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Steering Committee and Firewalls.
Actually, there may be conversations going on between a steering committee and the DMC.
3.2. Clinical Trial Steering Committees
In some clinical trials the sponsor may choose to appoint a steering committee; this committee may include investigators, other experts not otherwise involved in the trial, and, usually, representatives of the sponsor. A sponsor may delegate to a steering committee the primary responsibility for designing the study, maintaining the quality of study conduct, ongoing monitoring of individual toxicities and adverse events, and, in many cases, writing study publications. When there is a steering committee, the sponsor may elect to have the DMC communicate with this committee rather than directly with the sponsor.
Interactions between the steering committee and the DMC consist primarily of discussions during "open sessions" (see Section 4.3) of DMC meetings and the communication of recommendations following each DMC review of the trial. More extensive interactions might occur when early termination is being considered, or when external forces (e.g., announcement of results of related studies) impact the ongoing trial.
Doc Logic.
Larry Smith reprinted Doc Logic's statement on January 28, 2014. It's so enlightening, I thought I would also reprint it.
Doc logic said that investors must understand the need for a more complete antigen presentation (as is the case with DCVax-L) to the dendritic cells is only one part of what DCVax-L does. Another important aspect of the product is that it takes signaling compounds to the proper sites so that helper T-cells and killer T-cells can be properly informed and activated and T-regulator cells can be inactivated so that the proper immune response can occur.
DCVax-Direct has more than 10x the amount of signaling compounds on each dendritic cell than those of DCVax-L. These compounds in the tumor microenvironment are immediately put to work and because the tumor has been damaged already, as per trial protocol, the ability of the dendritic cell to identify antigens is improved and mobility is not more fully impaired as would be the case with a healthy tumor environment.
An article from Neuro Oncol magazine dated April12, 2010 titled “Intratumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment” which essentially states that intradermal (i.e. DCVax-L) vaccination is improved by intratumoral (ie. DCVax-Direct) vaccination because the microenvironment of the tumor is changed by doing so. This evidence is only a small part of the evidence that I have found that supports a long term investment in NWBO.
Red.
I added today and yesterday.
Other than the prospectus, I wonder if there is a way to determine the estimated number of total shareholders? Back in November 2013, it was about 2200.
Thanks Hodge -- it is a very hopeful post.
I hope all is well.
Well, maybe that's a famous interview. But I feel like I just watched a vampire detail how he sucks the life out of someone. Jim Cramer's voice would give life to a wonderful number of animated characters for childrens' feature films, but his heart is clearly insatiably connected toward burning those who are naive and/or not as smart. What a terrible conundrum. I almost respect the competitive spirit in him until I come to terms with the fact he destroys well meaning innocent investors on a daily basis. Those innocent investors expect the United States SEC to be smarter and more scrupulous than affable wolves, seductive vampires and grim reapers of innocence. I despise him, but I can't help pray for his soul.
We are close.
I think you are over thinking this minor article. There is only one interesting thing in it. Oppenheimer states it is "make or break." Well guess what? It isn't. Under the highly unlikely circumstances DCVAX-L is a bust, DCVAX-Direct is waiting in the wings. Oppenheimer knows this better than any other large investment company, and of course, they were the same ones that gave FOX viewers the head and shoulders back in November. So take everything with a grain of salt. There really is a very large Phoenix waiting in the wings if things go south. Want to know a 'secret'? Direct is not simply for inoperable cancer.
Occam's razor. Paperwork is always the simplest explanation.
I think looking at the international implications and clues helps keep us sharp. I also look forward to examining our correct and incorrect understandings once the trials and other processes run their course. I think there is a great deal all of us can learn that can be applied to future investments.
I definitely think it would reduce the concerns floating around about delay that might be caused by potential subtype divisional trial powering deescalation. This in turn may make the international response/decision to a halt in one or both groups much less bureaucratically delicate.
Clearly Adam navigated a quick back pedal on his positions regarding NWBO. Good Points Pip.
Welcome back Dok! I Look forward to hearing your thoughts in the coming days and weeks.
Here's a very enticing theory.
Germany does not want the pseudo progression group in the trial because they already know those patients respond exceptionally well to DCVAX-L, and more importantly, the efficacy can be determined exceptionally fast (see posts by doc, flipper and others). Thus, they are anticipating the pseudo-progression group will be halted before they start their enrollment.
Why would Germany know this? I think you can start with the clinical experiences in Cologne Germany and in the compassionate use cases in Israel and Great Britain. John has a lot of information he found in his internet research on the Cologne program.
