efficacy review is in fact going on?
I guess Pyrrho came up with some alter scenario to flat out needing to redo the trials if Optune is an issue. Some change to OS as the primary endpoint or something. I'm not following, but thought I had short-circuited the complex discussion in the Celldex feedback scenario... but maybe not.
Maybe a PR in the near future by Celldex will shed some light on the Optune controversy. Or not.
The summary states nearly half a million dollars rent for 6 months at one point, for office space for four people? Nearly a million dollars a year?
The square footage is not stated for part of that rental period. Not sure if it is the super expensive six months or not.
I hope your right. Keep talking. This is a big deal to me, and of course to AVII. If you can pursuade him, you will have done NWBO a big favor.
Afford: I was way back in the posts, and had not read AVII's post about who he is and what he does for a living, etc, when I wrote this last reply to your comments.
AVII sounds pretty credible in his post. I would agree that it is humbling, if that is what you were saying in a later post to Flipper. You had a typo in it, so not sure.
Still have to think for yourself though, of course. And your particular perspective is complementary to such analysis Afford.
I am invested, so not super anxious to air this dirty laundry here... but I should. Maybe somebody can even come up with an explanation. As I said, you can find this debate on IV, though it may have been some time ago. Look for Raven's rebuttal, if any. Just cut and paste a phrase from this 10K excerpt to google and find the IV thread.
http://www.rns-pdf.londonstockexchange.com/rns/5628X_-2009-8-17.pdf
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Uses of Cash
We used $2.1 million in cash for operating activities during the six months ended June 30, 2009, compared to $10.4 million for the six months ended June 30, 2008. The decrease in cash used in operating activities was a result of reduced activity in the U.S. and Switzerland due to reduced staffing and cash resources. We utilized $2,000 in cash for investing activities during the six months ended June 30, 2009 compared to $240,000 used in investing activities during the six months ended June 30, 2008. The cash utilized during the six-month periods ended June 30, 2008 and 2009 consisted of purchases of property and equipment primarily required to expand production capacity. On March 21, 2008, we executed a sublease agreement with Toucan Capital Corporation, an affiliate of Toucan Capital and Toucan Partners, for our corporate headquarters located at 7600 Wisconsin Avenue, Suite 750, Bethesda, Maryland 20814. This sublease agreement was effective as of July 1, 2007 and expires on October 31, 2016, unless sooner terminated according to its terms. Previously, we had been occupying our Bethesda headquarters under an oral arrangement with Toucan Capital Corporation, whereby we were required to pay base rent of $32,949 per month through December 31, 2007. Under the sublease agreement, we are required to pay base rent of $34,000 per month during 2008, which monthly amount increases by $1,000 on an annual basis, to a maximum of $42,000 per month during 2016, the last year of the term of the lease. In addition to monthly base rent, we are obligated to pay operating expenses allocable to the subleased premises under Toucan Capital Corporation’s master lease. During the six months ended June 30, 2008 and 2009, the Company incurred expense of $404,000 and $210,000 respectively to Toucan Capital Corporation pursuant to this sublease agreement.
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I wonder the same. If this type of analysis is not his profession, then he must be an alien to be this good at it.
The question is whether his focus on NWBO is his job, or his side interest. I understand why you would suspect that it is his job. I suspect the same, but I am not certain. Nor am I willing to completely write him off even if that is the case. I listen to reason, generally.
I am still invested, but I am not married to my investment. I still think it is a good investment. I still have very high hopes for DCVax-L and DCVax-Direct as major breakthroughs in the field. I still respect the die-hards that support this website hoping to give DCVax-L and DCVax-Direct a fair shot in a very nasty environment. But I am listening to everything and everyone that I can understand.
He's smart enough to manipulate... but is he manipulating of communicating? That is the question. He is new here. I am learning who he is. Others that live on IV will have formed a more solid opinion. So, I would pay attention to Flipper's posture in their discussions.
Thank you AVII, for the convolution example. I don't want to pretend that it was immediately transparent. I haven't looked at any digital signal processing for years, but I will try to oil my brain and recall or relearn enough to fully appreciate your example.
Impressive that you could throw together such charting, all labeled and noted, so quickly.
