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Sorry for not being so present nowadays, does not mean I am not following
But I am really busy on other concerns
I did write this today, hopefully it will help make the appropriate investing decisions
Article
Credit : Sushi for the editorial advice and correcting "my french". Sushi : love from Paris !
Interesting points Biobonic :
1) indeed. Also, they could have stated 96% completion and be in reality at 98% in terms of events (as for Modus 98% while trial completed). Does it mean that we could be closer from completion like 5 events away ?
2) I don't believe in "lower dropouts rates" anymore. Fact that SOC is so bad means necessarily that Dropouts are high otherwise trial would have ended early and positively. Hopefully dropouts contained under 20% overall for all sites.
3) All deaths are counted for in the 298, including road incidents, that's the way the trial is designed. This is why it is called "overall survival" as opposed to relative. Trial design will compare superiority of MK arm versus SOC whatever cause of death in both arms.10 % or more less death in MK arm and its a success. NB : Most of them will be due to this cancer (there is a 2 to 5% difference between relative and observed survival)
They have one statistician, no need for top one as they only need to measure, no calibrate the study
No news yet ?
@tarius,
"is it possible to estimate how many deaths might be required to provide 80% statistical power to get a feel for how many we're under? or is anything less than 298 basically less than 80% statistical power?"
That is the good question which I asked myself but I stepped back looking at the difficulty of the maths required. Dr Talor told me, to reach this number, they needed to hire a top world's re-known statistician. I am not a mere statitician
What I known is that they calibrated 298 so that with 10% OS improvement (what is called "Effect size") they would get statistical power. This means that with greater effect size they would in theory need a lesser number of events, but which effect is is required for instance to imply 286 is enough I do not know. What I do know is that, for a given effect, 10 patients less is 2% less power.
If interested you can read this article
Thanks !
Would that 96% be 6/30, endpoint should be reached by late October
Now like Rogue said, I believe this progress was reported as per the date of the slides (09/24)
Good point Sushi : they would have put today's date with no news, this would have been a concern, lol.
So they changed the date and expect a news soon
Oh yes I agree and share your sentiment M. Pijoe
I hate the way the Brits have increased inflation in Marrakech
I used to pay 20 Dh for a taxi to city center, now they are asking for 400 Dhs (half the mean monthly salary in this country), because they say that's nothing compared with London taxi prices.
While slide 26 should not be a surprise to anyone on this board as I hope we have done a good enough job to explain why this trial is event based, golden standard etc etc.... slide 27 is not news in itself but might hide a message :
"it ain't over till it's over"
As we know we are more or less 12 events away, no surprise shall be yet expected we mentioned in this blog post
... no surprise shall be yet expected at this point. With 2 to 3 events per month Expect 298 to be reached between end of Dec and early April.
Good point Biobonic on the dropouts digging.
Re event pace : I agree it should be higher than Rogue's, now don't forget events pace is not linear, it tends to slow down in time
My rate is higher than Rogue's : 2,4 to 3 per month which leads from early Jan to Late Feb
With a margin of error due to the human factor we could say between Dec and Late April as extreme points
GL all today, hopefully the end of the week will be Stellar
Fosco
Great finding Sushi, this Ergomed publication before it was changed.
We've got a proof point here, this 96% figure is a f...g good proof point
People who followed us a little bit can actually see it !!!
Huge $$$$ at stake now
If big moneys are following, they are going to be all over Cel-SCI for the key remaining questions and if they are satisfied they will have a 90% chance win here and we will have a huge POP in the meantime
GL 2 ALL
Fosco
yeah, is the caller "one of us" ?
I would like to thank him,
Thanks David !
In any case let's see how it translates into volume and pps,
The good thing is that the guy from California mentioned Zacks so viewers will have the opportunity to look closer to Zacks article
(Although the 14$ pps would not sound too attractive, it's better than nothing, and people might look for other sources like SA afterwards)
@Golden_cross
Reality check :
Late march 2019 you predicted a bullish chart
this was right before the "big run up"
Verdict : "Congrats"
Footnote : This was right before the IDMC recommandation, we are in a similar situation right now in terms of newsflow and apparently in terms of charting with the new low support above 7$ (VS 3$). Let's see what happens next. IDMC meeting should be this week or have happened last week.
Sab
Sorry, i don t understand what 9$ Fence you re talking of lol
I don t have cognac , but cheers (whiskey)
Fosco
@Sab
thanks sab. Happy to see you too.