It makes a great deal of sense to me, but I'm probably not taking enough time to lay it out based upon the other factors making this likely.
I'll just mention one. Germany is the toughest Country in Europe for a company to receive manufacturing approval, clinical trial approval and compassionate use reimbursement. In accomplishing this, they check every nut and bolt before giving the go ahead. One of the only things they required was that NWBO not include the pseudo progression enrollment and separate analysis in their part of the enrollment program. Think about that. They would not want to start enrolling people who might tomorrow be eligible for commercially approved (through Germany's expansive compassionate use program) DCVAX-L's treatment. Thus saving some patients from the placebo.
(Of course, imho any possible divided halt and continuance between the 2 groups could happen in reverse order, possibly due to the trial chronology)
I think the only way they would separate a continuance group from a halt is to use the pseudoprogression group which is in the same trial but analyzed separately. See some of my posts using search keywords mesenchymal and or classic. The pseudoprogression group may largely be composed of mesenchymal. Does this mean the separately analyzed group still has their own control randomization and primary endpoint? Maybe. If so, one could envision where the pseudoprgression group is halted first, while the main group is continued. Or visa versa.
Because they were separated in the first place, such different outcomes would not lessen powering in whichever group is hypothetically left to continue.
The additional good news is that IMHO the main group likely has a robust population of mesenchymal and classis tumors, so it is likely to respond to dcvax-l as well. So if they were halted at different times for efficacy, I would not bet on which group comes in first.
I added a bit today.
Did you miss your quote in my "data dump?" Seeing how you are concerned with grammar, I thought you would be pleased to see your name in the same breath as Churchill and Wilde.
See post #5272. Specifically:
["If a company is failing it's investors it isn't because they aren't releasing PR's enough to satisfy them." (Pyrrhonian)] (Should be its -- possessive form)
I also noticed you had 2 periods in your last post after the word "sicko[..]."
Perhaps this concurrent dilemma explains your sour mood today.
#4049 was/is such an intriguing post.
What fascinates me though is the 30 patients that were started on this trail when it was phase 2(before the update to three )in 2008.
These patients have been continued to be treated , despite the trail being stopped due to lack of finance.
This is when i first got involved in the story as part of a
group of so called angel investors from the Middle East.
The information on these 30 , plus the compassionate cases during this period will be known by the company, thus i feel (talking my own book) the confidence of Linda to invest so heavily in manufacturing.
There is often confusion between its and it's. If you delve deeper into this issue, you will see that there is good reason for the confusion. However, if you just want to know what is right, the matter is very simple:
It's
It's is short for it is or it has. This is a 100% rule. It cannot be used for anything else. If you cannot expand it's to it is or it has, then it is wrong.
Its
Its is like his and her.
His is used for a masculine possessor (owner). (These are his pies.)
Her is used for feminine possessor. (These are her flowers.)
Its is used for neuter possessor. (These are its footprints.)
Examples:
It's been raining for a week, and now it's starting to snow.
(It has been raining....it is starting to snow)
It's one of the hardest courses in it's history.
(The first it's is correct. The second should be its.)
["If a company is failing it's investors it isn't because they aren't releasing PR's enough to satisfy them." (Pyrrhonian)] (Should be its -- possessive form)
I think the company wants to have its cake and eat it.
(its – possessive form. This is correct.)
The reef shark chases it's prey through the coral.
(should be its, i.e., the possessive form. You cannot expand this to it is or it has.)
I'm astounded by people who want to know the universe when it's so hard to find your way around Chinatown. (Woody Allen)
A lie gets halfway around the world before the truth has a chance to get its pants on. (Winston Churchill)
There is nothing in the world like the devotion of a married woman. It's a thing no married man knows anything about. (Oscar Wilde)
Whenever cannibals are on the brink of starvation, Heaven, in its infinite mercy, sends them a fat
missionary. (Oscar Wilde)
Constant company wears out its welcome.
A frog can't empty its stomach by vomiting. To empty its stomach contents, a frog throws up its stomach first, so the stomach is dangling out of its mouth. Then the frog uses its forearms to dig out all of the stomach's contents and then swallows the stomach back down again.
A completely blind chameleon will still take on the colours (colors) of its environment.
Read more at www.grammar-monster.com/easily_confused/its_its.htm#fqRzhf4HxhlmAXSY.99
Pyrr,
I don't know how long you've been around, but Red Has been through many dilutions with this company. In other words, NWBO continued to exist on the backs of shareholders like him. The scientists, patients and Doctors deserve all the credit, but the long investors are using their hard earned money to keep companies afloat, and believe me, this company has not always been as solvent as it is today.
