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Here you go again...for interpretation of these regs, one must balance past history with current thinking which is provided verbally by FDA upon request.
For trials that may be terminated early because a substantial benefit has been observed, however, consideration may still need to be given to the adequacy of data with regard to other issues such as safety, duration of benefit, outcomes in important subgroups and important secondary endpoints.
7.3. DMC Recommendations for Protocol Changes
A DMC may, in some instances, recommend changes to the study protocol, particularly in the context of their responsibilities for monitoring patient safety. Many protocol changes have little impact on the usefulness of a trial to gain regulatory approval. Certain types of changes to the protocol, however, such as changes in the primary endpoints, could have substantial impact on the validity of the trial and/or its ability to support the desired regulatory decision if they potentially could have been motivated by the interim data. We recommend that sponsors discuss proposed changes of the latter type with FDA before implementation.
Much of what you say is food for thought...this however is not. It is misguided thinking clearly.
You can't just change the endpoints at the end of a 16-year trial and think everything will be hunky dory. That's not the way scientific study works. They have major, major problems with this trial. You know it, I know it, and everyone who has ever followed a bio-tech startup knows it.
Back in November there were about 775M shares on the market. That is about a $0.40ish (~30%) gain in price with a10% gain in shares.
I am wrong in finding this to be quite encouraging?
I am no expert here, but it seems to me that the rate of relief has slowed a bit as of late. I doubt there is a lack of willingness to help, so maybe the need has declined due to expenses declining for the time being.
It also seems that the market either hasn’t seen the 35M new shares, or it has no problem absorbing this volume. The question I have is whether that is because some people have seen the only way out and cover their behinds or whether Twitter and nets just keep growing. It may be all three, but for some reason my heart is telling those that have great exposure still believe in whatever the opposite of miracles are.
They do continue their feeble attempts at sowing doubt. Those damn Rodeo Clowns, they pick me up when I am down. Yeah, yeah.
This may be inappropriate, I do that sometimes and it comes with the territory...this morning, I dedicated my meditation set to Bigmahalo and Survivor... this one was added for today. If you like to play along, sorry it is as short as it gets.
OMG that us the place! The had a coconut chocolate almond that I dream about.
Bigmahalo, I am so sorry to hear of your PC. I hope there is something experimental for you to try. It isn’t worth much but I will bestow my energy on you today in hope that you can have some peace on this beautiful day.
A thought to ponder upon bedtime....
Once upon a time their was a princess or action hero whichever, and she was told on August 20something of the year 2015, told that she could continue on her pathway but that certain changes would be made to the trail design on her map and that she could not discuss the details of this meeting with anyone outside this castle. That the collection of reagents will work directly with your henchmen to implement these changes which we will not discuss in detail with you. You will be left guessing where you are heading...do you understand young princess? Well, Miss Daisy, to be sure that you do, we will warn you that if you should discuss this meeting with Mario or Luigi or even Donkey Kong, we will revoke your extension of grace. “Understood” said both Daisy and Peach at the same time.
Well, after the left the Bowsers Castle, they hugged and parted ways and promised to write often as they would need to coordinate their plans before completing their journeys with their new map together. Now, peach she lived many levels away, on a different world actually, where she planned what to do about the scientific dilemma. She also planned a future, a future so bright that they may just call it Peach’s Galaxy. There she would add red mushrooms to green mushrooms then cook them with some star power, because Peach is a superhero and Peach can do many things at one time with the help of her many friends across the world.
All this time that Peach worked away in her lab and theater (British nod), Daisy gathered her friends and she planned and hobnobbed and built and protected and filed and defended, even dogged an assignation attempt. Daisy had quite the wild ride, but she knew that she had to persevere and she had to press on because Peach was counting on her, and all her friends were counting on her, and all of Peaches subjects were counting on her. So she planned and she borrowed and she made shrewd investments that helped pay for the final equipment. But in the end all looked desperate, the end seemed far away and her tricks were getting thin.
