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Sorry for jumping in here.
You ask:
>>my question regarding CLSN is this----doesn't the FDA need to receive a NDA from Celsion before they will know what the results of the Phase III trial are-----and if the results show that for a specific subset of patients the PFS and OS exceed the goals set by the FDA in this study----wouldn't the FDA, given that doxorubicin is already approved---and we are talking about HCC----be justified in acting on that data.
So really 2 questions - 1) Does the FDA need an NDA and 2) Can it justify an approval based on a subset analysis?
1) Yes, an NDA would be needed for the FDA to take any action.
2) IMO no way. We had an SPA based on the entire HEAT trial and the second you try to justify approval based off only a portion of that trial, you are no longer under the SPA.
Now, companies do not NEED an SPA to get approval, but without it, you typically want two well-run ph3 trials with both being stat-sig. We have ONE, that failed (MT: "It wasn't even close").
Subset analysis may show that one group had brilliant results, but the FDA won't "believe" it until they run a ph3, placebo-controlled trial with that hypothesis built into the protocol.
IMO the "markedly" is being taken much too seriously. MT has a grandiose way of speaking sometimes.
Obviously, all the above is my opinion. I was one of the most bullish here since 2010, but I simply do not think that this story goes anywhere for at least 3 years. MLC is harder than HCC, and what are they going to do in ABLATE, start over? HIFU? RCW has a shot but that is 3+ years out, enrollment is very slow.
GLTA - hello to all the old bulls that might still be reading here.
-Trond
My comment on AF's hit piece:
(hello to all, been a long time. GLTA)
---
I was an uber-bull here, and am completely out the stock now.
However, your (Sobek's) point is a bit irrelevant. Based on their claimed MOA, it's not a spin-job of "extending RFA treatment beyond 45 minutes." I believe the point here is that the continued application of heat allows two secondary (and oft-forgotten) characteristics of dox to manifest:
* Its cell-killing activity is heightened by heat. Thus it’s even more effective than normal.
* It lowers the temperature of the surrounding tissue. This means heat-activated ablation is more effective, especially in the margin areas that otherwise would not be
completely ablated.
I am still not buying into the story here, but it does not surprise me that a longer ablation time is positively correlated with PFS and OS.
-Trond Hildahl
Pivotal wording:
This wording should not be miscontrued. Typically a drug needs 2 ph3 trial successes in order to be approved. Occasionally the FDA will approve based on one ph3 trial, and HEAT is one such trial.
Its use in the PR is neither positive or negative.
And may I say... FINAL-freaking-LY???? Can't wait until 5 tomorrow!
GLTA longs.
Trond
umiak,
Don't you agree that there are varying degrees of positive news?
For example, they PRed that ABLATE enrolled the first patient. Good news, it certainly is not negative, right?
They PRed that a HIFU trial was agreed on and would start early 2013.
Better news, right? We already knew ABLATE would happen, having verification of enrolling was good. But this was a totally different indication that seemed to take forever to get off the ground, so this news is *better*.
In a similar vein, knowing the FDA requested we skip ph2 is "good." Knowing WHY can let us rank how important it is.
LTG seemed to indicate that by itself this was very important. I attempted (in a very poor way) to say it was good-but-not-terribly important.
Let me try again.
I misrecall the exact post but at some point LTG said in his conversation with Jeff, he was told the FDA recced to skip ph2.
The reason given, that it was urgent to find a good treatment for HCC, is adequate but not important.
I'll go further. Later LTG said that the ph1 data was good enough to skip ph2. I'd like to know if [edited, got mixed up: LTG's words], or if those were Jeff's precise words.
IF Jeff said the FDA advised skipping ph2 BECAUSE the ph1 data was that good, then I agree this is of paramount importance.
BUT - if Jeff said the FDA advised skipping ph2 because it was urgent to find a good treatment for HCC - I'd argue it falls in the good-but-relatively-meaningless category. ANY treatment that has good ph1 data in HCC should therefore skip ph2.
I proposed an alternative theory, that FDA recced skipping ph2 because the ph2 and ph3 would be the same protocol, just with a larger N in the ph3, and therefore IF HEAT is successful, we's save about 2-3 years. THAT would qualify as meeting the urgency of finding a good Rx of HCC.
