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GGB, have you read his articles? this one back in 2013! btw they sort of ROCK BIG TIME!
Barunuuk Wednesday, 02/08/17 03:43:53 PM
Re: AVII77 post# 101261
Post # of 132748
Who is a statistician?
Below is the article I wrote where I used Wilcoxon Rank Sum Test a much more rigorous and conservative test when comparing two different populations of the Phase II DCVax-L data. I am very aware of statistical anaylsis. Probably too aware and trying to explain why I see such positive aspects to the PFS portion of this trial.
http://seekingalpha.com/article/1336331-northwest-biotherapeutics-statistically-speaking
What I am saying in layman's terms, is that because of the PFS endpoint update as well as the screen halt, we can get specific information: 83 patients have PFS >= 16 months.
So again, the p value for a hypothesis test to determine if two median values or two populations are different, is directly affected by the variances of both of the populations. MEANING, the greater the variance between the two populations, the more likely p will be smaller, and hence statistically significant. SO, if we know that SOC variances show very little populations >= 16 months PFS, but show DCVax-L Population having a longer and fatter tail (meaning larger standard deviation than the placebo groups), as long as the median value is >= +4 months of the placebo group, the more likely it will easily show statistical significance.
Another way to say it using ICT-107, the median values were only +1.9 months difference, so there was no way to show a 2 month increase, however, had that occurred, and 2 months were reached, as more and more of the ICT-107 tailed survived, meaning OS increased for ~10 - 20% of the ICT-107 group but didn't keep increasing for the placebo group, over time, the p value would get smaller and smaller, meaning it would be more probably that the two populations were at least a 2 month median difference.
Goodguy, maybe he should not of referenced Bohsie but the content of the article made sense mathematically given the data that is available. Dr.Bosch maybe should not of used those references, its a judgement call but then again a lot of credibility was given Phase V and that was anonymous as well. just saying... I would just focus on the content of the article and not the author. For all we know Bohsie could be a very well credentialed statistician.
Goodguy, yeah it's a blinded trial nobody can say anything except the data looks promising. Use your common sense and make your own conclusions. Until they unblind they can't say anything except like Dr.Liau everyone is living longer... why we can't say cause it is a double blinded placebo controlled study!... Good luck finding any credible scientist to say anything more than that. We have plenty of people saying the trial has failed or is a failure that don't have any proof of that knowledge. Bohsie, and AP actually have put out their hypothesis and generated data based on IMUC and historical datasets to model and project outcomes. Anyways as shakespeare would say "a rose by any other name would smell as sweet" Dr. Bosch does not have many options since no one is writing about DC-Vax cause it doesn't cost 500K and no BP is partnered or invested in them.
AP thanks and let's hope FDA does the right thing given little to no side effects and those OS curves. It's all about the money unfortunately. LP has to get it through her head the big fat checkbook matters!
CDRD, AP reposted.. DCVax-L GBM trial Result PFS Model based on IMUC Control DATA
Reposted now with updated working links.
Discloser: I am long this stock; I have no inside information; I am a clinical researcher.
Hypothesis 1: The Control Patients in the DCVax-L GBM trial should relapse at a rate similar to what was shown in the IMUC trial. The IMUC trial is the most similar to the DCVax-L GBM trial in terms of eligibility entry criteria. The progression free survival (PFS) was reported recently at the 2014 American Society of Clinical Oncology (ASCO) meeting.
https://www.dropbox.com/s/a90hj1507dd2ekr/bosch%20nwbo%203.PNG?dl=0
Hypothesis 2: Given that we know the number of PFS events in the total DCVax-L trial at this time (first interim analysis) is 66 December 2013;
https://www.dropbox.com/s/qy0zlxwehjf5f9l/nwbo%2066%20events.JPG?dl=0
And NWBO reported 248 PFS events on before 2/1/2017
https://www.dropbox.com/s/w60sbgacpzi28ck/bosch%20nwbo%201.PNG?dl=0
Then one can model using JMP(SAS) software, model the control arm PFS for the DCVaX-L trial to be the same as the corrected IMUC trial results and thus obtain an estimate of the probable number of events required in the control arm of the DCVax-L. When one does this with a Kaplan Meier plot, one obtains a result of 100 events in the control arm with the total number of patients in the control arm of 111. Then one can deduce that the number of events in the experimental arm for the DCVax-L trial would be 331- 111 or 148 events.
