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Fantastic odds. The pseudo patients that are randomized to vaccine have the potential for never having a progression free survival event. And then there is the fact that pseudos are more likely to live 2 years even without the vaccine, so once vaccine is added at recurrence/crossover, along with avastin, the patients might have a longer timeframe between first progression and second progression event then they did from newly diagnosed surgery to first progression. Time will tell.
Agree. I think LP’s aim is by data lock in time for ASCO late breaking submission.
Those patients with higher TIL are more responsive to DCVax-L treatments. But the early on patients with highest TILs would have likely be in the pseudo progression tertiary arms. A few of them were also in the compassionate arm and it will be interesting to see how many in those groups are still alive. Some high TIL won’t have shown up at baseline and if patients are already responding to radiation, than adding a second and third working therapy will further improve survival.
To me I think that once patients are on Avastin and DCVax-L (regardless of early or late) will be found to be synergistic. Very low ratio of second surgeries in this trial.
The PR honestly sounds to me as LP is expecting the process to take time but there will be no further delays on their end! How long will it take to close out the 80 clinical sites? I’ve got no idea. Hopefully some where already closed out (as far as reviewing progression events MRI). But I’m thinking 2 months is unrealistic and 4 months is optimistic to close out the last sites in the study (those that has still been randomizing patients in 2015). It’s smart to release the final unblinded data at ASCO. I’m praying they get it done by then. But I have no idea if they will.
Blinded long tail results looks promising. I’m also expecting that once unblinded they will have 2+ years of data after 248 patients progressions, so we will get to see how long those patients survived after progression. It to me is the most important data. It’s that early (DCVax-L at start) and late (DCVax-L at crossover) data that will get this approved. And if we find a decent percents of patients live 2 years after their first progression event this should get approved regardless of the primary endpoints findings imho.
They have to complete their visits to 80 or do sites. We are talking months and in my opinion we’ll see results at ASCO.
These results do not even include the tertiary data of the 32 pseudoprogression patients removed at baseline.
That’s a nice long tail. :)
The last reported loan was a bridge. Seems to me that this next finances should be able to take the company to reporting of data and more — potentially fund part of the next study — would be my guess. Someone wants the share price to rise at least for now. If they still plan to go it alone, then this next finance deal may pave the way nicely.
The 248 PFS event — Phase Iii primary endpoint — occurred sometime late 2016. They just didn’t do the statistical analysis.
The 233 OS secondary endpoint passed sometime last summer. They planned to do the analysis on that until after the study ends.
They are opting to let additional progression free survival events and overall survival events accumulate, from the 331 patients enrollment, as the trial heads towards data lock completion. It is my long-standing view they plan to conduct the primary, secondary and tertiary endpoints once all 331 patients complete their study consents.
No. They were clear about end of the trial.
You may have forgotten that I’m actually the one who transcribed Linda Powers’ 2014 speech. Been back then she was consistent in letting us know the statistical analysis would be done at the end of the trial.
“Very importantly, in the latter part of the year we had some regulatory enhancements to the trial, which allow us to add some factors to the statistical analysis at the end of this trial. Nothing changed about the eligibility for the trial. Nothing changed about the treatment in the trial. But by adding these factors at the end of the trial, counting more events, and adding factors, we were able to significantly de-risk the trial. “ — Linda Powers 2014 Oppenheimer speech.
“Now, I want to go through some of the highlights in each of those two programs. It's been a very busy year. We're proud of this year and had a lot of major milestones this year. But most importantly, besides those milestones in and of themselves is, those milestones position us for really exciting 2015. So our DCVax Phase III trial for brain cancer is our lead program. It underwent a major expansion across the U.S. and in Europe. We had a safety-only evaluation, of the, by the Data Safety Monitoring Committee. Very importantly, in the latter part of the year we had some regulatory enhancements to the trial, which allow us to add some factors to the statistical analysis at the end of this trial. Nothing changed about the eligibility for the trial. Nothing changed about the treatment in the trial. But by adding these factors at the end of the trial, counting more events, and adding factors, we were able to significantly de-risk the trial. For example, in order for it to be a successful trial, we need only to show, instead of showing a six-month difference in the time to tumor recurrence, in patients who receive DCVax and those who don’t, we only have to show four-month difference. That’s a big lowering of the threshold for success. We actually think we’re going to show a much bigger difference than that, because in our earlier stage trials we showed a year-and-half of difference, not six months, not four months. We tried to design this trial to be very conservative and to maximize the chances for success. We had to get separate regulatory approvals from the U.S. FDA the German regulator in the UK regulator - all three, in order to make these changes and we were really excited to achieve that. “ — Northwest Biotherapeutics – Linda Powers’ Speech Transcript at the Oppenheimer 25th Annual Health Conference on 12-10-14.