I probably lost 2/3 of you and I really don't care to argue anymore. We're (mostly) bulls here and all want HEAT to succeed. We'll know within 1 week, and I probably will simply spend the entire weekend starting tomorrow at noon in blessed ignorance of ALL social media conversation about Celsion, expecting a PR on Monday morning.
GLTA (except shorts)
Trond
You're right, a lot of words. *grin*
And end results is the same:
>>"Reason being is, HCC is such a serious problem, there is urgency in finding treatment"
Re-reading this, we made the same point. Saving those 3 years DOES equal stressing the urgency.
I guess my point was more along the lines of don't attach too much importance to it beyond that it IS a positive. The FDA suggested it in a discussion about the ph2 protocol. The company was planning a ph2, and the FDA suggested going straight to ph3, BECAUSE the ph2 would have the exact same nature as the ph3 would.
Please note if they'd shut their mouths, we'd have ph2 results, would know what to expect, and the SP would probably be $12-15 NOW, and we'd only be ~15 months into enrolling HEAT with results still 2+ years out.
Peace. As you say, only my opinion.
Please, please, please can we just get the freaking results with an early Monday morning PR scheduling a cc at 8:00 EST.
LTG,
WRT "After phase 1 results, it was the FDA themselves that suggested they move straight to a much larger trial...Phase 3"
...
I questioned this awhile ago because it seemed too good to be true. I am totally assured, personally, that it is true, with several people I trust.
HOWEVER,
>>"Reason being is, HCC is such a serious problem, there is urgency in finding treatment"
is IMO false - also based off interviews of those people who assured me the first fact was true...
The reason appears to be that ANY phase 2 trial that would have been conducted would have been structured almost exactly alike to HEAT, although probably with a much smaller N.
Even with an 80-or-so patient trial, the timing would have been only ~24 months less than we are experiencing now. So we would have gotten final ph2 results approx 1Q11, and only NOW been really gearing up with "final enrollment" for the then-to-be-conducted ph3. And that trial would probably not yield final results until eo2015 or so?
It sounds like in reconstructing the ph2 planning meeting, the FDA simply asked Celsion mgmt why they didn't simply run the planned study as a ph3 and save ~ 3 years. (Add in the fact that we are now registrational in Europe, China, S Korea, and Taiwan and the trade off doesn't seem so bad!)
You can believe or disbelieve this as you please. My point is simply that 1) yes the FDA initiated the suggestion to skip ph2 and 2) no, it is not nearly as important-sounding as it seems.
Best,
Trond
replying to both Rawnoc and Kris Kade here because I'm running low on posts for the day. :-P
KK: >>They [mgmt] indeed would be very surpised to find it's 50% more.
As would I. But as you noted, they are basing that off historical studies.
Look at http://jco.ascopubs.org/content/early/2012/12/26/JCO.2012.42.9936.abstract for a more recent example of a 95 patient RFA-only group that were up to 7cm and has around a TWENTY FIVE month median recurrence. (YES - I know it may be apples to oranges, just about ALL these stinking studies are. But it's <7cm which is a nice find since most RFA don't go beyond 5cm. And I am NOT claiming HEAT has that high a placebo.)
Mgmt is safe claiming 12, that's beyond question.
KK: >>Also I should add that a range from 12 to 18 still will meet the trial expectation. A 50% margin..a comfortable thought indeed
Ummm, yes. And at the beginning AND end of my post I noted that 18v26 would still be successful.
I THINK THAT HEAT WILL SUCCEED. I've said, blogged, and been on cc for 3 years thinking it will succeed. Just trying to make the point that 12 months is not sacred.
Rawnoc:
>>79 sites -- it's inevitable in my experience no matter how great/experienced/skilled the pool of experts, the law of large numbers inevitably has some incompetent baboons in the mix. There's going to be a few doctors or sites at least that simply suck no matter how hard you try and those sites/doctors are going to have patients with low PFS or even treatment failures.
Disagree. If you aggregate all sites that do RFA, sure. And honest mistakes happen. But to get your site hooked up as a clinical trial site you need better than baboons.
>>Those few incompetent sites will keep it under 18 months (worst case for investors) IMO.
