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"If interim reports are shared with the sponsor, it may become impossible for the sponsor to make potentially warranted changes in the trial design or analysis plan in an unbiased manner (see Section 6.3). Even aggregate data on safety and efficacy may be informative; these data may be needed for some trial management functions (e.g., sample size adjustments, centralized endpoint assessment), but are best limited to those who cannot otherwise carry out their trial management responsibilities."
Reviewing 6.3 provides some additional important information about the conduct of the trial and the extent to which remaining blinded is protected.
You presume to know my time zone and what my job requires. Most weeks I work seven of seven days. That's the way it is in basic research. Animals, cells and experiments don't take a day off. I didn't buy back. If I'm wrong then I'll buy back at a higher price and that will be my penalty, a stupid tax if you will. If I'm right then I will buy back at a lower price. Either way I'm okay with the outcome.
Yes OU, that is exactly the point that I was trying to make. There must be some reason that enlarging the cohort now is coming up. If it were all about making it safe while having no new information then why did they settle on the 312 number in the first place? When drafting the protocol for the latest incarnation of the trial they would need to have provided justification for the assumptions (outcome measures, event rates etc.) underlying the power calculations that they used to come up with 312. The sponsor is blinded to the data so it would need to be coming from those with access to the data. Unless it is of course as some have stated just a preemptive move. To me that seems really really unlikely. That doesn't send a good message to shareholders and more importantly to institutions that could crush this stock if they dump their shares.
I can think of one other explanation but it seems really remote. NWBO could consider data from related studies. I'm just wondering if the PFS of the placebo group in the IMUC trial is known. If that is very different from the assumptions NWBO made when making their power calculations for the current trial then you could speculate that it might make one rethink what is needed to show a significant difference in PFS. Just a thought...
I just made a primary astrocyte culture from the cortices of neonate mice. Carving out their brains didn't help....got me to thinking though. Good not to be a mouse. I don't do a lot of DNA work anymore. Mostly cell biology and protein work.
I understand that giving information about trends is a no..no. But it could be as I wrote it. More patients will make the analysis more clear. That's all. More clearly no difference in PFS or more clearly positive difference in PFS. As for adding patients to target subgroups, I would think that would be like cherry picking the patients. Not that there is anything wrong with targeting a subgroup, just don't do it in a trial that wasn't originally designed for that. Maybe when you said targeting you didn't mean actively seeking certain subgroups? Just getting another 30, 60 or 100 on board would by default add certain subgroups???? Beyond just wanting to be sure you've got the data you need to seek approval, I've not heard a convincing argument about why add now (just after the first interim look).
Come on Pyrrho. You know I know what a double blind trial is all about. And I've never said that Linda has seen the data. I don't think she has seen the data, at least she better not have. The steering committee and the DSMB have definitely seen the data. I believe that the recommendation has come down to enlarge the trial. Telling the sponsor they need more patients doesn't unblind the data. If you write in to your study protocol that you have the option to enlarge the trial as needed, then you also have to have a mechanism for deciding if and when to do that, no? I think that mechanism is how you decide to "think about" enlarging the trial. That's my point. No mention of the DSMB in her talk yesterday, but she did mention, strangely don't you think, that the trial could be enlarged and in fact her and the management team are thinking about it. Almost as if to prepare us for news that the trial will be enlarged. My best guess is that the DSMB said "Hey Powers, your trial is going good. No safety issues to speak of but we have reviewed the data and believe based on what we are seeing that having some more patients in the trial would be helpful in the final analysis of the data...it's your call."
How exactly do you just blindly decide to increase the size of the trial? I mean do you just wake up one morning and have a gut feeling that you just need a few more patients in the trial to get to where you need to be for licensure? I'm pretty certain that one of the roles of the steering committee or DSMB or both is to make such recommendations based on the data. They can't unblind to the practitioners or the sponsor so as to change how the trial is being conducted, but they can see for themselves that the trend line is separating from control, but maybe not enough to be statistically significant with 312 in the trial. So, they recommend enlarging the trial. Linda made the point in a roundabout way that if PFS is short of 6 mos they might/would need a more stringent p-value. Can someone please explain to me how you come to the point of even discussing enlarging the trial without some news that you might need too? I've never heard Linda say that "they are thinking about it". I've only heard her say that they could if needed enlarge the trial.