Just then, however, they she and Peach, however, had one more meeting with the reagents of Bowser’s Castle. And the reagents were pleased with the details and the new ideas and the buildings and they said, you have spent years preparing for this day. Now lock down your carriages for you have planned well and collected all your supplies. You are ready for this journey. You will encounter more Bosses on these next stages, but you will come back to us and we expect you will be victorious and you will need to prepare bigger plans as we have many more challenges for you and adventures along the way.
And the world lived happily ever after...except for the Kuppas crushed along the way.
For the slower paced among ius there is a beautiful geographical formation called Ioa Needle on Maui. The only hike is through a buddist garden representing like five or seven homelands of Buddha. If you like golf, don’t miss the county course on Haliakala. It is like the best view in the islands at public prices. You can still play the resort courses, but I am telling you that one is special.
My only request Poorman is that you whip up some GF noodles for me. I love them pad thai or italian anything, but I will enjoy eating me some raman style too. They just have to be rice noodles. I’ll bring a nice red and white to enjoy with them and we three can cheers to Linda Liau and to IHUB together.
Peace my brother. I wish you nothing but good tidings. You have been a warrior for the cause. This should be respected by all longs and I believe is by those who are long longs. We all have you to thank. The same is true for Biosect whom I also wish nothing but good tidings.
This is more clearly my point. I thank you both and respect you both.
It was intended as a gesture of peace.. How you choose to interpret it, is your eyes to the world.
My parents would bring the family to the Sheraton Kaanapali back then. I have some very fond memories of Maui and snorkling the reefs around that corner. Once, my uncle grabbed my arm then grabbed a sea turtle that took us on a pretty fast short ride. I gonna take my kids there after we rock it. They should see Maui.
They had an ice cream place in downtown Lahina that I swear had the best ice cream on earth. I am pretty sure they made it themselves and we have Oberweiss here.
Just as an observer, I think people are anxious to know when this gets released including myself. This creates an atmosphere where many like to speculate on breadcrumbs including myself. I think people spit ball about speculation and may imply things to some that was not intended or maybe not consciously, including myself.
Speculation can be fun, speculation can be helpful, speculation can build excitement which also builds anxiety, speculation can be dangerous, speculation can have unintended consequences, etc. etc. It is good to hear all sides of an argument which helps inform decisions and friends can disagree and even be disagreeable. That happens more during periods of high anxiety. In the end, there is a line in the sand here and this is an argument between friends.
I love the saying they use in some sports that winning doesn’t solve everything but it solves most things. I am pretty confident that I am starting to chalk up a long win streak here which means we all are, that should solve most of these things between us. Here comes the music...maybe this week, maybe this month, maybe this quarter, definitely this year.
Biosect, I can’t stop thinking about two days ago. Like Captain Lou Albano, I called out a challenge in the ring on the cause for the halt. After delivering a cross arm to the neck, you tagged in with a suplex followed by a pile driver, then I tagged back in with a flying off the ropes Superfly Schnooka pin down.
There still is no other reasonable explanation for August 25 2015, other than DSM calling for a halt to all placebos. That is also how you get to >90% exposed to DCVAX. No more placebo.
Poorman, there are a few things to consider when considering what seems to be the heart of your dilemma.
First, at this point I actually really do believe that there are oodles and oodles of noodles on the market even with the 500M sitting in storage. I know that my net has grown and added as I assume most here may agree. So, I think the mound of cheerybombs we plus THEY used to manage has grown. I think a useful gauge of friendliness is the annual shareholder vote. It seems to me the passive plus mildly active reporting system is nearly 100% in favor. That seems pretty damn friendly.
Second, the last guidance given was ‘in the coming months’ which was not changed at the ASM. So we are in Q2 and I would say Q3 is in the coming months, that the ESMO release is in Q3, the UK facility comes on line in Q3, expansion continues through Q3, a paper will be published or in process in Q3, regulatory submissions may have happed already but not PRd until acceptance of such package which could lead to an accelerated approval in Q3 (outside chance?), LL will have several presentations with peers to review her current lines of research before Q3, I would love to see the validation of the adjudication committee by Q3, my wife may breakdown and allow me to loosen the belt some more by Q3, we may be leveled back at $2.5 by Q3, the nets and fishes here along the the bakers and breadmakers on Twitterverse may just grow the bounty by Q3 which leaves little room for the Rodeo Clowns to find air before Q3 which could level us higher than $2.50 by Q3.