IMO the better argument for 12ish is that treatment failures will be PFS = 0 and the RFA-only arm should fare worse for failures due to tumors > 5 cm. (assuming TDox follows dox rules and increases ablation margins while also cooling the tissues.)
Ugh, didnt want to get sucked in to the 12 month argument again.
MY POINT was that 1) DCup's model agrees with timing wrt both interim and final at 18v26 and 2) even with 18 we should be successful. You can disagree with DCups model if you wish (and I have reservations myself).
Best,
Trond
WRT "we expect no surprises" ...
How can you expect to be surprised? :-P
Seriously, we have beaten the 12 months to death. Like I said, no interest in opening that again. I expect 14ish personally, just think it's reasonable to keep an open mind.
DCups on [another board] has been very pleasant recently, willing to look at his models with a new eye. Posted today that running his model for 11/1/12 with about 400 events AND for 9/15/11 for 219 events both yield placebo at ~18 months and TDox at 26-27 months.
First please note that 18v26 is still successful for HEAT.
12 months placebo has been hashed out so much and I do not want to open that can of worms again. Suffice it to say I'm unwilling to assume it HAS to be 12 months.
My reply, FWIW:
Davis, I would not discount the two timeframes converging on 18 v 26/27.
1) that fits the projected median total time of 22-23 months or so.
2) a very narrow miss at interim fits with Kid's 19v27 post.
3) Several new studies that Sia and others have found make me rethink "12-months-as-gospel." One Chinese one-center study had 95 RFA-only, up to 7cm tumors with a PFS calculated around 25-26 months. Ouch!
4) Most important, having the two timeframes converge really makes my itch go away. If a model "fits" one timeframe but is out of whack for the other, there obviously is something wrong with the assumption in the model.
I'm still bullish, 18v27 would suffice for success, but especially here I'm scaling back any assumptions. My official estimate for your contest is still 14v24ish.
Drano,
"they can have the article all written up except for the exact figures, plug the figures in, make any changes needed in verbiage, and submit it. "
OK you're right. My bad. Can't wait for the article by next week or so.
WRT share price, I suspect a spike to $19-28 on reasonably good news. Great PFS I could see $30+ but I do not know if that is sustainable for more than a spike.
Over the next year there are multiple milestones between more partnerships, the NDA filing and acceptance, more products, other trials, and of course the macro. I have absolutely no predictions except $30-40 at some point and probably $40-60 after approval in Jan14ish. But then we need to prove sales and execution.
I guess I will predict multiple AF put-downs over the next year, lol.
All IMHO.
Trond
Question:
"Why do you think it would take a year? How do you know when an article was submitted for publication, and to what journal?"
Answer:
The data included in the journal would need to include all the data that needs to be sussed out over the next 6 months or so that it will take to file the NDA. The top line data we are waiting on is not all the data they will eventually generate.
It may not be a year, I said months-up-to-a-year+. After they review ALL the data and generate the data to be used in the NDA, they will then turn to publishing. It needs to be well-written, internally reviewed, then submitted, then peer-reviewed, then those reviews considered by the editorial staff, THEN scheduled for publishing. So please tell me how that gets done in the next couple days before they would release the top-line data?
I have no clue what journal and never attempted to try to guess.
JohnCM,
A little history:
Mgmt received updated event counts from trial sites. Through mid-2012 they were expecting data around the end of the year.
After the last DMC safety review in Sept12, they changed the guidance for "in January."
DMC has access to more data than the company gets and obviously told them eoy was not feasible but if there were ANY chance of going much later, they would have just said "in 1Q13." Because they went with January, and recently reiterated that to several shareholders, I simply have to believe it happens In January.
Drano,
You said, "So that is a perfectly legitimate reason to sit on data -- let the journal break it, then send out the press release."
The problem with that statement is that peer-reviewed journal publication will not take place for months, if not a year+.
We'll get data in January. Mgmt repeated that only a few days ago, and the recent Hisun agreement appears to have been dated 1/13/13. So even after signing this deal, they reiterated data in January.
Patience and Patients.
Oh I'm quite conversant with the walkdowns.
I'm just suspicious of the posts that don't get the call:share ratios correct and don't mention the downside of the raid thesis.
It was orchestrated, absolutely.