AVII does not like Linda Powers. That likely generates a bias on his part, even if he tries to fight it. He has provided at least one reason that he does not like or trust LP; the Toucan lease price gouging of NWBO that Linda Powers setup or at least went along with. Data from a 10K. Unfortunately, with no explanation from NWBO, it is a pretty disturbing issue. I have found a link to the previous discussion of the issue on IV. I look forward to reading it and hope that Raven and others managed a reasonable defense for Linda Powers' actions.
I think that any bias would be the biggest concern regarding AVII's input.
AVII: "Doktornolittle You might consider reviewing some (all?) of these videos
EMA workshop on multiplicity issues in clinical trials
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A few minutes into the first lecture I get the gist of the issue. That is a broader issue than what I brought up in response.
In fact, early on the speaker states that setting up multiple efficacy goals in advance avoids the problem, and it is not clear to me that even fully addresses the issue.
If you don't setup the multiple goals in advance, then that certainly introduces a major problem if you, for example, search scads of subgroups for an efficacy win after the fact. That is related to my example of being able to chose when efficacy is high in a running average, if you had a running average for efficacy, even for the whole trial. Being able to select when the noise was in your favor.
But this multiplicity issue is broader. Not just deliberate selection of statisitical outliers, after the fact, but even setting up "Many Chances to Win" in advance, increases the odds of one of them winning by chance. Which is where the lecturer started on page 1.
Clearly very important stuff. I feel lucky to understand the gist, but I'm anticipating this getting very confusing as it goes deeper.
I have a masters in DSP, though it is ancient and unused. DSP splits between unrelated analytic and stochastic realms. I kicked butt in the analytic realm, but the stochastic realm never fully jelled. There was no prep class available, so I had to start at the graduate level in stochastics, which I didn't want to do, and which did not work out for me. But I do get the gist of this multiplicity issue. Fortunately, it is intuitive to some degree. Not that even the simple example of two 50% population subgroups showing the same level of efficacy is entirely clear yet. Probably comes down to an apriori vs not issue. Apriori what...?
Part of the answer must be that if you setup multiple ways to win in advance that this must also be multiple ways to fail, the entire trial. No... can't quite be that. I know they are going to be talking about alpha spend for this... but.... back to the lecture.
"That's probably my fault.
I was the first to note that the odds of FULL approval based on an interim look here (Stat sig PFS and OS) are much higher than the odds of an Accelerated Approval based on an interim look here (stat sig PFS)."
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AVII is off doing chores... but I know Turtle would be left hanging if I didn't reply... so;
I was thinking the opposite. I am sure that the topic of AA has been brought up literally hundreds of times in the last 6 months, but I don't remember regular early approval ever being brought up, and I wonder why.
It appears that at least AVII has brought it up, and I wouldn't be surprised to find that others, including Flipper have brought it up many times, but in my only occasional look at the board before recently landing back here, I don't remember seeing it in any posts. And again, if so, I wonder why? Because it doesn't have a cool name and acronym?
For me it is because the things he says ring true. He does appear to have a huge amount of regulatory knowledge. But to assume he would never remember anything wrong, or that he would always analyze what he knows correctly would be a mistake, in my opinion. So far, such an enormous database of regulatory detail appears to be a handicap to proper analysis, at least once in a while. I worry that the FDA may be vulnurable to the same error, on occasion, for the same reason. Myself, I am unburdened with extensive knowledge, as advertised.
I did research to see if his acusations about the bazaar leasing arrangement were real. Turned out to be directly from a 10K, though he had not sited it. Maybe he pulled it out of Phase V.
AVII: Thank you for the links about multiplicity. I really will read/view them all today. As dry a subject as it is, I am curious enough to push through material.
But I do want to comment on the issue of penalty for an unplanned look:
I argue that if Northwest did not call for the unplanned look then there should be no penalty. I argue that for the following reason.
The intuitive reason for this penalty is the following:
If you did have access to all efficacy data as the trial moved along you would see a very noisy signal slowly dropping in noise as it moved along, but with a moving average mean value that remains nearer the center of that noise spread, more-so, of course, as time goes on. So you might guess what the signal is going to converge to by looking at these peak to peak values. If you had that info, you could deliberately pick a point where the noise was near a positive extreme in efficacy, and ask for consideration of early approval at that point.
Northwest does have some data. They know when people cross-over and when they pass away.