Here’s the entire speech so you can see I haven’t doctored it!
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=109058160
I think you took her words about the finish lime to mean statistical analysis. But it doesn’t. Instead it means the primary endpoint threshold finish line on that Phase III trial. Stated another way she meant this:
“Taking into account the time required for these approvals and implementation steps, and the 36-patient increase in the trial, as well as the gradual ramp-up of the trial in Europe, the Company currently anticipates that enrollment will be completed in approximately Q3 of next year, and the primary endpoint of the trial will be reached about 3-5 months after full enrollment or by around year-end next year.” NWBio August 2014
Hi Doc Logic,
Correct. In prior trials many patient were only received 3 injections. This trial has InductIon, Booster and maintenance phase injections as shown in Bosch’s slides. Incidentally the slides also show the minimum threshold of OS needed before analysis can be done. Folks should not confuse that to mean that they would do statistical analysis immediately upon crossing. In fact, it should point that they needed a minimum of OS events PLUS ALL data from ALL of the treatment visits and follow up visits for ALL 331 patients to be subjected to quality control checking.
https://www.nwbio.com/NWBio_ASCO_Update_On_Trials_6-5-17.pdf
What you’re choosing to ignore is that the trial continuing after an statistical analysis would mean the said trial hasn’t officially ended. Meanwhile they told us they would do the statistical analysis at the END of the trial. This at face value means the trial is DONE. You can’t have a continuing trial if it ends. And so I take their words to mean END of the trial.
There words are clear. Yours includes your own context.
“The Company has been blinded at all times, with no access to any data in the Phase III trial, and WILL REMAIN FULLY BLINDED UNTIL THE TRIAL IS COMPLETED. The changes relate to the statistical analyses that WILL BE DONE AT THE END OF THE TRIAL, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects.” August 2014 PR
They also made it clear in February 2017 that ALL treatment data needed to be in before analyzing the data.
“The external parties managing the Trial are now moving forward with the process to reach data lock. In this process, ALL data from ALL of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking. The process involves in-person monitoring visits to all of the 80-plus sites in four countries to review the files onsite, as well as other documentary confirmation and checking of all MRI images. As such, it is a multi-month process. While this process is under way, OS and PFS events will continue to accumulate.” — Feb 2017 PR
You read this below, you must read above to get the meaning of Quality Control Checking is, and it is ALL not some treatments. ALL
“The Trial will reach data lock when the threshold events have been reached AND the QUALITY CONTROL CHECKING has been completed for both the PFS and OS endpoints. When data lock is reached, external statisticians and experts will make an independent analysis of the Trial data. The Company will remain blinded until data lock has been reached and the external data analysis has been completed.” - Feb 2017 PR
How can they complete quality control checking before ALL treatments. According to your context you can. According to their words, “ALL data from ALL of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking.” So ALL 331 patients consents must be complete the 36 month treatment and crossover schedule.
Nice try. The company SEC statements make it clear that ALL treatments must be given to patients (unless market approval arrives first) as anything other than completing the trial would be considered stoping the trial early and subject to a hefty $3 million fine. You know this.
They did state they would wait until the end of the trial just not in that press release. You just decide to focus on releases where they speak about possibly ending sooner. Only they don’t remind you of their own words that they plan to do the statistical analysis at the end of the trial — which isn’t the same as minimum threshold crossing. But they wouldn’t of had to because hey, they told us in August 2014 that they would remain blinded until the very end. And yes, I also believe they were subtle when they reminded us they needed a minimum of OS threshold crossing, along with ALL the treatment data clinically checked — which would be to complete at at the end. :)
The Phase III study randomized patients who had the minimum of 5 vaccine dosages. If they ran out then the patient would just receive placebo without the doctor or patient knowing of the switch. Here is the patient consent form portion which matches the protocol.