Couple notes:
If they bought 9K calls, that equates to 900K shares upon exercise, not the 9M you list in step 2.
If DITM calls bought, then exercised, they've spent $9.50+. Then they sell those for cascading $8-6... buying back their shorts for 6-8.
That means they are still out the $ for the days work.
That might work for one short, being short maybe the nearly 1M you show from the 9K call example. But we had 6M SI. I'd prefer to assume a smart short would simply hold those calls, hedging the origanal bad bet they made?
bioman:
You imply they will wait with top line data until they finish the NDA.
IMO impossible. They need to tease out "everything" they can from the data before even asking for a pre-NDA meeting with the FDA.
It will be ~5-6 months from topline data to filing the NDA.
The co. had said in 2012 "by the end of the year" until the Sept DMC meeting when it was changed to "in January." Mgmt recently responded to a question (Siavoche) and confirmed "in January" so I assume the DMC meeting is scheduled. So I do not expect any particular timing, and it could well fall into Feb by a couple days. (If a snowstorm occurs shutting down transportation right around whenever the DMC was suppose to meet, they'll simply wait a couple weeks.)
If its tomorrow, great, if not then it'll be later. But I am not playing with the Jan13 options so I have no dog in that fight.
GLTA, sincerely hope we do get news soon. As I memed on twitter, #HEATexhaustion.
BTW apologies for the OT post and having to have it deleted.
I have no particular allegiance to any mb and think its silly to ban information when a simply ggl search will uncover it anyways.
2nd of two posts from a different mb.
Initial had highlighting which makes it much easier to read, doesn't appear to xfer here.
--
"May I ask, based on your investment here, and your research and any SIMS you may have run on your own, do you have a prediction to HEAT and if so a brief explanation of how you got there? Thanks Has2"
It seems as though that lately, the more DD I perform, the worst my investments turn out so in that regard you’ll be happy to hear I haven’t run any models on CLSN (though I may this weekend if I have time).
I am long here with my purchase in the very low $2 range. Still haven’t sold any and, when push comes to shove, I would have to attribute my “hold” to managements bullish actions and my belief that it is, at least, possible that they were un-blinded to the interim data (either immediately after the IA or at some later point, perhaps upon full enrollment). I know many dismiss this, and they may be correct. Kid posted a well written argument against them being unblinded (I think either you or Trond reposted it here). He laid out the rational for blinding and made his case rather nicely. There is a flip side to his argument though, The FDA has, on occasion, allowed the sponsor access to interim data. Dendreon is a good example (and one where Fleming came out vocally AGAINST the unblinding). There are other lesser known examples, such as the recent Zytiga 301 and 302 trials. My point is, it happens. Perhaps not routinely, but on occasion it is allowed with the blessing of the FDA and a mechanism is detailed in the regs. The unblinding plans are detailed in the DSMB Charter, a document that is much more secret than the SPA or the protocol.
One argument FOR Celsion having had access (w/ the FDA’s blessing) to interim data is the very comments MT offered when they were denied the additional interim. He said (March 12 CC) the FDA said that doing so would risk the integrity of the trial (not a direct quote but the general gist). The main way the trial integrity would be at risk would be if the request for an additional interim was made with the knowledge of the interim efficacy data. In that case it would introduce a bias that was not quantifiable. The FDA hates that. So the denial is evidence (not proof) that they may have been unblinded.
Now, in the rare occasions where I think a sponsor HAS had access to interim efficacy data, such access was for the purpose of drug development (expedited filings) and care was taken to NOT let those at the sponsor involved with the trial to have access to the data.
I explored this in part with my earlier question about insider trading: if someone at the Sponsor (legally) had access to interim efficacy data would they be legally precluded from purchasing stock? I have given this much thought and conclude the answer is: No, they would not be precluded from buying. Suppose for an extreme example that the IA showed an HR or 0.55 and the p value approached or even crossed a stringent hurdle (say P=0.000003). The DMC would approach the Steering Committee at CLSN who might then consult with the FDA. The FDA might, correctly, counsel against stopping. The reason being it is possible that the PFS results do not actually relate to a survival difference. Ethically, the question about true efficacy is still open, and ethically they can continue to randomize patients to placebo and continue the trial. But now at least SOME at the sponsor would know. There is certainly no guarantee that the PFS results would not change at the final analysis with continued follow-up. Basically, they would know the interim but not the final results. The uncertainty allows more patients to be ethically randomized and it allows insiders to make purchases.