Hypothesis 3: Using the derived 148 PFS events in the experimental arm, one can model the experimental arm to be similar to the IMUC control arm trial results but, in this case only allow for just 148 events out of 220 total patients in the DCVax-L experimental arm.
When one does this with a Kaplan Meier plot, the data and curves are shown below. When one applies log-rank and Wilcoxon significance testing to the two curves one obtains a significant result of p<.0001
https://www.dropbox.com/s/o6270dlwrcx3wr8/PFS%20NWBO%20COMPARE%20jpg.JPG?dl=0
My best-educated hypothesis is that clearly, the DCVax-L trial is going to return a positive result on the primary end point
This result will be a practice changing result. Especially when one sees the plateau in the treatment curve. The nice thing about this PFS review also is that there is no crossover effect between the curves such as could occur with my prior overall survival analysis OS.
129619 Alphapuppy Ihub post
Just to put this into perspective the Stupp GMB trial PFS only increased 2 months by the addition of temazolamide (TMZ) (5 to 6.9 months). Yet this became almost immediately, the new gold standard of care in this disease and TMZ almost immediately became a blockbuster multi-billion dollar drug.
DCVaX-L increases in the operable patients even more than this and with none of the chemotherapy side effects and will quickly be the new standard of care in this disease.
AP reposted this...
CDRD, AP did repost, thanks.
ou, just because he is on a mb or seeking alpha does not mean his analysis is not worthy or credible. His math and projections are valid. He gives you his methodology and provides you the hypothesis. It is unfortunate that NWBO is not respected because they are not aligned with any big money or BP but that does not mean Dr.Liau's research is any less worthy or important. IMHO she started this immunology field way before it was popular, two decades ago. Just because nobody knows about her research doesn't make it less worthy.
btw phase V was anonymous and that was given credibility? lawsuits were even filed based on that!
GGB, well alpha puppy is a clinical researcher and have you looked at his work? He puts out the data generated and plots it in a very clear understandable chart. LP & LG are lawyers so they may not have the data put in a concise and presentable format. There are very intelligent people on this message board some of which the company would be lucky to have working for them. Some folks here are very worthy and credible. IMHO nothing wrong with some good help and advice. We all can use new perspectives. I much rather have alpha puppy's charts and analysis than AF's paid commentaries..
xena here is barcode's post on the documents in court and how NWBO lawyers responded... thanks barcode for the docs...
I believe you xena, but barcode posted their response to the judge with lawyers,asking for leniency due to not having sufficient staff and they were not aware of the lawsuit and therefore did not respond in a timely manner and asked that the default judgement be dropped. They said they were so busy that the lawsuit was overlooked and they were not aware of it's existence even though the receptionist must of signed for it. idk looks like they are overworked and supporting staff not too proactive with mail.
Thanks alpha puppy, for the repost and quick response. Yeah like if barcode would of notified them that they had a lawsuit filed against them they could of responded in time before the default judgement. Barcode knew before they did of the lawsuit, but he assumed they knew and just did not respond, when actually they were not even aware of it cause their receptionist most likely signed for it and dropped it on their desk which they most likely never looked at, cause they don't go into the office that much but work from home, imho.
So goes to show you never assume anything with them. They wear too many hats and have trouble delegating because they have no one to delegate to... remember when LP had the flu and everything came to a stand still? I really appreciate all their hard work but there is just so much they can do with all that has to be done in a timely manner. So there is the perfect instance if barcode would let Les know he could of saved a lot of lawyer fees cause now they have to back track and plea with the judge for not responding in time.
I think your work would be helpful to present to institutions or BPs interested in financing them. Given the data and statistical significance. There is no doubt of efficacy. imho it would also help if they could get Dr.Liau to present with them, after all she is the principle investigator.
alpha puppy, yes please repost with updated links and please forward your analysis to LP,LG& Dr.Bosch. I think it is very informative and relevant. They are a very small operation and needs all the help they can get, imho. They ref. Smith and Barunnuuk analysis in Dr.Bosch Presentation on 8/31. Your analysis is even more convincing with all your generated data and graphs, plus you are an actual clinical researcher. Thank you! Best..