"we all know the level needed to be broken", yes , I too, the total stranger to TA, am longing for the $50 barrier to be broken soon ROFLMAO
Rogue2, scarce poster but valuable insight
Thanks
I have come to the point that I have little doubt on the fact that SoC survival for the actual trial population is pretty under 60% at Y3 and 50% at Y5 (and I made various cross checked with other countries figures such as Canada, UK, Germany), which bodes pretty well for the success of this trial ... provided that dropouts are contained under a reasonable number.
Like I wrote in the last two post that's my last area of uncertainty, where I am not 99% sure : how many patients does the standard design of the study allow to lose for tracking (meaning losing the capacity to assess if living or dead) to preserve its power ? Is it 144 (928 - 784) or 630 (928-298) or another number ?
Obviously, IDMC would not complain about dropouts and study power as long dropouts have not reached this number. "There are likely not such many dropouts because IDMC didn't say anything " sentence as reported from M. De Windt various times could be true if this number is 144 (dropouts containment by 15.5% max).
Depending on the answer, we could be in full confidence of success right now or just only "reasonably" confident,
Fosco
Lightrock, I am glad we do !
Like Geert said to his audience "just do the maths" : there are scenarios where the only outcome can be success.
Sorry, no comprendo. In plain english, what do you mean ?
Dropouts could be higher and still a success ?
I do fully agree, like I said previously, dropouts could be up to 30% and still a success, but that 's not my point
My point is that if Cel SCI requires, for significance purpose, less than 15.5%, then we have a winner, I will bet my bottom dollar, 100% garantied.
If dropouts are only contained by the fact that they need 298, we can't conclude with such certainty, dropouts, necessarily high because of low survival expectation, could go from a wide spectrum from 20% till 60% and trial continue with no significance at risk
Dropout and condition for success
===================================
I see that the interest and questioning is raising because we feel that we are a few bits of information away to assess the full successfulness of this trial in advance with a pretty good certainty and this is exciting !
May I begin with what I am 100% certain (and I would like you please to believe it because I am 100% certain to be right and discussions around these topics have already been addressed thousands of times and solved).
Let me give a simple definition of dropout. In fact, the definition which is critical to us.
“A dropout is a patient who has been accounted as enrolled and whose outcome (dead or alive) has been lost and will be lost forever for the study at a point in time”
Again, sorry to insist, a patients rolled over by a 10 ton truck is not a dropout. He is an unfortunate man who only had an incurable disease and unfortunately died in a tragic manner.
He will be accounted as an Event in this trial if the sponsor of the trial is aware of his death because they are accounting “observed survival” and not “survival relative to the illness”. If the investigator is not aware of his death, he will be considered as a dropout.
Now a little bit on how they assess success in this trial (Primary endpoint)
1) Global efficacy is assessed on a binary way and needs significance
(Skip the following section if you don’t like details)
At end point and as well on regular basis during the IDMC meeting they will build two Kaplan-Meier survival curves spanning from year 0 (date of treatment) till a year corresponding to the timeline for the longest surviving patients. They are running from this the so-called Logrank test, which is a simple sum of gaps between the two curves and is aimed at assessing GLOBAL efficacy between the two curves. This is a binary test which basically says : “YES MK is efficient” or “NO MK is similar to control” and also gives a P which gives the significance of the results. Until P>0.05 then the TEST is not significant which means that even it says “YES MK Is efficient” and p=0.25 the credit to give to this assertion is that it is significant with 75% of probability which is insufficient they need like in all clinical trail a 95% of probability. So the IDMC will say “trial will continue” until they will see p<0.05.
Cel-sci calculated that significance should be reached (p<0.5) when when 298th event is reached which is the reason why we need to wait till 298 to happen. Significance could be reached sooner (let’s see what the IDMC says soon) if the two curves show a very neat difference (or similarity in case of futility).
2) Overall improvement of 10% in survival is required by the clinical trial between the two comparative arms
That’s a claim from Cel SCI . How they measure the 10% improvement is a bit of a statistical mystery to me (and not only me). However they might use Hazard ratio (an outcome of the Kaplan Meier analysis) which assess the % gap of deaths between both arms and is a global number for the whole curves and infer from the Hazard ratio the 10% overall survival improvement (“If we see 15% less events in the MK arm then it means 10% more survival”). Not sure.