Management seems to have an agreement with our tag team partners to provide non-dilutive funding as needed on a weekly basis. I am happy watching the rodeo clowns dance, sweeping up the floor, opening up the door, turning on the lights, getting ready for the night, cuz nobody is romancing cuz it is TOO early for dancing, BUT HERE COMES THE MUSIC!
At least that is what my heart is telling me, you have to listen to yours. I am pretty positive about you being able to buy two food trucks to sell your oodles and oodles of noodles during the party.
I’ll have to share that one with my friend. We are holding strong.
Poorman, I will not pump ESMO, but I will inform.. the staistical model was built by April 12 per Linda Liau presentation at Salt Lake City.
https://www.esmo.org/meetings/esmo-congress-2021/abstracts
ESMO Abstract Submission Deadlines
Deadline
Abstracts Trial in Progress Intent to submit LBA
Friday, 14 May 2021
10:00 CEST (Central European Summer Time)
Late-breaking abstracts (LBA)
*Tuesday, 17 August 2021
21:00 CEST (Central European Summer Time)
* A preliminary abstract indicating the data expected to be available by the LBA deadline must be submitted online by 14 May 2021 as an “intent to submit a late-breaking abstract”.
To reveal would be to break a confidentiality contract as well as to reveal material information to a limited audience.
Some people are Paula Abdul, while others cannot dance well.
Spartex, my best friend is a Spartan as is his wife. Your post made me want to listen one more time.
Well, Poor Man, I will give the two that I believe. One, I believe LG when he said that they were out for revenge but not in those words and I believe his barroom chat where he once said present, publish release in close proximity but later shortened to publish & release in my recollection.
Two, despite the lack pf predictability about the publish path, the present path is in stone and neither of these have anything to do with the regulatory path which is entirely up to them. In fact, one may consider the manufacturing submission the beginning to one path while others may also consider the August 2015 agreement reached with FDA to be the beginning of another. Some may say that the EMEA and UK acceptance and publication of the new SAP actually began the first path.
ALL I KNOW IN MY HEART is that I AM ON The RIGHT PATH at this time in MY LIFE.
Click back and apply all statements contained within. I follow my heart, but you must follow yours, not mine.
The answer to the question of whether or not Ashkan is in the loop is 100% concordant with the answer to whether a paper or poster abstract has been drafted. It also therefore 100% correlates with this answer because he will be an author on both.
Just as 5 separate trials’ placebo groups are highly concordant as well as the Norwegian National Registry and they both correlate well with the original Stupp SOC trial. The Norwegian registry is also acceptably concordant with the recurrent plus pseudo progressed GBM populations when separated appropriately.
As well, two failed treatment arms are highly concordant with the group of 5 plus Norway which externally validates both of these sets and the Helmet is not concordant with these which positively validates it a third time.
Now the combined DCVAX arms are not anything like any of these, not even the helmet. It is so much better because in this similarly risk stratified, similarly selected cohort 48-49% live 2 years, 28-29% live 3 years, 19-23% live five years and likely 17-20% live 7+ years, at least by KM estimates comparing 2018 to 2017 with a reasonable assumption about the impact of the final 100 patients as they march along. Given that the Norwegians say only 8-9% should make it to 5 years, I would say this is one FAT TAIL.
Anyone familiar with the history presented in the 9 ndGBM cohorts listed above knows just how remarkable this is. Anyone enrolling patients knows exactly who they entered into the trial knows how that prognosis relates to the rest of their populations and is doubly certain of the outcome as I am.
Apply all my caveats about given advice which I do not do. You must invest at your own risk with your own decisions. You must trust your heart not me.
At Mt. Sinai, Dr. Liau showed that when you resect what looks to be tumor growth, instead you find a whole lot of T cells, or Macrophages plus T cells., along with dead cancer cells. I wonder if these are the first resections she has done in her UCLA population and I wonder if she has Matching MRI imaging for this cohort. I wonder if she has internal and external validation that PFS needs to be adjudicated. I wonder if FDA has seen this data.