My guess is that at this first interim look there is a trend that is positive but may not meet the endpoint. If you are going to change something you do it now rather than at the end. I don't know, I'm totally puzzled by this. Fox..do you have any thoughts you would like to share?
The same two issues that were of concern to you are also of concern to me. Here is exactly what Linda said about the powering of the trial:
"We have the luxury to enlarge the trial if we want to do even further de-risking of the trial. The more we enlarge the trial the even stronger the powering would be and even smaller difference we would have to show. Instead of 6 mos maybe 5 or 4 mos of extension. And that's icing on the cake for us. Now we haven't decided whether were going to make use of that or not. We are thinking about it; it's a strategy point for us. But it's a wonderful strategy option to have."
That verbage tells me all I need to know about where this is headed. So much so that I barely slept last night and sold all but 1k shares this morning at $7.25. I've held most of those shares for more than a year and never traded them. I just think at this point if they enlarge the trial the share price is going to tank. I admit though that after I sold I thought I had made a huge mistake. I had sellers remorse. But then just now I read the Smith article and he also thinks they will enlarge the trial.
Your other point about the DMC is truly bothersome. Linda knows the recommendation and if it were stop for efficacy she would immediately release the news and never have brought up the powering of the trial. I also wonder about financing. Where is the company at with needing more cash and when? If they enlarge the trial (that cost more) and then they announce needing money on top of that where will that leave the share price? I watched a near triple evaporate with NVAX in the last few weeks. My stomach for losing (on paper)profit has decreased.
Lastly, in my free time I'm reviewing the literature on tumor immunology and I'm hoping to release several posts covering the area for those that are interested in knowing more about the science behind immunotherapy. As I've said before, my training is in molecular biology, virology and glycobiology. I'm not proficient with immunology despite working right next to an immunologist.
GLTA
4000 shares. If I could afford 4,000,000 I probably wouldn't be investing it in micro or small cap stocks. Lol. Maybe in Jose Cuervo on a nice beach somewhere in the South Pacific....
No, if Direct could eradicate the tumor that would be an overwhelming success. I think you are confused about regression or necrosis vs eradication. Have you read the Triozzi et al. paper? Injection of tumors with DCs has been done more than 14 years ago. To repeat that would only be a stp forward in the sense that NWBO is poised to be able offer that to a broad group of patients and not just the occasional clinical trial. Importantly though, the tumors aren't necessarily eradicated when injected with DCs. One might even be able to mount a compelling argument that disrupting the integrity of the tumor could release cancer cells that find a new home in the kidney, lungs or liver etc.. I'm not a physician. There are physicians on this board and maybe they know of a specific case in which surgery or drug treatment actually can be negative if you don't either kill all of the tumor or if you don't develop a systemic response that will find all of those rogue cells. Just about anything is possible when your dealing with cancer.
I'm no hater and I don't expect a silver bullet. I hold >4000k shares that I have held for more than a year. I keep an open mind and when I see a post that I think I can add something constructive too I do. You mentioned "misleading someone". I feel the same way when someone posts something (positive or negative) that I don't feel accurately reflects the facts. That's when I post something respectfully disagreeing or at least trying to add some facts (as I see them) to the discussion. I hope it's helpful and i'm certainly open to having my mind changed.
At about 25 minutes and 40 seconds she describes what they are looking for as "tumor necrosis" where they injected it. I don't doubt that there is more to the story... I'm just trying to listen carefully at what is being said and determine if I'm hearing good news or outstanding news. I think killing at the injection site is good news, they have replicated the previous work by others in published trials. Now, have they advanced from that point? I'll bet they have but she didn't say it (maybe couldn't) and so I will wait like everyone else for news. I would think at some point some one in the trial might let it leak out that tumors other than at the injection site have regressed if that is in fact the case. That would be news you would want to share with others struggling with cancer.
I'll listen again. I though she said at the site of injection... I hope for the patients sake and for the investors sake that the regression is at other sites. Even an understanding of the mechanism at the site of the injection would be an advancement in our understanding and a positive outcome.