Hope we get through this and hopefully they will start dialogue with BP cause they need all the help they can get. imho they are very optimistic and seem to underestimate all the time frames and monies needed to achieve their goals. Hind sight is 20/20. N.Woodford still believes they have a shot as the science is solid. Wish they can get the help they need financially to pull this off. Kite, Bluebird have all aligned themselves with BP's.
Yes I will and I will call him too!
pgsd, Les should be calling Neil Woodford everyday to get a better financing deal. They are not doing their homework as far as financings. NW has a vested interest in seeing them succeed and raise SP. He has the money and the influence to do so. Powers should be doing her job as CEO and calling NW to update him and gain his advice as to financing that's what he does for a living. He is one of our largest shareholders and should be treated with respect, I feel all this could be worked out to be a win/win for all of us. It is ridiculous they are this close to topline data and struggling to keep the lights on and no team to help with approval. imho I think we would do a lot better if Dr.Liau was doing the financings, but thank god she is the principle investigator. She is definitely the bright light in this trial!
thanks pgsd, for the update, well if he so confident of survival rates then I hope they unblind and get topline data out so they can start the approval process. They need to hire an additional staff and team to get that going. Hope all this is discussed at the ASM.
china, it's unbelievable there are still 100 alive patients in a trial of 331 Ngbm, over six years long with last surgery patient 24 months minimum in trial. why are they living so long when the trial has already failed??? it doesn't add up... maybe you should talk with alpha puppy again. He seems to respect your opinion.
pgsd, when did you talk with Les? CDRD posted that his talk with Les last week, 5 month monies ( July to Nov.) they have will carry them to the trial results, and start of the two phase II trials. Sounds like the 233 event has not yet occurred. At some point they will want to unblind, as per Dr.Liau she is glad they will see the trial come to completion. With close to 100 survivors if would be crazy to deny efficacy, especially if close to 40% are from the treatment arm with PFS. imho Best!
alpha puppy, have you sent your analysis to LP and LG? I think it would be worthwhile. IDK if they have this type of modeling available to them as they are both lawyers and not clinical researchers. Thanks for all your work and faith in the science of DC-VAX. Basically I think there is only LP,LG,Dr.Bosch and the receptionist at the company. Not many hands on deck they are running a tight ship.
thanks alphapuppy. so if data lock is 9/1/17 the PFS will look even better given 7 additional months have passed and so should the OS curves, right? thanks! P values should be even smaller...
Thanks alphapuppy, data lock date, will count censored patients that have not yet had a event as having that event that day. PFS will be clean and not confounded. OS will be confounded should vaccine works for rgbm patients. (DC-Vax Late) Thanks so much for your explanation. The curves look excellent for PFS success! Best! OS looks great as well compared to historical data as per Dr.Liau.
alphapuppy, can you address how the censored data will be handled once there is data lock? Thank you.
Thanks alphapuppy, Hope it comes true soon. Makes perfect sense to me, IDK why BP is ignoring these results, I guess 500K per treatment price for CART therapies are the HOT item du jour. NWBO has to price theirs at 200K and maybe they will get some respect, maybe LP can say we charge them per PFS month 10K per month for PFS so if they live 5 years PFS it could be 600k per patient. We don't charge them if they progress within the first 6 months of vaccination.
Thank you barunuuk, great explanation as always you make it so clear. Best!
FDA approval brings first gene therapy to the United States
CAR T-cell therapy approved to treat certain children and young adults with B-cell acute lymphoblastic leukemia
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058
August 30, 2017
Release
The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.
The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”
Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.
ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.
“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”
The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.
Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.
The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.
Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.
To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.
The FDA granted Kymriah Fast Track, Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA's Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.