Now, I don’t necessarily think the above situation unfolded although the timing (delay) in the announcement of the IA1 “continue” is curious. I think it more likely (though certainly not definite) that the sponsor was allowed access to the interim data so that they could prepare their NDA. (in fact, didn’t they say recently that they have started preparing some sections? Or am I confusing that w/ another stock I follow).
Anyway, below is the FDA’s view on the Dendreon unblinding and how that trial was affected. It addresses most of Kid’s argument.
Interim analysis: A planned interim analysis occurred in May of 2008 after 247 death events had occurred. The hazard ratio, 95% confidence intervals were provided to the sponsor by the independent Data Monitoring Committee as per the IDMC charter. Since the primary endpoint was overall survival, accrual was completed and the study remained blinded, FDA does not believe that the study integrity was compromised by this procedure.
The reviewer goes on to reference the DSMB Charter (something we never get to see).
Reviewer’s comments: The IDMC charter version 4, submitted to the FDA, specifies that the IDMC will provide overall survival results (hazard ratio, 95% confidence interval) to the applicant. The study was closed to accrual before the date of the interim analysis. The annual report submitted in March 2008, confirms that the study was closed to accrual, and 466 subjects had received at least one infusion of sipuleucel-T or placebo. No protocol modifications were made subsequent to the submission of the interim analysis data; therefore, the integrity of the conduct of the study was maintained. In addition, the interim analysis did not result in unblinding of any of the study participants to treatment allocation for individual subjects; maintenance of the blind decreases the risk that management of the subject would be biased by the results of the interim analysis. Also, survival, the primary efficacy outcome measure, is relatively resistant to biased assessment. Furthermore, this review included confirmation of subject deaths by examination of death certificates and Social Security death indices. In summary, the applicant’s access to the results of the interim analysis is unlikely to have compromised the study integrity or the results of the primary efficacy analysis.
Would Fleming let it happen in a trial he was involved in? Probably not, but if it were allowed, he would insist that the trial investigators and enrollees not HEAR about it (his main objection to the Dendreon interim )
TL;DR: I guess that I want to believe that they either KNOW the interim efficacy data or they ARE OUT OF THEIR FRIGGIN MINDS for not diluting at these prices. So, I am holding (but I am well diversified)
Per request, 1 of two posts from a different mb.
Includes pictures of some docs, which don't seem to xfer, which is why I initially just posted the post #s.
"His [MT's] caution about an Interim halt was most certainly based on his knowledge of something but what that is we are all guessing. The powering of the interim, the OS needed at interim or at final to be seen or frankly another possibility would be that becasue the FDA permitted TD to go from P1 right to P3, isn't it possible that part of that agreement was to see HEAT through to final no matter interim numbers to establish full and unequivical safety since there was no P2 to establish safety signals, thus setting the bar so high it was virtually impossible but maybe TD came close hence the second look? All conjecture but interesting to say the least,"
I’d like to offer my perspective on this.
I doubt VERY much that they used standard OBF here at the interim. The FDA does not want PFS trials to stop at interims. Certainly not one stopped based on an alpha calculated at the “standard” 0.05 (2-sided) level - which would equate to 1-sided 0.003 hurdle at the 50% mark (slightly higher at 57% of information or whatever it worked out to – perhaps 0.00315).
I would not be at all surprised to learn that the stopping hurdle was in the neighborhood of 0.000003 (That was the START trial hurdle at 50% info fraction, they too had a SPA)
Why use such a strict hurdle for efficacy? Well, I think the main reason is that the FDA wants to see compelling (highly persuasive) statistical data, especially for a single registrational trial (especially one with PFS as a surrogate endpoint). MT basically said so much in his March comments about the “continue” explaining that the interim was essentially a surrogate of a surrogate and their expectation was “continue”.
Consider the recent approval of Inlyta: The FDA made it abundantly clear in their End of P2 meeting that they didn’t want to see the trial stopped for efficacy at the interim. However, ANY interim efficacy analysis requires SOME alpha adjustment (a cautionary note to DCTH investors – we will hear about this at their AC meeting, but I digress). How do you implement this? You assign a very stringent hurdle; still calculated using OBF methodology, but just not one based on a final alpha of 0.05.