NB 1: At no point there is a 3 years assessment. The Analysis is global for the two KM curves. Everyone who think there is something happening at Year3 survival milestone should forget about it. The analysis takes place at each IDMC meeting AND the last one, unblinded to Cel SCI will take place when 298th is reached. “This is an event based study”
NB 2: A patient who dropouts is not an “un-followed” patient. Because actually he is followed until he disappears. That’s what they call right-censoring in KM analysis. Their survival is tracked and accounted for in the KM analysis until they disappear. This data will be useful to assess global efficacy (as per point 1 above).
3) Max dropouts allowed
Generally speaking, max number of dropouts allowed in an event-based study is the number of dropouts which don’t prevent 298 to be assessed as events. In our case it is 928 – 298 = 630 patients, 63% : Obviously, if you lose more than 630 than you won’t be able to count your 298 events.
The reason they recruit so many patients is
a) To be able to complete the study in a timely manner
b) to reach statistical significance even if dropouts are significant
Now, when I wrote my SeekingAlpha article I mentioned in the comments to readers that they needed 784 evaluable patients (see Cel SCI scientific presentation) to assess enough power for the study. But truth is that to assess global efficacy, you don’t need 784, you just need 298 events. To assess the 10% improvement, you might need more and that might be the reason for the 784 but I can’t rule this in my certainties.
If 784 patients at least need to be followed (max dropout number = 144 patients) when 298th event comes, this means that there is a ceiling on the number of potential dropouts : 15,5 %.
And that’s why I didn’t use a Socs survival as bad as Cel SCI. Because with such bad SoCs survival as they published, this implies that the trial should have ended sooner OR that efficacy is mind blowing (miracle drug) OR that dropouts are well above 15.5%.
In conclusion
====================
If it is confirmed that 784 need to be followed from treatment to death, this means that we have a winner, with certainty, and I will personally bet the farm on it. Real SoC is likely better that the one they mentioned because , well that ‘s an average and patients in this CT are probably better treated with complete scale S-CRT, dropouts are contained under 15.5%.
This is a simple question to ask, and a simple answer to get. No need to ask for how many counted dropouts, this could be a blinded data for the sponsor.
Fosco
We don't know, but may-be a big chunk of dropouts came from there. Now we're talking about 15% of total recruitees : still if all of them would be ousted (which I doubt) you would need a dropout rate above 30% in the remaining patients population in order for current length it takes mean that no efficacy is shown so far
George,
To be honest they never seemed to be concerned about the power of the study since 2015 (or '16 ?) when Geert wanted more people. They seem to be confident on current numbers.
The big "OR"
============
I have considered Cel SCI survival data. They have hired a professional team to extract it. I believe they have used same or almost same assumptions as I did on inclusion criteria, population and year of treatment.
Like I stated it is a bit different from my own SEER extract that I published in Seeking alpha article, simply because I took the most conservative survival (Stage III), like I explained in the text.
Otherwise it matches pretty well my blend of ST III + ST IVa stats as per my XL spreadsheet, there is more prevalence of STIVa (more than 2x more patients) so that takes the survival down.
The reason I have not considered these figures is because they are way too bad and would show excessive success of the CT ! I preferred to be conservative to show that success is highly likely.
The other reason is that, like Lightrock, I am a bit annoyed with such survival numbers as this implies dropouts numbers
This implies
1) A huge efficacy
OR
2) A really unbelievable number of dropout and no efficacy
OR
3) Still a huge number of dropouts and a reasonable efficacy
That's the big OR
Basically what is says is :
Let's assume 298th event happens by Dec 2019 (very reasonable assumptions)
1) A huge efficacy shown at primary endpoint: we would have 15.6% of dropouts and a survival improvement of 85% in Multikine arm VS control (206 events VS 92 events)
OR
2) A really unbelievable number of dropout and no efficacy : More than 40% of dropouts and less than 5% survival improvement in Multikine arm VS control
OR
3) Less than 36% of dropouts and still 15% survival improvement in Multikine arm VS control
Most conservatively, we can respect SEER data, but we could also imagine like a poster mentioned, SEER represent averages and the study population gets a better treatment than the average population, so SOC survival might be better than this one. Then the figures will show more reasonable outcomes.