But if the Germans or anybody else setup in advance a look at efficacy at the point of full enrollment in the old trial design, and that is the reason for the current look, if there is a look going on, then there should not be a penalty even though it is unplanned by the sponsor or it's dmc. As long as it is a planned look, it does not matter who planned it, because the advantage I describe above would not exist. Maybe there would be rationale for a penalty moving forward, but not for the current consideration of approval.
Quote AVII:
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First of all, they can't stop a study for overwhelming efficacy based "on a look at data that they may not have requested by NWBO or their DMC". That would be an "unplanned interim". Now, unplanned interims can be performed (and there are valid reasons to perform them), but then going ahead and stopping (claiming efficacy) based on that unplanned interim is really problematic.
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"on a look at data that they may not have requested by NWBO or their DMC".
--> "on a look at the data that may not have been requested by NWBO nor their DMC."
Last minute edit gone bad.
I will read your post a couple of times, and maybe more will sink in, but for the moment:
The current hold is at full enrollment in the old 6 months pfs threshold scheme. If the hold was for data collection by the Germans to gauge reimburement for HE, for example, then it could be that the point at which this look was going to take place was agreed upon long before the trial "enhancements" and the Germans may have chosen to keep that event threshold in spite of the enhancements.
The current level of recruitment and enrollment appear ideal for simultaneous consideration of AA based on PFS as surrogate to a co-primary metric of OS, and regular early-approval based on PFS with PFS as a co-primary endpoint. When I look back over Flipper's equation examples that is probably what I will see, now that I know that there is such thing as early regular-approval based only upon the primary endpoint.
(by the way, why is there no nifty acronym for early regular approval? It is not just regular approval, because it is early. That is very different from regular approval and fully deserves it's own f%#&n acronym. Over the last six months, how many times has AA been brought up? How many times has early regular approval been brought up? What is that ratio? Why so extreme a ratio?)
If this look at the data for consideration of both AA and early regular approval would require an alpha spend that would make this a do or die situation, then another description of the situation might be, "Win or Go Home", though LP was more likely referring to the very large (apparent) expenditures for large scale mfg.
It would appear to be very difficult to achieve statistical significance for a subgroup; more difficult the smaller the subgroup.
However, if the follow-up data for the early unblinded trials recently presented by Linda Liau resembles the current trial data, the mesenchymal subgroup may already be statistically significant. And if not, at least the methylated mesenchymals, assuming the advantage of methylation holds for that subgroup, which seems likely. Early approval of even a small subgroup could provide revenue to complete the trials without any difficulty, if only due to the immediate increase in SP that would result and the investor interest it would garner.
The problem would be that the status of mesenchymal is not outwardly observable. That may be the reason for the strong emphasis on outwardly measurable subgroup divisioning.
Genetic testing to determine subgroups, for example, is a wonderful idea, but I don't know how expensive or accurate it is at this point.
I can't engage anyone in this conversation, but I go on, because I know that Turtle anxiously awaits my every post.
Question for anyone regarding efficacy bars for subgroups:
The question regards the patient polulations required to show SS efficacy in subgroups. In general, not just here for DCVax-L.
Example:
Take a normal phase 3 randomized trial without crossover that goes full term with OS as the primary endpoint. If 9 months improvement over the control group was the base threshold for efficacy, based on the enrollment, then what would the thresholds be for the following subgroups?
Say there are two subgroups that split the population 50:50. If the subgroups both showed 9 months improvement in OS, then they would both have met the primary bar, and ignoring the fact that many other factors are considered for approval, base SS efficacy would have been demonstrated.
But if you look at the subgroups seperately... the patient population would be half that of the main trial, so the efficacy bar would have to be higher to achieve SS, ie, higher than 9 months improvement.
These two views appear to conflict.
Good answer. Judo rather than Karate.
Linda Liau did talk about crossover being a problem for the trial, and spoke of the comparison between the experimental and the crossed-over controls being the measure of efficacy. And true that only OS would fit either of those descriptions. But is Linda Liau privy to such trial details at this point, or is she just assuming that OS is now the sole metric of interest? I realize she was the chief scientist for the early trial(s), but what is her current role?
So far you have not refuted the possibility that they could currently be looking at PFS for early full-approval if the old bar of 6 months improvement is currently shown, based on a look at data that they may not have requested by NWBO or their DMC.
The current level of enrollment, not recruitment, is sufficient for consideration of full early approval based on the original primary metric of PFS with the original threshold for approval of 6 months improvement.
Turtle, turtle, turtle.