“A minimum of 5 and up to 10 doses of DCVax-L or placebo will be administered into your arm, under your skin at day 0, 10 and 20 and at months 2, 4, 8, 12, 18, 24, and 30. Each visit will require you to return to the investigational site for approximately 2-3 hours. Some patients may not receive 10 immunizations due to insufficient material. If your supply of DCVax-L runs out, you will be switched to the placebo preparation without either you or your doctor knowing about it. Each administration will require two injections. You will be observed in the clinic for 2 hours after the injections, and have your vital signs (blood pressure, heart rate, temperature, and respirations) taken. You will be asked about side effects, if any, that you might experience.”
http://neurosurgery.ucla.edu/Workfiles/Site-Neurosurgery/Brain_Tumor_Program/11-000686-%20Main%20ICF%2007Nov2012.pdf
That’s easy. They had the ability with the adaptive design to conduct the statistical analysis before ALL the treatments were done. They clearly opted against doing so and so yes, it’s very clear to me they opted to wait until the end of trial.
You keep adding context to their words. I keep spelling out their exact words.
It’s very important to me that you don’t add context to their words. Their words are clear.
“The Company has been blinded at all times, with no access to any data in the Phase III trial, and WILL REMAIN FULLY BLINDED UNTIL THE TRIAL IS COMPLETED. The changes relate to the statistical analyses that WILL BE DONE AT THE END OF THE TRIAL, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects.” August 2014 PR
There are also clear that there is an AND. They don’t just need thresholds crossed. They needed both thresholds crowded AND quality control checking. Why do you refuse to see that quality control checking doesn’t mean “data collected to date”. That is content you added to their words that is not their. They state “ALL” not “Most”, not “some”. They state ALL, which I reason matches their 2014 press release about them not planning to unblind until the end of the trial.
“The external parties managing the Trial are now moving forward with the process to reach data lock. In this process, ALL data from ALL of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking. The process involves in-person monitoring visits to all of the 80-plus sites in four countries to review the files onsite, as well as other documentary confirmation and checking of all MRI images. As such, it is a multi-month process. While this process is under way, OS and PFS events will continue to accumulate.” — Feb 2017 PR
“The Trial will reach data lock when the threshold events have been reached AND the QUALITY CONTROL CHECKING has been completed for both the PFS and OS endpoints. When data lock is reached, external statisticians and experts will make an independent analysis of the Trial data. The Company will remain blinded until data lock has been reached and the external data analysis has been completed.” - Feb 2017 PR
You point out the OS threshold target date and think that has something to do with when they would finalize quality control checking. Meanwhile it didn’t. They just needed both thresholds crosses PLUS the trial to be complete before they do the statistical analysis. It’s clear to me that they surpasses event thresholds. It should be clear to you that quality control checking aligns with Trish completion!
“The PFS events have surpassed the 248-event threshold, but the OS events have not yet reached the 233-event threshold. Based upon the pace of OS events during the last six to eight months, the Company’s current anticipation is that it will be several months until the Trial reaches 233 OS events.”
In my opinion you are not following that same press release you post about makes it clear that thresholds are variable B. But variable A is “quality checking”which can only be done once the trial treatment active phase (36 months) has passed.. “ALL of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking.” These week their words. That’s the end of the trial. Just like they told us in 2014. They told us in 2017. They will do the statistical analysis at the end of the trial. Not at a threshold crossing.
Here is the PR portion data lock portion that some perceive meant summer 2017. I on the other hand perceive it to mean end of the trial.
“The Trial will reach data lock when the threshold events have been reached AND the QUALITY CONTROL CHECKING has been completed for both the PFS and OS endpoints. When data lock is reached, external statisticians and experts will make an independent analysis of the Trial data. The Company will remain blinded until data lock has been reached and the external data analysis has been completed.” - Feb 2017 PR
We were told data was accumulating beyond the thresholds. Why would that be? Because the trial needed to go through quality control checking. Again “quality control checking” aligns with trial completion. All treatment data (not just what was collected to data) would need to be in. That quality checking process would not be done until 36 months consent elapse.
This part of the same press release makes it clear trial would continue until “ALL of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking.” Aka the end of the trial.