In any case it is not realistic to find so many dropouts, the data we got from a clinical site in Sri Lanka implied around 11%, not 35%, therefore there is so much room for optimism that my mind cannot grasp it at this time.
In french "OR" means gold, and behind this "OR" lies whether we are golden or poor fools
@Cotton
I am glad that you are still around
As for IDMC meeting, we believe it will happen in second half of September with no specific date
There are three possible outcomes from IDMC : futility, premature stop and "continue the study". Depending on how much events are left, IDMC migth stop it or not. But we don't know how many events are left to happen, with
CEO hinting at BMY study for which 15% left took 2 years to happen (this should lead us till late 2020!)
I have computed the new numbers they have issued. As you noticed they are really bad, reason I was reluctant to use such un-conservative survival
I 'll explain why
Fosco
Pres is out,
See slide 20 which matches on the lower boundaries of stage III+IVa survival as I have published in SA article :
https://docs.google.com/spreadsheets/d/1iVkDqatmv_R9kQgKPYy-dLizhwAlaq-LQbD5T1venV4/edit#gid=611558201
(I didn't consider those figures because I wanted a conservative analysis but it is even better if they do indeed reflect the study population)
Btw the old sheet link is still valid but is available on google request, because I think it holds obsolete assumptions to be widespread, I prefer the new sheet
What to say then : This kind of survival curve must imply an even better OSI of Multikine group or a high dropout rate, but even the higher dropouts rates imply efficacy, drop outs would have to be well above 20% to imply so much delay in 298th occurrence
Fosco
I tend to disagree
Isn't the fact of not having news a news in itself ?
Also each new presentation is room for novelties. Who knows what novelties might be included in this one ?
(Answer in 1 hour)
Right + they already had a 4B market cap and they're going to 8B.
Gaining 4B just on a early success... impressive and room for hope, jumping 4B at the open out of the nothingness we are currently standing wouldn't deplease me
Congratulations Chukster1
I did a similar thing with Jun '20 and Dec '20 10$ calls.
Didn't want to take any risk of "no news until Q2" so didn't take any earlier call. You got a better price than I did on the jun ones (2.60).
Overall if it goes really up in 2020 it should be a good bet b/c you get more calls than shares for same amount
have a good day
Fosco
No news from Cotton Farmer ?
Cotton, I hope you are still around
new article out in SA
Unfortunately his analysis is a bit superficial and he lays his advice in 2014 and 2016 IDMC events we all know too well.
Fair enough, superficial analysis can only lead to mistrust but is a way like another of selecting tickers within a large basket of candidates
and yes, I posted before Sushi ! Hope he is not sick in bed
Link to article
@sab
Thanks,
I have no knowledge on this matter, but intuitively it looks like consolidation is much more solid this time than last time we hit 8.xx and pulled back. Hopefully the market does not prove me wrong
Fosco
@'ErIsKoffie'
Right, ah ah ah, but that is 9 sites not 18
... we would need to check all publications mentioning closure and assuming we wouldn't have missed any ... and the figure left would not give much valuable information on how many really survived.
Vriendelijke groeten
Fosco
Thanks Sab
So support leve is 7.53 ? We've been to 7.60 yesterday. Hopefully we rebound from here
Folks
-----
Have a look at precise wording :
"termination of the Taiwan University Hospital and the Taichung Veterans General Hospital"
How many sites are in Taïwan ? A quick look at CT sites will give the answer (see bottom list).
So 2 are closed, plus if you look for instance at report 105 - A - 10 dated 2015, Hualien Tzu Chi Hospital had been closed before (verbiage is similar).
It looks like this IRB is following all trials happening in Taïwan, for all Taïwan sites.
These sites have been opened as early as 2014, 5 years from now, stage IV cancer survival is 1/3. If some hospital has been passing stage IV patients (not stage III) 2/3 should be wiped out. Some hospital might have no more patients anymore to follow, some still open for follow up. May be the number of patients is very low (1-5) in some hospital, hence when they pass away there is no more to follow.