I've been busy. I know you wanted more. I'm glad others could provide what you were looking for. My default response is that everyone must conduct due diligence and determine their own risk tolerance. Never stop learning. I am passionate about this company because of what I deduct/induct they will achieve. However, despite my personal confidence, I would never dare to convince someone to spend more than they can afford to lose.
I have a decent forebrain, but every blessed family member of mine exceeds my planning capacity by at least two fold. Therefore another rule is: you must know your limitations.
My rule of thumb is that if you can't lose whatever you invested in one single company, and the next day be happy, kind and ready to help another company, then you invested more than you can afford to lose.
Everyone has their own risk tolerance.
Yes the 33 patients carried over from 2005-2008. This has been discussed in older posts along with multiple other factors, like 80% response rate in over 200 patients with 1000 treatments excluding the phase three trial.
I saw that too. I have a few pharmacist friends that will probably need to increase their security precautions at work in order to avoid robberies.
But its BLINDED. They can only tell if the entire patient population is living longer than a global average, you can't tell which ones were treated and which ones were not. I doubt NWBO gets the kind of detail you are expecting -- (unless a halt for efficacy has already been place on the table). Many have tried, (i.e.., IMUC posters), to figure out efficacy based upon thin enrollment information. The IMUC Yahoo board had very smart people tearing their hair out trying to run the numbers. I am convinced it is nearly impossible to do in this type of trial.
These protocol agreements are written different ways. However, from what I remember about DMC guidance rules, enrollment updates are often shared with a company at the interim analysis. I believe they can also be shared during open session meetings if any have been arranged. I'm just going off memory now. See the PRANA (PRAN) enrollment updates from last year as an example.
Regarding Doc's theory:
If NWBO is using the 4 subtype classification:
I do not know if just certain subtypes in the trial can be halted for efficacy. I'll probably let Doc site that rule instead of researching it.
However, if the DMC can do this, I think the halt for efficacy would be for 2 subtypes -- classic and mesenchymal. This is explained under several previous posts. Keywords "mesenchymal" and/or "classic."
That does not likely get you to the 80% response rate, so, under this hypothetical, the pro-neural and neural subtypes would likely continue in the trial.
To me, this peeling away of benefitted subtypes would be another 'systematic' chipping away from the barbaric (yet unavoidable -- so far) placebo trials. The cross-over arm is another way to do this. Interim analysis is another way to do this. They can cohesively play their parts in keeping people alive who might otherwise die in the old version of the double blinded placebo trials.
No.
The DMC determines the 66th event by counting the events, not by guessing when they should have happened. In this case the 66th event happened near Dec 10 2010.
Its not always a devilish number.
The most common carbon isotope (Carbon-12), the basis of all known life on Earth, consists of 6 protons, 6 neutrons and 6 electrons
Yes, I'll admit I'm having trouble walking (DCVAX-L) and chewing gum (DCVAX-Direct) at the same time .
I was probably a little less enthusiastic about Direct at ASCO until Vivek confirmed the abstract was not a T.I.P. submission -- he did that by stating he might be sharing some data, which you can't do with a T.I.P.. Consequently, I'm excited by the chronological crescendo presently developing.
S.P.A. .
Responding to AF's 'concern' that NWBO does not have a S.P.A.
The Facts.
*A special protocol assessment is not available for trials that have already started.
*Moreover, a phase three trial protocol assessment is worked out post-phase 2 and pre-phase 3.
In the case of NWBO, a S.P.A. was not available (nor necessary) because the trial morphed into a phase 3 trial from a phase 2 trial.
When a company has already started enrollment, their protocol can still be evaluated by the FDA (CDER and CBER), but procedurally, no S.P.A. will be issued. This quirk in the FDA protocol evaluation procedure as it relates to NWBO's trial timeline does not lower NWBO's chances to ultimately be approved, nor does it raise red flags -- it is simply a different procedural route.
Money, so they say.....
Great post longusa!
LTT's response confirmed my suspicion that he has an agenda. We seem to be mired in AF stock tankers today. This too shall pass. AF and his buddies are determined to turn lemonade into lemons (probably so they can by on the dip created by the Ukraine and AF's hit article.) Apparently they are not familiar with the concept of "irreversible change."
What are you talking about? "Not blockbuster in nature?" If they get the results they had in their 2 phase I/II trials, You'll feel pretty silly. If a family member had GBM, you'd feel pretty strange arguing for an OS primary endpoint that would delay treatment beyond near term hope. I could go on, but I know you are smarter than this.