“The external parties managing the Trial are now moving forward with the process to reach data lock. In this process, ALL data from ALL of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking. The process involves in-person monitoring visits to all of the 80-plus sites in four countries to review the files onsite, as well as other documentary confirmation and checking of all MRI images. As such, it is a multi-month process. While this process is under way, OS and PFS events will continue to accumulate.” — Feb 2017 PR
You’re wrong. Data lock will not be reached UNTIL data from ALL treatments were in. They will not do that until the end of the study. Primary endpoint completion and secondary endpoints are not expected to be done until the end of the trial. Those are their words, not mine. You keep focusing on B but completely miss A. A is trial completion.
If the trial ended, yes —to your rhetorical question — we should be informed. If it remains on-going beyond the 36 months of active treatment phase we should be given an update — in the form of an sec 10Q statement is okay too. But unlike you I do see that they have informed us that the trial would run to the very end.
They told us outright that they did not end to do the statistical analysis until the end of the trial. The primary study endpoint is PFS (progression free survival), and the first secondary endpoint is overall survival (OS). Endpoints are not the same thing as trial completion. Trial completions match IRB approved trial consents. They align with treatment injection protocols. Kind of clear to me that the expected first crossing of the primary completion date and secondary completion date isn’t the same thing as an ended trial. But sadly, that isn’t clear to everyone. They did not plan to do unblind at thresholds crossings. They planned to unblind at the end of the trial. This is a SAP change due to the suppressed WBC they wanted to account for. Part of that PR is below.
“The Company has been blinded at all times, with no access to any data in the Phase III trial, and WILL REMAIN FULLY BLINDED UNTIL THE TRIAL IS COMPLETED. The changes relate to the statistical analyses that WILL BE DONE AT THE END OF THE TRIAL, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects.” August 2014 PR
The company also told us “The PFS and OS events are continuing to accumulate as the trials continues.” What they left out is “until completion”. They should have written “The PFS and OS events are continuing to accumulate as the trials continues TO COMPLETION”. On that we can all agree. But that doesn’t mean they didn’t tell us. They sure did. Again we were told in 2014 that the end of the trial would be when endpoint analysis would be done. We were also specifically told in February of 2017 that the trial isn’t scheduled to end until ALL data from ALL of the treatment visits and follow up visits for ALL 331 patients is subjected to quality control checking. What does “ALL” treatment visits and follow up visits mean? Answer, it means until ALL 331 patients complete their study consent of at least 36 months — until all patients were in the considered “follow up” phase period. It didn’t mean those treatment visits to date. It means ALL protocol treatment visits and follow-up available data which matches the active phase — 36 month study consent.
The company has written this “ALL treat visit data” in their press release. Again, those quality control checking can not be done until AlL patients data from ALL of the treatment visits and follow up visits are in. With a disclosed treatment schedule of Two intradermal (i.d.) injections of DCVax-L(treatment cohort) or autologous PBMC (placebo cohort) per treatment which were to be given at days 0, 10, 20, and at weeks 8, 16, 32, 48, 72, 96 and 120 and known built in follow-up, the “moving towards completion” should have been understood that it was going to take awhile (36 months from last enrolled patient) for the trial process to reach data lock final mode. Before then they would be closing out clinical sites one by one, visiting them once final consents periods elapsed. I perceive they will be going to the last enrolled sites at this stage. And just like the others clinical sites that could take a few months. Anyway, that’s how I interpret it. You can choose to interpret it differently.
“There are 331 patients enrolled in the Trial. The Trial endpoints involve thresholds of 248 “events” for PFS and 233 “events” for OS. PFS events are primarily tumor progression (i.e., recurrence), although they can occasionally be patient deaths which occur without prior evidence of tumor recurrence. OS events are patient deaths. The PFS and OS events are continuing to accumulate as the Trial continues. The PFS events have surpassed the 248-event threshold, but the OS events have not yet reached the 233-event threshold. Based upon the pace of OS events during the last six to eight months, the Company’s current anticipation is that it will be several months until the Trial reaches 233 OS events.” — Feb 2017
“The external parties managing the Trial are now moving forward with the process to reach data lock. In this process, ALL data from ALL of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking. The process involves in-person monitoring visits to all of the 80-plus sites in four countries to review the files onsite, as well as other documentary confirmation and checking of all MRI images. As such, it is a multi-month process. While this process is under way, OS and PFS events will continue to accumulate.” — Feb 2017 PR
They haven’t lied. They just haven’t spelled it out for you like I’ve done imho.
The IRB approved the protocol. I can’t imagine they are discarding product at the 3 year mark. But if they are, then it means all crossover injections stop this month too. NWBO should submit a press release if all treatments are done. We deserve to know where the trial stands.