Lots to wonder about this morning.
I will just follow the Sun, and which way the wind blows when this day is done.
If you know the effective dose and it is safe, you can just start new indications at Phase IIb. I am glad to see others are trying their own recipes in Phase I. Perhaps they can catch up, perhaps not. My guess is that the sails will be full of wind already in most cases, but there is always another slice to the pie.
Gorilla, it does not take the Utah presentation by Dr. Linda Liau to see the concordance that standard of care has across multiple trials including the original stoop protocol as well as the Norwegian national registry. When Germany agreed to change the protocol end points, they were essentially agreeing to approve DCVAX. The German manufacturing partner has been itching to get their hands on this for many years.
When FDA evaluates a drug they look at Efficacy first and then safety. EMEA does the reverse. A drug must be safe. The registry belongs to EMEA, not Germany.
https://www.clinicaltrialsregister.eu/ctr-search/search?query=Dcvax
However, if one does not see the hand of FDA in this process, especially the August 2015 process, then perhaps one might not know what to look for. Perhaps, after looking at clinicaltrials.gov to see that FDA approved a new study. This may help to clarify things.
Sometimes the market does not anticipate news, but is instead reactive to news. That can be quite exciting.
King, “All patients are living longer.”
I agree totally with Biosect. I think of cancer cells like normal flora. This analogy helps me. If you give an antibiotic that kills one of your flora, another expands or a new transplants to take its place. I think that some day we will be able to smack cancer with the right cell at the right time. I believe in Linda Liau.
GBM is the mother of all cancers for multiple reasons, one being that it morphs faster than almost any other. Another being that the brain is immunoprivelaged, meaning it is harder for cells to access the tumor but not impossible, and still another being that the skull is fixed volume with a drain at the base. This presents difficulties with added pressure as the brain stem controls breathing and heart rate. Expansion of a tumor too large can kill which means you need the immune system to be in control of volume as well.
Some tumors will grow and/or mutate too fast for the single punch, but Linda will get us there. Or at least lay the path for others to expand upon. Dendritic cells check!
What we are talking about here is the ethical nature and safety of continuing placebo, not a question about safety with treatment. This would not require patients be reconsented because the information they had been given about drug remains accurate and a formal efficacy analysis was not performed. If, however, placebo were to continue then this would require IRB approval and new consent. This can take place between FDA/DMC and CRO without the sponsor’s approval. I have been part of running a regulatory trial or two, EX. One was where results were provided in an unblind fashion to investigators and patients despite not knowing if the result had meaning in the name of patient safety. The sponsor did not know these individual results. As far as I know, this was never done previously either.
From https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guide-informed-consent
Consent documents should not contain unproven claims of effectiveness or certainty of benefit, either explicit or implicit, that may unduly influence potential subjects.
The CRO is almost always unblind to patient disposition. Who do you think executes the randomization? This would not change the contractual obligations to the sponsor and the sponsor need not be involved in the communication with DMC/FDA. Also, FDA does allow for one individual among the sponsor to be unblinded to what is occurring if necessary. However, provisions need to be discussed in advance to ensure this individual provides no conscious or unconscious bias to the design.
Also, in the midst of this all FDA approved another trial involving DCVAX, however, in this trial all patients had to receive DCVAX from the onset. The randomization was for the drug where efficacy was in question. This does require new consent.
Biosect and Dendream on the tag team...uh oh!
In general, trial PIs are listed on trial papers, usually as the XYXPDQ Study group and a footnote or addendum lists everyone by name. This does not mean that they had any input into the paper itself and can remove their names if they do not agree with this. The authors listed by name in the first, second, third and last position are usually paper editors, along with the statistician.
People like Dr. KA can keep a secret an knows there are ramifications if they do not. That does not mean, however, that an occasional Freudian slip make come about. It does not matter in terms of the analysis if he has been unblinded or not, or if he leaks unconsciously or not. The SAP is submitted and approved before data lock and the trial data is set in stone at that point.