What exactly do you think ends up killing you when you have metastatic melanoma? The Direct trial is geared towards people with no other option.
criteria:
Patients with a histological or cytopathological confirmed diagnosis of a locally advanced or metastatic solid tumor malignancy for which standard treatment is no longer effective or does not offer curative or life-prolonging potential per clinician judgment.
I would wager virtually every person in the trial has cancer that has spread either to adjacent areas or to far off regions. The idea that a person with colon cancer has one big tumor is absurd.... What exactly are you going to inject when a kidney or liver or lung is riddled with cancer?
These people have tumors all over their bodies. You can't inject them all. Some are tiny and yet undetected. Chemo is systemic. Radiation before a tumor spreads can work. I'm not saying they aren't seeing good results. But look at what it was about Direct that was different....Memory. Tumors beyond the site of the injection were eliminated. Future tumors were stopped. Tumor regression at the site of injection is not success. Regression at other site is success. Maybe they see that and she just couldn't or didn't say it.
I swear I heard her say that they are considering enlarging the trial, not just expanding sites. The context was that they could show differences that are smaller than 6 mos...5 or 4 are statistically significant.
Austin,
Tumor killing means absolutely nothing. It's already been shown with DC injection. Its the memory, the expansion and recruitment of T-cells that disseminate throughout to mop up the cancer that is important. Tumor regression is a given based on literature from 2000. The key is to show a mechanism and show that it spreads.
Did she just say that they are considering enlarging the trial??????????????
I guess we will know shortly. I'm just speculating that if nothing new is released today then the late announcement is going to really look like an attempt to avoid a certain person in a public forum. I sincerely hope that isn't the case. For me, this comes from seeing the way the DMC review, recent PRs and a lot of other things have been handled. All of those things have really shaken my faith in the company management.
Agreed. They must PR any new information prior to the conference. And i guess that is why I am leaning towards a last minute announcement of the presentation in the hopes of avoiding getting grilled by AF. I know that seems like a lot of manipulation to just avoid one person...It's not like the company cares what he writes. I mean if they did then they would have refuted his claims in not one but two different PRs....wait a second....
I'm just getting in to read the board posts and I saw the news this morning on the wire about the conference presentation. My immediate question was is this really the first announcement of the presentation anywhere? My next question was why the last minute announcement? I know some of this has probably been discussed, but the last minute nature could be good news or not so good. AF lives in Boston, not too far from the conference. Was this last minute announcement an attempt to not give him time to show up and ask awkward questions? I assume anyone that pays the fee can attend, right? The presentation is today so Linda didn't find out about this yesterday. So why the surprise?
Using that logic then we should all encourage AF to write another article that NWBO can refute in order to get some more free press.....I mean heck, look how well that strategy has worked out for the shareholders. Maybe I can even get my cost basis below 3 bucks before the big news hits sometime this year or next or next or whenever NWBO feels like cluing us all in to what the hell is going on with the trial! Maybe they are just waiting to parade out some tumor regression in the Direct trial at ASCO before they let us know what I am certain they already know about L.
Yes, I seem to recall that's how Dendreon managed it. In reality, the vast majority of the submission is the trial data that is probably already outsourced. But you can't outsource everything. The FDA wants direct contacts with the company. They like to build a relationship. It's about trust, if they don't trust you it will not go well. No single person or even handful of people can convey this much less manage all of the request for more information that will come. And every time a request for information is made the clock on a decision will stop. But then all of this is getting ahead of ourselves. Look at what Dendreon went through to get approval...I sincerely hope that isn't a model for NWBO's path....
I'm not sure what you mean about it being illegal for her to call/ask. Unless there is some obscure federal statute that I am aware of it isn't illegal to for the sponsor to ask the DSMB for an update on when they will complete their evaluation of the trial data and even why it is taking longer than anticipated.