That’s the length of the active phase of the study. Isn’t the shelf life of the vaccine something like 5 years? if memory serves it is.
At this point they can only be treating crossover patients. But supply has to be diminishing.
Crossover patients follow the same vaccine schedule as treatment cohort patients. If a vaccine patient used 10 before crossover and event after 3 years, they might still have a few injections to use after crossover. I don’t think I’ve heard of any patient having more than 17 injection supply on prior studies. But this study they will likely not have as many as they also need to receive some of the cells to make placebo supply. In But let’s say they do have 17 supply for some patients in this study, including the last patients, the 7 extra it would be used up very quickly as early on injections are not spaced far apart. No more than 4 years. And as you and I know, majority of the patients were enrolled well over 3.5 years ago. Only the last 26 patients were enrolled after the August 2015 halt. So all supply should be exhausted soon imho. They can’t keep the study running forever.
All randomized patients receive up to 10 immunizations of DCVax-L or autologous
MNC (placebo cohort) at days 0, 10, 20, and at months 2, 4, 8, 12, 18, 24 and 30)
A minimum of 5 immunizations must be available for treatment as determined by
the contracted manufacturer.
Patients for whom insufficient DCVax-L is manufactured, i.e. less
than 5 doses, will be eligible to undergo additional apheresis if it is determined that
the leukapheresis can be completed and DCVax-L manufactured and released prior
to the Baseline Visit (approximately 40 days). Peripheral blood mononuclear cells
(MNC) are purified from the leukapheresis material at the contracted manufacturer,
and an aliquot of the MNC is cryopreserved for use as placebo for patients who are
randomized to the placebo cohort. The remainder of the MNC is used to prepare
DCVax-L. Both DCVax-L and the placebo are tested at the contracted manufacturer
prior to release to the study site. Patients for whom sufficient DCVax-L was not
generated are not eligible to continue on this protocol.
8.4. CROSSOVER (OPEN LABEL) ARM
Patients enrolled in the study for whom disease progression is established at any
point after randomization (as defined in section 14.2 of this protocol, and verified by
independent review) will be offered the opportunity to receive DCVax-L and/or any
other established treatment of the physician’s choice. All procedures below should
be followed. Patients who do not participate in the crossover option of the study will
return for an EOT visit and continue to be followed for survival.
Study Procedures for Crossover (Open Label) Option:
Patients who, wish to continue in the study after confirmation of disease progression,
will have the option to receive DCVax-L under the crossover/open label option of the
study (except in rare cases where they were originally randomized to DCVax-L and
have exhausted their supply). Patients enrolled into the crossover arm will be
required to follow the same study visit schedule as patients enrolled into the
treatment arm of the study (Appendix A1). Patients may be treated with any
additional established therapies, and the administration guidelines should be
referenced as described below.
Labs will be collected prior to the first immunization of a patient following crossover
as specified in 8.4 Labs. A negative urine pregnancy test must be obtained for all
female subjects of child bearing potential prior to receiving the immunization.
Immune Monitoring
• Immune monitoring samples will not be drawn for patients enrolled in the crossover
study arm
Labs:
For all scheduled lab tests during treatment with DCVax-L, central laboratories will be
used. Prior to the first immunization of a patient following crossover, the following
samples will be collected for the central lab (but results are not required prior to
immunization):
• CBC and differential
• Blood chemistry - Comprehensive metabolic panel, including electrolyte balance,
and hepatic and renal functions
• Serum hCG for pregnancy
• Anti-DNA
• Urinalysis
• All scheduled and unscheduled MRI and other radiographic images should be sent
to central radiology for independent review
Clinical Drug Supply:
• Clinical Drug Supply vendor is notified that a patient has confirmed disease
progression. Refer to the IXRS manual for further details.
• Patients will receive up to 10 DCVax-L injections at days 0, 10, 20, and months 2,
4, 8, 12, 18, 24 and 30. Day 0 is the date of the first immunization and must occur
within 3 months of crossover (date of confirmation of disease progression). For
the immunizations at days 10 and 20, the variance may be ±2 days but the
minimum interval between injections must be at least 9 days. For the
immunizations at months 2, 4, 8, 12, 18, 24, and 30 the variance can be ±1 week
with a minimum interval of 6 weeks between injections.