Taïwan sites :
=============
Kaohsiung Branch Chang Gung Memorial Hospital
Niaosong, Kaohsiung, Taiwan, 833
National Cheng Kung University Hospital
Taipei, Tainan, Taiwan, 704
National Taiwan Research Hospital
Chengshan, Taipei, Taiwan, 100
Linkou Branch Chang Gung Memorial Hospital
Guishan, Taoyuan, Taiwan, 333
Changua Christian Hospital
Chang-hua, Taiwan, 500
Buddhist Tzu Chi General Hospital, Hualien Branch
Hualien City, Taiwan, 970
China Medical University Hospital
Taichung, Taiwan, 404
Taichung Veterans General Hospital
Taichung, Taiwan, 40705
Shin-Kong Wu Ho-Su Memorial Hospital
Taipei, Taiwan, 111
cialis being cialis
Most likely "he" is just a short troll
How would you call someone called M. V Agra ?
beware Cialis effect, lol !
@sab
You have here the warrants owners list
most are private investors
Look at MM series, Germans like Dirk Oldenburg : Geert's pals ?
Must have a damned level of confidence to have bought that early in 2017 and still hold $5,486,035 of potential benefit.
Wondering what Geert is telling them lol, "Sie werden eine goldene nase verdienen " ???
Spidey
------
While I tend to agree that you did not deserve Sushi's tone
As long as we are talking about cash burn, we are not talking about expenses. For instance Ergomed payment in shares will count as an expense, but will not burn cash.
The simplest way to count cash burn (if the figure is not provided in the 10Q itself) is to compare cash in the beginning of the period to cash in the end of the period, and adjust with cash received in between, in the case of cell sci mostly from warrants (I saw as well they received but marginaly, 300K of grants in 9 months). This is your "gross burn rate" and this is what we want. The "net burn rate" includes the cash in from warrants, which we don't want to include because it is not sure money, sure revenue.
In our case for this Quarter, that is the calculation that I have made and cash burn (gross burn) is about $ 1.47M / month. For the 9 last months, Sushi's right and it's about $1.4M / month.
If you want net burn : you had $ 9,485,495 by 06/30 and $ 5,514,013 by 03/31 (by previous 10Q), therefore quarterly net burn is negative because warrants did bring in net cash : $ 8,393,019 (net cash burn = $ -3,971,482).
Sorry but we can't compete against sushi, he's a CPA.
Take care
Fosco
@Biobonic
exactly, the interesting one is the "107-A-05"
All non related deaths are counted in the number of events counted so far until they get to 298. That's why we often say that the number of events reports the Overall Survival, not the relative survival.
In the final report, they will likely need to adjust the figures so that they can compare apples with apples (that's were you will hear about "age adjusted", "relative survival" , "stratification" etc..)
They got it through the development safety update report that was communicated to the hospital IRB by the sponsor : that's a standardized mandatory annual report required by the FDA and other agencies in the world which the sponsor has to produce (or at least the CRO on behalf of). Don't forget that the CRO has a consolidated view of all events site by site, not necessarily by arm (test or control), but at least a consolidated view.
Taïwan Feb 2018 Minutes
search for "multikine"
you'll have to translate or believe my word that the translation is :
"4. SF14218A (Fourth Report)
1) The company entrusted the director of the hospital's otolaryngology head and neck, Zhongyu Wang (???), to conduct {an open, randomized, multiple centres clinical trial to compare the use of Multikine (Leukocyte Interleukin, Injection) plus standard therapy (surgery + radiation therapy or surgery + radiation combined with chemotherapy) and the use of standard treatment in primary advanced squamous cell carcinoma of oral and soft palate cancer (program number: CS001P3; IRB number: SF14218).} By reviewing the registered clinical laboratory result, the case is listed on August 25, 2014, Zhong Rong Ren Zi Zi No. 1030020068 was approved.
2) The safety of the drug Multikine has not changed since the seventh safety review of the drug development report. A total of 208 deaths have been accumulated so far. During the reporting period, there were 75 deaths at home and abroad. This trial was suspended from September 26, 2016 and has been notified by the Institute for reference. It was released on August 10, 2017 during this report period. In addition, there were no new safety or efficacy issues related to drug treatment, and no SUSAR was involved.
3) A copy of the Multikine Drug Safety Development Report (Development Safety Update Report No. 8, Date of Report: 16 Mar 2018, for the reporting period from February 4, 2017 to February 3, 2018) is sent to you for reference."
What it says is that 208 events where reported in Feb 2018, 75 more than Feb 2017.
It is useful in the sense that it allowed to predict a date for 298, a date which contradicted all previous publications for an early end for the trial published by Cel-SCI ("early Q1" or Ergomed's "H1" 2019), also the number was under the expected number so good hint towards efficacy