The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058
evaluate, yes those are just my opinions... based on historical data for ngbm patients. I truly believe Dr.Liau when she saids there is efficacy. Basic common sense would say that you have 100 survivors of ngbm in a trial that has lasted over 5 years, there has to be efficacy with 331 patients. midpoint of enrollment may 2014, we are now 40 months from the midpoint. 83 PFS patients as of Jan. 2017 and we still have not reached 233 OS events now in August 2017... JIMHO...
best to your sister bioinfo, great she got to meet Dr.Liau. Glad her tumor was benign.
hi doc, no problem you are too kind. I didn't even notice, thanks for your response. I really admire the loyalty you have to DC-Vax, Dr.Liau and NWBO. warmest regards.
thanks barcode, looks like they are overworked and understaffed... hope they unblind soon cause I think at this point the death rates have basically stopped... which is a good thing cause everyone is on DC-Vax that is alive. Control are mostly passed away or some crossovers maybe benefiting from vaccine. Which will help with the Rgbm trials, like Jeanine Walston , having surgery upon reoccurrence and new vaccine made.
thanks forum reader, for all your science updates! very informative and reassuring.
Thanks Doc! you are the best! So glad we are at 24 months from last patients screened for trial and most of all control patients have evented and passed so we will have very accurate OS data and the PFS patients will most likely be from vaccinated arm with 98 still alive we are looking very solid. I trust Dr.Liau as she is the principle investigator and her work is top notched. She is very precise and accurate maybe too modest, imho. Looking forward to great things from UCLA and Chairperson Dr.Liau!
Doc, Flipper,Rk,senti,has anyone looked at Argos and their trial to see why they failed their interim look at OS with control beating treatment arm? Did they not wait long enough for patient deaths? they looked at OS events 290 out of 462 patients enrolled? I wonder if NWBO can learn from their trial? I don't know about their technology but apparently the company was founded by Ralph Steinman in 1997?
very similar methodology with using activated tumor lysate to vaccinate patients? Would they have had long tail of survivors if they waited longer for their interim look? Did they look too soon and the results were not representative of what was really happening for treatment arm if treatment had more patients that had not yet passed? Or control arm was skewed by not having later patients pass yet? Thanks for your thoughts! Just seems odd that the treatment arm had OS of 27.7 months with control of 32.4 months and yet when they look at the OS for first third of patients enrolled the MOS was 30.1 months for treatment and 22.2 MOS for control? seems like MOS is not a good measure of effectiveness in IO trials and you have to look at HR as Dr.Hoos said you have to wait...
senti, hope NW reengages with LP to bring them to the next level or get AZN involved with possible BO?
Now Gillead has priced KITE at 12 Billion it will make things a lot easier for negotiation and valuation!.
eagle there was 8 million shares short on KITE, Ouch for those shorters... couple of billion they just had to come up with... NWBO will be next! YAY!
bioinfo, would be nice if they price it per vaccination, 10K per visit one shot per arm. Total 10 vaccinations or 100K total for 3 years. That seems pretty reasonable given it prolongs life for five years or more. spreads the cost over 3 years. GLTA If they showed PFS quality of life and no AE's then that is even better.
BSB you were right on the Gilead deal to acquire new technology and 11 billion again was the price for KITE. nice job!
BSB, I second that emotion!
senti, hope everyone watches this NW video you posted.
http://citywire.co.uk/new-model-adviser/news/criticism-does-hurt-me-says-neil-woodford/a1030681?section=money
Very enlightening on his contrarian investment style. Market loves things that are expensive and hate things that are cheap! He is a contrarian value investor. I think NWBO definitely qualifies as being cheap!!!
thanks biosectinvestor, you are right, we have to wait for results... just crazy how the market values things and NW is right, market is momentum driven and he sees value in things that takes time to reveal themselves and is often criticized for those decisions in the short run...
flip so what should NWBO MCvaluation be if we cover the other 90% of all cancers?? This should give LP a good reference and bargaining point. imho should they be successful in their Phase III?
yeah but LP has already sold a hugh amount to shares to those same hedge funds so they should be covered by now. imho if she would just open up the channels/communicate with BP for partnership and investment we would be in a totally different position. We would be and should be in a position of strength given an imminent Phase iii positive readout, imho... commercialization and marketing are still big obstacles with out proper funding and implementation, BP already has that infrastructure in place. pricing is also a issue, Kite 500K, NWBO 33K??? big disconnect..well I just hope for the best for patients and shareholders...