That is a stop the trial early fee.
At this point all the vaccine cohort patients should have completed all 10 injection treatments per protocol. A minimum of 5 injections + 10 placebo was needed for each patient to enter randomization. Each patient is only supposed to get 10 vaccine injections either before or after crossover. But the patients supply will vary, so some might have more than 10 vaccine injections available, which would leave the rest to be used after a crossover event. Trial cost at this stage should, in theory, be minimal but in practice it might be that they were able to make over 10 injection supply for patients. We have no idea how many patients matched the 10+ vaccine supply. If it were many then depends on if/when patients event within these first three years to determine whether additional vaccine supply would be used at crossover.
They are only treating crossover patients who have had PFS event. However since the trial is randomized 2:1, and 3 years have gone by it is likely very few patients have remaining supply. Most standard of care patients (which placebo patients technically are) event within the first year. But it’s a 2.5 year injection schedule, so these next few months could be the last of all treatments for late cross over events. The company in theory could try to keep the trial on-going until all supply is exhausted. But they don’t get individual patient data, so it’s a guessing game of how many patients have yet to use their 10+ vaccine supply.
Hi DMB,
No, it’s standard to discuss GBM overall survival times from the time of surgery on all GBM treatments. They simply deducted the “time to treatment” variable, which I believe in this study was referred to as 3.1 months, in order to have a comparable yardstick to measure survival times against other GBM treatments. They did the same thing on their other phases studies as well when discussing overall survival. It’s simple the way the industry speaks about GBM treatment, as at the end of the day when either scientists or regulators compare DCZvax-L to other treatments they will do so not from the survival time of first injection but instead from the initial GBM surgery.
Treatment start times do not change. The active phase of this trial from when treatment starts remains 36 months. The protocol lists it as such. As do study consents. Nothing about the protocol treatment scheduled changed when the trial resumed in 2014. The only thing that changed was the statistical analysis plan.
“The Company has been blinded at all times, with no access to any data in the Phase III trial, and WILL REMAIN FULLY BLINDED UNTIL THE TRIAL IS COMPLETED. The changes relate to the statistical analyses that WILL BE DONE AT THE END OF THE TRIAL be done at the end of the trial, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects.” August 2014 PR
The Phase III consent form also makes it very clear that the active trial phase is 3 years.
“The clinical trial will consist of three phases: the initial evaluation phase (also known as the screening phase), the active treatment phase, and the follow-up phase. During the evaluation phase you will undergo some testing noted below to indicate whether you can participate. The next phase, the active treatment phase, is when patients are treated with DCVax-L or placebo. During this phase, which lasts up to 36 months, you will be asked to return to the clinic once every two months for MRIs and other tests as outlined below under Study Visits Procedures to determine how you are doing. During the follow-up phase, which starts after the 36 months is completed or after you leave the trial for any reason, you and/or a designated contact will be contacted every third month to collect medical history including data on long-term progression or re-growth of your brain cancer as well as survival data.. Please read the section titled Follow-Up Information.”
Data control completion was never meant to be done until the end of the trial. I’m not accusing anyone of lying. I’m stating they are very cleaver with their disclosures.
You know full well that the trial does not end until every patient completes their study consent. And so data control process can’t be complete until after study consent ends. Consider data control aspect as variable A. And Variable B should be considered as passing PS and OS thresholds. The trial doesn’t end just because thresholds (B) are crossed. It’s ends when A (data completion) and B (thresholds are both crossed) are both done. It’s that simple.
And they told us they wouldn’t do the statistical analysis until the trial ends In that same August 2014 press release. Just because the trial has PS and OS numbers it doesn’t mean they intended to not let all the data accumulate for the 3 years. They changed the SAP. They planned to keep collecting data until the trial ends. In fact, I’m saying they told us they didn’t plan to do the final analysis until the trial ends. We may have not noticed it at the time but yup, they told us.
**
If one accounts for the last patient in, also in clinicaltrials.gov, one can see the study is expected to go on several years, when including treatments and monitoring, for each and every patient (survival permitting).
“Two intradermal (i.d.) injections of DCVax-L(treatment cohort) or autologous PBMC (placebo cohort) per treatment. Treatments will be given at days 0, 10, 20, and at weeks 8, 16, 32, 48, 72, 96 and 120.”
The Phase III consent form also makes it very clear that the active trial phase is 3 years.