Ex, You are wrong. Read for yourself, you can start on section 3. The CRO can implement the change of no more Placebo without NWBO knowledge. NWBO needs to remain blind so as to be able to review blinded interim data and then suggest and make necessary changes without bias. Providing answers to questions like the disposition of the final 32 would create bias in investigators and patients.
https://www.fda.gov/media/75398/download
7.2.1. DMC Recommendations to Terminate the Study
In almost all cases, a DMC is advisory to the sponsor; the sponsor decides whether to accept recommendations to discontinue a trial. FDA will rarely, if ever, tell a sponsor which decision to make. For trials that may be terminated early because a substantial benefit has been observed, however, consideration may still need to be given to the adequacy of data with regard to other issues such as safety, duration of benefit, outcomes in important subgroups and important secondary endpoints.
7.3. DMC Recommendations for Protocol Changes
A DMC may, in some instances, recommend changes to the study protocol, particularly in the context of their responsibilities for monitoring patient safety. Many protocol changes have little impact on the usefulness of a trial to gain regulatory approval. Certain types of changes to the protocol, however, such as changes in the primary endpoints, could have substantial impact on the validity of the trial and/or its ability to support the desired regulatory decision if they potentially could have been motivated by the interim data. We recommend that sponsors discuss proposed changes of the latter type with FDA before implementation.
Unfortunately, EX there is one huge flaw in this rationale...
. In discussions with the FDA, the FDA allowed the trial to continue treating, but denied them the ability to recruit new patients. It was over that time when LP was stating they hoped to restart recruitment soon.
One rational explanation is all I ask for, just one.
I am not surprised that you ignore this request and instead divert. There is no other rational explanation, what this patient has is the opposite of ALS. They will go from being unable to walk and barely breath, to becoming a world class sprinter.
Nobody’s romancing cuz its too early for dancing, but here comes the music!
LC2020, The August 2020 halt was a halt in the use of placebo, not a halt in enrollment or a halt in the study itself. Whether FDA initiated this halt or agreed to follow suit with another regulator is irrelevant. The process outlined at the time looks very much like an FDA process, but this is opinion.
If you can give a rational explanation other than the idea that the DSM called for this halt after viewing unblinded safety results which since the drug has no side effects must be the ultimate safety signal, i.e., death, that leads to such activities that have transpired ever since, I am all ears. The key word here is rational. This explanation has no flaws based on what has been seen. All others do and I am happy to crush any that you put forward.
Not one rational explanation other than DSM seeing an efficacy signal through death rate has ever been given on this board. Not one.
Many definitive diagnosis are made through exclusion of other possibilities, for example ALS. There is no test for this, but there is a way to exclude everything else.
My diagnosis here, and I am not a physician but this is not a patient, is that DSM saw a clear difference in death rate as they are unblind on death, and then called for a halt in the trial. Regulators allowed NWBO to continue on in a blind fashion, but required all Placebo to be halted. This begins one quiet period which pulls through until TLD is reported and a package is submitted. This is a regulatory quiet period, different from the one which is self-imposed currently but there is a high correlation between the two. PERIOD.
I do have a flexible mind, however, even for rodeo clowns. So have at it?
This quite the change in course. Any idea what gives?
To me this casts doubt on the loaner program idea that I once ignored, but later reconsidered. Now, I am back to thinking that he is just like the rest of the class and is bouncing from opportunity to opportunity based on his own personal reasons. I know one of his first degree contacts. I may do some digging if I have time, but don’t really want to waste time on a rabbit hole.
Would it be do bad to go halfsies with Charles Rivers and get to $3B real fast?
SYNERGY, one plus one equals $70B MC, pretty damn fast.
Jesster, all I keep thinking is what if we all HOLD TIGHT. Everyone on this board, all of the minions and lurkers, and of course LP and her minions and friendlies. That is a lot of guacamole. Tons of bananas. Mounds of cherrybombs. It sounds to me like the Twittersphere and Discorders are pretty damn excited about a rocket ship. I don’t know about these things and count on my wife and kids to loop me in. That could be oodles and oodles of noodles for Poorman to serve up. Oh yeah, don’t know how big they are but sounds as if Redditers have high hopes too. Maybe that is a little whip cream on top.