"Independence of a DMC depends on the relationships of its members to those sponsoring, organizing, conducting, and regulating the trial..... Independence is defined on a continuum. DMCs are rarely, if ever, entirely independent of the sponsor, as the sponsor generally selects the members, gives the committee its charge, and pays committee members for their expenses and services.....Additionally, while sponsor involvement in looking at comparative data threatens independence, sponsor representatives, study statisticians, and study investigators may contribute valuable perspectives regarding the trial that may not be available to the committee from more independent sources. With regard to sponsor/investigator involvement with the DMC, this tension is best resolved by permitting interaction with the committee in a carefully defined and limited manner, as described in Section 4.3.1.2. The involvement of such individuals with the DMC will typically be limited in terms of what interim data may be viewed, which sessions may be attended, what topics may be discussed, and what roles (e.g., observer, consultant, member), may be played."
The biggest concern is to not unblind the data as that could in the eyes of the FDA invalidate the trial.
Maybe I misunderstood you? Anyway, I try to bring humor to this as much as I can. I use to post over on the Yahoo board and once there was some discussion about Linda putting down some serious cheese for website domains. The discussion was about what it could mean for the company. Here was what I wrote...maybe you will find it funny too
Top 10 reasons Linda bought the cancervaccine domains:
10. They were buy one get one free and everyone knows that “soccer moms” (a quote from the molester) love a good sale!
9. NWBO thought they could get a little bump in the stock price so that insiders could dump their shares for a slightly smaller loss!
8. Doctors really like to have their pictures on websites administering a vaccine to terminally ill patients they know doesn’t work!
7. The websites will be used to sale cookies and brownies to raise funds!
6. The websites will make it easier to auction off equipment after the bankruptcy!
5. Linda bought the domains right after having a big cup of NWBO special blend KoolAid.
4. Linda left a college intern in charge of marketing while she was in Venezuela trying to score some Chavez tumor cells for a new vaccine marketed to latin America called DCVax-increible
3. Linda lost a bet with the IMUC CEO and had to buy the domains for their vaccine.
2. Linda is going to sale them for a premium to another immunotherapy company..after all she has to do something to keep the lights on!
And the number one reason Linda bought the domains is…
1. She just needed a couple more big purchases on her SkyMiles credit card to ensure she has plenty of miles for last minute tickets out of the country when this all implodes!
I agree totally with what you posted. They have to come out with some information soon or risk losing further credibility. This has happened time and time again for little biotechs. You have to believe what they are telling you or else it's all just noise. After to many shenanigans, investors lose faith.
Hiring some heavy hitters would be extremely positive. It takes time to staff. I don't know what the complexities will be for filing a BLA with an autologous treatment like DCVax, but I can imagine it will still be a major endeavor that will take many many months to complete. And that's assuming they have enough people in place from the start.
Afford,
They are in fact the judge and jury. They are the sole reviewers of the clinical data up to this point. While they have no real power to force the trial one way or the other, their recommendation carries serious weight. NWBO developed and agreed at the beginning to a set of guidelines for how the data will be interpreted and also to the actions that will be taken based on the data. And as for the timeline, Linda herself set that when she indicated the normal time for these kinds of reviews. I think history would support clinical reviews in line with what Linda indicated. This is outside of a normal time for review.
"Remember if they take too little time they are viewed as a rubber stamp and assumed to be inept if the drug fails/causes damage and if they take their time with such a new fangled drug it can only be on their side if just from appearance sake."
This process is not an opinion, it is a guided review of the data that either meets the threshold for an efficacy stop, meets the criteria for stopping for futility or is in line with the expected results and should meet the endpoint. Nobody is asking these members for their "gut feeling". The data are black and white or they are grey. If they are grey then the trial design is at risk.
Lastly, I don't believe that what the DMC recommends for the trial has to be released immediately. It is their recommendation and NWBO has the right and obligation to shareholders to verify and confirm before taking any action that might benefit or harm. And yes, I've dealt with the government more than you know. They have nothing to do with and want nothing to do with news getting out, bad, good or otherwise.
I'm not saying the delay is good or bad, I am saying I am losing faith that this is being handled professionally.
I would bet every last share I own that somebody at NWBO knows what the hold up is about. In fact, they've known for a while now. NWBO picked the members of the committee and is compensating them for their time. They are an independent in their decision and the conclusions they draw from the data, but they are not fire-walled away with zero interaction with the sponsor. To think that NWBO is just sitting around in the dark wondering what the heck is the hold up with their multi-million dollar trial is insanity. Can you imagine what a conversation would sound like...