“The clinical trial will consist of three phases: the initial evaluation phase (also known as the screening phase), the active treatment phase, and the follow-up phase. During the evaluation phase you will undergo some testing noted below to indicate whether you can participate. The next phase, the active treatment phase, is when patients are treated with DCVax-L or placebo. During this phase, which lasts up to 36 months, you will be asked to return to the clinic once every two months for MRIs and other tests as outlined below under Study Visits Procedures to determine how you are doing. During the follow-up phase, which starts after the 36 months is completed or after you leave the trial for any reason, you and/or a designated contact will be contacted every third month to collect medical history including data on long-term progression or re-growth of your brain cancer as well as survival data.. Please read the section titled Follow-Up Information.”
The SEC statements make it clear to that the study would be considered early termination if the last patient in did not receive their final dose.
"Prior to the last dose of the last patient enrolled in the Phase III trial for DCVax®-L or After the last dose of the last patient enrolled in the Phase III clinical trial for DCVax®-L but before any submission for product approval in any jurisdiction or after the submission of any application for market authorization but prior to receiving a marketing authorization approval: in any of these cases, the fee shall be $3 million." -- NW Bio 10Q
And the protocol also makes it clear that the company can stop the study — meaning not go the full duration of the patient treatment schedule — with this line:
“Treatment in this study must be discontinued for any of the following reasons:
• if the sponsor decides to stop the study” — protocol
“18. STOPPING THE STUDY
The sponsor may decide to stop the study at any point, for any reason.
APPENDIX A: SCHEDULE OF EVENTS
Visit 1 2 3 4 5/5a 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Surgery
Post-surgery MRI
Pre-leukapheresis
Leukapheresis
Radiation and
Chemotherapy
Baseline Visit (2) b,n
Enrollment
Immunizations
End of Treatment
Survival Follow-up
1 2 3 4 5 6 7 8 9 10
-1
wk
Time
0d
day
10
day
20
2
Mo
4
Mo
6
Mo
8
Mo
10
Mo
12
Mo
14
Mo
16
Mo
18
Mo
20
Mo
22
Mo
24
Mo
26
Mo
28
Mo
30
Mo
32
Mo
34
Mo
36
Mo
Ongoing”
So yeah, that too makes it clear the study is 3 years.
Yes they did. Reread that press release. They told us they would remain blinded until the trial ended. The trial does not end just because sufficient PS and OS events accumulate. It ends after every last patient completes their trial consent.
Press release below.
“The Company has been blinded at all times, with no access to any data in the Phase III trial, and will remain fully blinded until the trial is completed. The changes relate to the statistical analyses that will be done at the end of the trial, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects. The changes were driven solely by external factors — particularly research reports about a newly discovered variable which has been found to significantly affect GBM patients’ survival times, and which the Company recognized could significantly skew the clinical trial results if the trial’s statistical analyses did not control for it. The Company’s Phase III trial design and statistical analyses already controlled for key variables known at the time when the trial was designed, such as a particular genetic factor (referred to as MGMT methylation), the extent of tumor removal, and others.” — NW Bio August 2014
I see that they told us they would continue the trial to the end with their August 2014 disclosure. We just didn’t notice it at the time. In the summer of 2017 it was clear to me that their SEC statements that they didn’t plan to unblind the trial at least for another year. I got attacked back then and accused by flipper to be manipulating the stock. You agreed with me back then. Let’s hope we are right and they let us know that data lock process is near its final stages. If we have to wait for an unknown “ongoing” period beyond the 36 months, then yeah I won’t be pleased. But I do know that they have to end the trial at some point. They can’t just not end it.
I know it’s 4 months. Obviously I think if we are still waiting in March that the company without any news on the trial that will mean that the company is going beyond the 3 years “active phase” and extending the “follow-up” phase. I’m expecting that we hear an update before March, as in February the latest — before then. If we are not told a thing before March, I’m going to start getting annoyed, as we should be told how long they plan to keep the trial running.
Consent form.