I think what he is inferring is that everyone will cross-over if and when they progress. Thus they will compare trx arm against the crossover arm. We already discussed how this has been handled in other trials previously.
How about that? AF upgraded NWBO!
AF previously predicted NWBO would fail (aka:"blow up")
AF currently predicts the NWBO trial will be continued and infers it will ultimately pass its primary endpoint.
(AF now has a fallback position that the Primary Endpoint should be OS not PFS.In other words, he argues more people should die around the world before this drug is approved.) Adam forgot to mention this is a treatment with orphan designation.
Here is a fairly comprehensive study on using PFS as a primary endpoint. Remember, NWBO worked with the FDA to develop their endpoints; moreover, if the first and secondary endpoints are statistically significant, there is no way in Hades that anyone would stop this drug from getting to patients if the extensions are nearly 6 months or more.
http://www.ncbi.nlm.nih.gov/pubmed/20167815
I'm at the point….
Where I think all our hand ringing and/or confidence is a waste of time -- because the decision is severely imminent.
Some people were at my current status way before me. Others are still analyzing the hell out of this.
I'm all in.
Am I right? Am I wrong?
I pray for the patients that I am right.
If I am wrong, I'll take my hit and try to help the next best treatment.
God bless every patient, investor and everyone else.
See you on the other side…. of the DMC decision.
(A continuance will prolong everyone's consternation. But I'll remain fully invested.)
They'll have enough money to test both theories in a little while -- maybe side by side.
Komen said:
Also, no one really mentioned anything about the possibility of the number of subset patient group analysis built into this trial that may be causing the delay in the interim analysis. Anyone know what the predetermined subgroups are?
I read somewhere recently that non-solid tumor lymph/blood cancers were showing even more complete responses to various forms of immunotherapy. Your post would be one of those cases.
It makes me think about DCVAX-Direct applicability to blood and lymph non-solid tumor cancer.
At first, it does not make sense to utilize dendritic therapy that is specifically delivered into the tumor (aka: intratumoral injection).
However, I think; just as some of us expect DCVAX-L will be made more potent in the future -- through DCVAX direct preparation advancements that occurred after the phase I-III tDCVAX-L trials were already in progress -- conversely, I think; DCVAX-Direct administration techniques will be used to expand its therapeutic range to blood cancers.
How could this be done? Most likely most of you nonscientists, and many other scientists have or will determine a better way then I will propose here, but I'll suggest one avenue.
First, it is a given that DCVAX-direct supercharges a precursor dendritic cell into the perfect phase of maturity. In the next stage of preparation, NWBO next takes the "teenage" dendritic cell set and concentrates it by selecting only the types previously determined to be most efficacious.
At this point you have highly efficacious, nontoxic and highly mobile dendritic cells ready for intratumoral injection.
But wait…in cancers like leukemia, there are no solid tumors to inject. What do you do?
The same blood sample that was used to gather, mature and select precursor cells into DCVAX-Direct -- that same blood sample -- would also contain leukemia cells.
While the DCVAX-Direct is being processed from part of the extracted blood, another part of the blood sample could be used to concentrate leukemia cells. Unlike the DCVAX-L process, these cells would not be ground up, but rather they would be stressed ex vivo. The stressing process might take the form of hyperthermia such that some leukemia cells would die while others would become too weak to mount a defense. Finally there may still be a few leukemia cells that can mount a full defense.
Into this concentrated blood sample of stressed leukemia cells we than introduce DCVAX-Direct dendritic cels. The timing of the commingling phase before reintroduction into the body would likely be critical. I say this because apparently dendritic cells appear to be only fully actualized if they are exposed to natural environmental conditions as well.
To do this, you probably do not want every single reinjected dendritic cells to be fully educated ex vivo, therefore there may be a perfect educational phase-time at which these dendritic cells are frozen or simply immediately reintroduced into the patient. This may dependent on the geographical location of the process in relationship to the patient's location.
Homely Analogy:
We learned that dendritic mobility, orientation, uptake, expression and other factors can and will be affected by their environmental circumstances during education, therefore I submit that it would behoove scientists to use the above technique to enhance the probability that dendritic cells will not all be exactly educated at the same time and place. This subtle, but to me, very profound pool of "olympic dendritic cells" trained in different environmental "countries," some even trained on home "turf" all by different "training techniques" will provide the ultimate "closing ceremonies."
What does the fox say?
Regarding where NW is in the DMC-FDA loop, I do not think such [conversations] were going on at least at the time of Linda's last presentation. If you go back and listen, she implies or states flatout that they are waiting as well.