"Yes Ms Powers, we know that we are taking a long time but you will just have to be patient. No Ms. Powers, we can't tell you anything at all about why this is so outside of the normal time-frame for review of clinical data. okay, you have a wonderful day too!"
You won't hear any argument from me that we don't need a better SOC. Chemo is awful. I just don't know that anyone really knows yet if NWBO is better, worse or the same as SOC with regard to PFS and/or OS. The PI/II is not reliable enough to draw solid conclusions. Thus, the PIII that we are going through now. Trust me, I have wagered a sizable amount that it is of some benefit. My expectation is a benefit in PFS that hopefully will translate to some OS benefit too. Personalized medicine is the future. It will likely be X, Y and Z treatments from an equal number of companies that will be selected based on knowing your genome and the genome of the cancer/disease you are suffering.
Do you really want me to put the bad news on this message board for the shorts and bashers? I can... The treatment has and does fail GBM patients. Anything outside of a trial is anecdotal evidence.
ou,
Nice post. I appreciate that you stay grounded in reality.
I've been burned by CEOs also. I take so little of what they say as truth I hardly listen to what comes out of their mouth anymore.
And it's not just the CEOs that you have to worry about. I'm a research scientist and I've published quite a few first author manuscripts in good journals throughout my career. I've tried once or twice to get my studies into the elite journals (Nature, Science, PNAS etc.) with not even a referral for review by the editor. But if you search the internet for articles reporting on how much of the science published in those "top tier" journals can never be replicated, you would probably be shocked. A lot of it is fraud, pure and simple.
That said, the fact that Linda has a lot of skin in the game is a good sign. But I sometimes wonder how much all of that cheese (on paper) actually cost her? I don't know that answer, but I know when I'm playing with the house money I tend to be a little more reckless.
I give our chances about 50/50. But the longer this DSMB recommendation goes MIA the more concerned I become. This smells of amateur night and I sincerely hope that I'm wrong.
The last thing that worries me is when the message boards all become circle jerks declaring we have found the goose that lays golden eggs. PPHM thinks they have it too, so does Advaxis and many many others.
And where exactly will you get the tumor from to use as antigen for a new crop of cells that will need to be harvested? I just don't even understand what you are arguing about...
Why do you think that the Triozzi et al. study showed a systemic effect?
You said:
"The systemic response is the most important part of this equation though, as otherwise it would be impossible to keep up with such aggressive metastasis. And that's what was seen in Triozzi."
I agree that the most important part of the equation is to show a systemic effect. A systemic effect indicates that DCs acquired tumor antigen, migrated out of the inhibitory tumor microenvironment and initiated a meaningful T-lymphocyte response. However, that was not the case in the Triozzi study. In two patients, tumors immediately adjacent to the injected tumor site had some response. It was not systemic and the mechanism by which the tumor regression occurred was not determined in the study.
"There was no clinical evidence of systemic antitumor activity in metastatic lung or liver tumors present in the patients enrolled."
Characterization of the injected DCs showed that the levels of CD86 (and other surface molecules) had declined; which is characteristic of a reduced capacity for immunostimulatory activity, and suggests that the DCs probably de-differentiated in the microenvironment of the tumor.
Yeah, I think your right long. The use of the word "independent" should have clued me in to what Smith was trying to say which was PEI regulators would not be "free" to serve on a DMB being that they are employees of the German government. Someone that is part of CBER certainly couldn't be on a board for a drug on trial in another country. That makes sense.
PEI review of clinical trial data:
Yesterday I posted a comment on Larry Smith's article: "Northwest Biotherapeutics (NWBO, Buy, $7.90): DCVax-L Is Approved in Germany under Hospital Exemption Early Access Program"
My comment and question was regarding the possibility that someone involved in the PEI review is on the DMB for the PIII. I also inquired if the article had been edited since I had first read it. I would have sworn that somewhere I read a statement that clearly stated that the PIII data was not used for the review by the PEI. but I can't find it anywhere and Smith didn't respond to my question. What he did say however was:
"The PEI employees are regulators who would under no circumstance be part of a DMB.".