“The clinical trial will consist of three phases: the initial evaluation phase (also known as the screening phase), the active treatment phase, and the follow-up phase. During the evaluation phase you will undergo some testing noted below to indicate whether you can participate. The next phase, the active treatment phase, is when patients are treated with DCVax-L or placebo. During this phase, which lasts up to 36 months, you will be asked to return to the clinic once every two months for MRIs and other tests as outlined below under Study Visits Procedures to determine how you are doing. During the follow-up phase, which starts after the 36 months is completed or after you leave the trial for any reason, you and/or a designated contact will be contacted every third month to collect medical history including data on long-term progression or re-growth of your brain cancer as well as survival data.. Please read the section titled Follow-Up Information.”
Yes. Still in my 40s. Hope you are too. :)
I’m patiently waiting for the trial to end. The trial reaches 3 years this month at some point on every last patient. It took the company until February 2017 to give us an update on PFS data — after the December 2016 data collection announcement. And so I’m giving them the same 3 month period to do their final sweep before I get impatient. That is all.
I’m not anyone but myself, RK. I’m not on Twitter. I’m not following the crazy conspiracy theories. But not surprised to see folks still chatting about investors. Not much to do as the time passes.
I was gonna say.. no I’m not. :)
(Been super busy, I’ll reply to other post from a few days ago later.)
Standardizing apheresis centers — to be precise.
Fresh vs Frozen topic sounds interesting too.
Lots of great topics.
http://www.phacilitate-leaders-world.com/your-interactive-agenda/agenda-at-a-glance
Lol.
If you look further, the agenda reveals that a topic includes better luekapheresis. Fits my halt theory. :)
In 2014, the company disclosed they planned to remain blinded to the end of the study. They also disclosed they plan to do statistical analysis once the study ended. They didn’t elaborate on when the trial would end, but i suspect many agree that the study consent period is accurate as for IRB trial duration — 36 months. So instead of 248 events once 248 passed, they plan to look at 248 PFS events when all enrolled Phase III patients complete the 36 months trial consent — this ensure the separation of the survival curve. I believe it was right under our noise the whole time that the unblinding of the trial would not occur until the very end; and the statistical analysis would occur only when the trial ended.
“The Company has been blinded at all times, with no access to any data in the Phase III trial, and will remain fully blinded until the trial is completed. The changes relate to the statistical analyses that will be done at the end of the trial, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects. The changes were driven solely by external factors — particularly research reports about a newly discovered variable which has been found to significantly affect GBM patients’ survival times, and which the Company recognized could significantly skew the clinical trial results if the trial’s statistical analyses did not control for it. The Company’s Phase III trial design and statistical analyses already controlled for key variables known at the time when the trial was designed, such as a particular genetic factor (referred to as MGMT methylation), the extent of tumor removal, and others.” — NW Bio August 2014
The Phase III consent form also makes it very clear that the active trial phase is 3 years.
“The clinical trial will consist of three phases: the initial evaluation phase (also known as the screening phase), the active treatment phase, and the follow-up phase. During the evaluation phase you will undergo some testing noted below to indicate whether you can participate. The next phase, the active treatment phase, is when patients are treated with DCVax-L or placebo. During this phase, which lasts up to 36 months, you will be asked to return to the clinic once every two months for MRIs and other tests as outlined below under Study Visits Procedures to determine how you are doing. During the follow-up phase, which starts after the 36 months is completed or after you leave the trial for any reason, you and/or a designated contact will be contacted every third month to collect medical history including data on long-term progression or re-growth of your brain cancer as well as survival data.. Please read the section titled Follow-Up Information.” — patient consent form.
Conference in January 2019. NW Bio is a sponsor.
http://www.phacilitate-leaders-world.com/your-interactive-agenda/agenda-at-a-glance
Conference in April 2019. NW Bio is a sponsor.
http://www.phacilitate-leaders-world.com/sponsors--exhibitors/northwest-biotherapeutics
Yes, I’m sure the study duration is 3 years. If the company decides to not give patients their 10 treatments, according to SEC statements it qualifies as a study early stoppage and hefty fine to Cognate— unless the company filled for marketing authorization first. Study doesn’t end until the consent period ends.
"Prior to the last dose of the last patient enrolled in the Phase III trial for DCVax®-L or After the last dose of the last patient enrolled in the Phase III clinical trial for DCVax®-L but before any submission for product approval in any jurisdiction or after the submission of any application for market authorization but prior to receiving a marketing authorization approval: in any of these cases, the fee shall be $3 million." -- NW Bio 10Q
I’ll look for another area of the protocol that mentions study consent. Clear to me the regulators approved a 3 year enrollment period and on-going monitoring.