I am not so sure there are a lot of true shares that are for sale any time soon.
If that doesn’t make it hard to sleep, then you my friend have one calm disposition.
I hope that other buy was worth it.
The end game is not TLD, not a journal article that by the way Keymours will be in a top position on and therefore have editorial privileges, not UK approval, not EMEA approval, not even FDA approval....
Not UK launch or German launch or even Swiss/Nordic and other non EU launches, not blockbuster status, the first $3B year, not the $15B revenue year. Those are all stepping stones my friend, stepping stones. At $15B revenue, that may just be GBM plus Colon cancer, and that my friend is one big hot dog. Then add the toppings with a side of fries, some chili, and a milkshake. What the hell, let’s just go Groundhog Day Bill Murray and order up some pie, doughnuts, a gyro, a tamale, a polish...and then shove a whole piece of cake in our faces.
All while watching Linda save peoples lives without any side effects.
Let’s just say, hypothetical here, but lets say the crossovers get benefit, but almost match history and those that stay on placebo died fast. At 3 and 5 years, the original cohort could be 40% vs 10% and 29% vs 3-5%. If the trialists selected slightly sicker patients this could happen.
If this was seen when FDA halted all placebo, then you could imagine question marks when the PFS gets analyzed. Then, you would plan for another model. You could validate that model in a blinded fashion (PFS vs adjPFS correlated to OS) then you may want to retain both as proof and solid proof. Then you may wait until that last group hits 5 years, so that you can be certain the wacky original randomization still hits too.
They planned for the worst case, but what if it is the best case and KA had what is called a Freudian slip.
B
O
O
M!
When I listen to Dr. Liau and Dr. Askan speak, I am reminded of both the difference and similarities of a bench researching physician and a clinical trialist, not just the trial participant but specialist who really masters the human trial. Both are absolutely clinicians, don’t get me wrong but the two have a certain SYNERGY when they are combined.
Connecting the Pond helps too.
Who is the best European Colorectal oncologist? I don’t know but I will take a look.
How about female reproductive oncologist? Not in my wheelhouse.
One will come from Germany. It is only right.
Thank you for this humongous bread crumb, AeK!
If the 21% at 5 years projection is accurate, and all come from the original to DCVAX cohort, then about 30% live five years. If 5 years is cure then maybe somewhere just south of 30% could make it to seven. Some people would estimate that as one in three.
Not saying, just saying
Perhaps, ESMO is next up.
Abstracts
Trial in Progress
Intent to submit LBA
Friday, 14 May 2021
10:00 CEST (Central European Summer Time)
Late-breaking abstracts (LBA)
*Tuesday, 17 August 2021
21:00 CEST (Central European Summer Time)
* A preliminary abstract indicating the data expected to be available by the LBA deadline must be submitted online by 14 May 2021 as an “intent to submit a late-breaking abstract”.
Outcome notifications
Outcome notifications are expected to be made available to first authors by 20 July 2021.
https://www.esmo.org/meetings/esmo-congress-2021/abstracts
I can’t tell if this is good news or bad. Someone smarter than me about methylation and other mutations can weigh in.
https://pubmed.ncbi.nlm.nih.gov/34018316/
I think it supports the idea that GBM is constantly mutating and thus tumor lysate is preferred to off the shelf, but Biosect’s idea of using multiple donors to grow a super multiforma lysate for autologous Dendritic cells may be even more effective than one’s own tumor.
Perhaps there is a better pre-adjuvant therapy or maybe adjuvant than CIs in development as well.
https://pubmed.ncbi.nlm.nih.gov/34021868/
We shall see where this goes.
AeK, I do not know how the combined line was prepared. My guess is that you may be correct. Once you get to that next step in the process you would need to get down to the individual patient data level and this would likely be normalized back to a single starting point.
When checking the individual studies for concordance, however, this need not be done. If one is off by 3 or 6 weeks, it would not change that part of the analysis much at all. You can see if the similarly enrolled populations behave similarly without making this correction.