I find that viewpoint extremely disheartening if true and I have to doubt that it is. You can read his comments for yourself, but I don't see how a regulator (e.g. not an MD, PhD or statistician) could review the existing data and make a decision to grant hospital exemption. Something just doesn't add up. If that were the case then the German decision would say nothing about the efficacy of DCVaxL. You can find the article by going to smithonstocks.com and the story is under recent blogs. I like Larry but something about his reply doesn't add up and I'm hoping he can clear up how a regulator can evaluate a product with no scientific, medical or mathematical background...Maybe I'm just not understanding what he said?
I don't think it sunk in until just now that NWBO is comprised of only 7 employees. Is that certain? I realize that the manufacturing is done by cognate, but I'm a little shocked that they can manage everything that needs to be managed with so few employees. They must rely heavily on cognate for tasks beyond simply the manufacturing. Anyone hoping to bring a drug to market will need a QA, QC, Regulatory, Upstream and Downstream process development departments plus a dedicated Clinical project manager. Not to mention the other items unrelated to the product like accounting. It must be that they have consulted most of this out?
You beat me to the punch. I read about the swiss thing in one of his tweets. Who knows how complex the agreement might be between PEI and NWBO. You practically have to take the engine out of a modern VW to change the headlight.
I'm sure they didn't want to screw it up! And don't forget they aren't allowed to advertise the drug for use in Germany, that might have factored in to how they released the news.
In view of yet another hit piece and his bravado on twitter about NWBO destroying themselves, can anyone really still believe that responding directly to AF was the right choice? This thug will only be stopped when he is held accountable for his statements. I've heard arguments that NWBO should stay focused and not get tied up in a legal wrangle. That's what attorney's are for! That's what they get paid for, to handle this garbage so you don't have too. What about a release that said: "NWBO today announced the offering of 150k shares of common stock at $8/share. The proceeds from which will be used to fund a legal team in NWBO's bid to bring an action against Adam Feuerstein and The Street for defamation". Do you think F'r would joke about that on twitter? Or what about all of the other false statements he's said about other biotechs. I wonder if the CEO's would agree to file a class action? Cramer and street exist because of sponsorship, these kinds of headlines about small drug companies trying to develop treatments to help the terminally ill being attacked by greedy Wall St hacks would not bring more sponsorship. You can write all of this off as it doesn't matter I guess, but it will effect the bottom line of the company during the next raise and may even disuade some patients/doctors from taking this treatment more seriously. How do you think this negative information impacts an individual investor's decision to buy shares, much less the decision of a person with terminal cancer to enroll in the DCVax trial(s)?
It's time to stop reacting to this person and play some offense. He can criticize all he wants about the science and the data, but this is pure speculation, opinion and outright false accusations.
I agree. The response to AF should have been filing an action against him and the street for defamation.
After my last message I considered selling the lot and waiting for his piece to buy back. But that just isn't my style. Maybe the shake out of fair weather fans will be good in the long run. It does bother me they sat on the news. But only because F'r made something out of it. My hope is that the reason they sat on the news was to burn the shorts off the shorts and to possibly put off the announcement to a date closer to the next fund raising. I haven't followed the companies financial situation as well as I should. I'm guessing they might need some cash soon? In this era of litigation, I just don't understand how this sort of trashing of a company's reputation can go unchallenged.
You are giving most retail investors/traders way too much credit. I think a lot of people piling on are like the "low information voters" in this country. The people on ihub and on other investment boards educate themselves of the risks and potential rewards associated with any given company. And they make decisions based on their research. Others move in herds reacting to every little piece of news. For instance, lots of the herd sold after the last F-Stein article only to miss out on a big move to the upside. I only mentioned the article because I know that not everyone has the same timelines for investing. I for one will stay long until the end, be that approval of dcvax or its failure. I'm betting on and expecting success but I'm prepared for failure should that come to pass. GLTA
Another article from F-stein is on its way....
I don't have time right now to keep up with the posts so if this already was brought up, I apologize. In reading tweets between F-stein and Smith it was mentioned that another bash article is in preparation. Not surprising but it will no doubt have some impact on the stock. I'm sure he will time it to hit when there is a normal and healthy pullback after this monster run. Some of F-stein's turds are begging him to knock it down so they can cover...