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And how did they decide to implement these requirements? They used asymmetrical stopping rules. When they say they used a “fraction” of the alpha for efficacy at the interim, you can be fairly certain it wasn’t the “standard” fraction (0.003 or so)
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So, what’s the relevance? If they indeed used a very strict interim hurdle, Kid’s theory about the interim “continue” indicating the control arm is achieving at least 19 months is based on an erroneous assumption. It is possible that the control arm is exhibiting less than that, and such an outcome would still be consistent with the interim “continue”. (and of course, this argument says nothing about the chance that control is doing better than 19, it just argues that the continue doesn’t necessarily limit the control to “at least” 19 months – 12 is possible as is 25)
Weekend reading
I'd call attention to post #s 1246 and 1248 on InvestorVillage's celsion board. REALLY valuable stuff from AVII77, wrt DMC and what the company might possibly know.
Data timing:
IMO we will not get data in the coming week. Today is nine weeks from the announcement of projecting 380, and I figure it's 10-12 weeks to compile & report out. Personally, I think Jan13 calls were safe to sell but not to buy.
That is only my opinion and we could get data in 10 minutes.
LTG, I thought there was enough sarcasm there to make it obvious...
There're some idiots out there who would call the company to complain that we're 'late'. *sigh*
Really?? Call Jeff?!
It's January 11th and they promised results IN JANUARY. OMG - they are late!
lol...
Thanks for that.
Sorry, message double posted - edited to reflect that...
LTG, hope you don;t mind more "babble". :-P
First,
>>"I'm tired of all the dialogue and BS articles and am ready for the data release."
A-freaking-men!!! I've been in this sucker since March of 2010 or so. Way past time for resolution!
Second,
>>"the 380 event occurred around the time the company had projected from 5 years before..."
Clinical Trials keeps an archived version of every modification to trials that were ever made. In Feb 2008, the trial was expected to be over in Dec of 2009, with OS data available in ... Feb-2013 (next month!!)
When I started looking in 3/10, HEAT was supposed to be fully enrolled by the fall and the interim to be a couple months after that!
As enrollment dragged on ... and on ... and on... they kept pushing it forward, coming close to misleading investors about how enrollment was going.
It wasn't until after they increased enrollment to 700, having hit 600 last summer, that they were able to project "1H13". They then backpedaled that to "end of 2012", until the Sep-12 DMC review, when they solidified it to Jan13.
Since about 13 months ago, they have consistently underpromised and overdelivered. But they have definitely NOT been able to project with any kind of confidence from 5 years ago!
http://clinicaltrials.gov/archive/NCT00617981/2008_02_15
I notice you don't answer the question, because you can't.
2 person trial:
local progression at 9 months.
ex-hep at 16 months.
TTP (9) is less than PFS (12.5).
How can you argue this?
(of COURSE the numbers can be switched around, that is not the point. The point is you insist it has to be one way and I point out one simple way it can be the other. And local progression ALMOST always will have a lower median time than ex-hep. PLEASE note I'm not talking the number of events, as you tried changing it to once before. I am talking the time TO the events - which is the PFS that HEAT is measuring.)
OK - I am a non-paying member so this is my 15th and last post today. All I'm asking is you answer my question posed above. NOT the Oxford trial, or anything else, JUST THAT QUESTION.
He cited the study and then proposed an example. The example was DIFFERENT than the study.
GL at the game. I love poker.
Here's a very quick example. Two patients:
One has local progression at 9 months.
One has ex-hep preogression at 16 months.
I am saying that TTP (your definition excluding ex-hep) is 9 while trial PFS = 12.5
Thus TTP is less than PFS. What say you?
"Your example is wrong. You treated 5 people as 10 events. Impossible. No one person can have more than 1 event so your distribution made no sense. Each single person would have two numbers and the smaller number would quaify as the date the PFS event took place."
It's late so no jokes about reading comprehension. NGD made no such claim of it being the same 5 patients in his example. 5 patients with local, 5 with distant.
LMAO. Thank you no-dough-go. I wish I'd read your post before making my previous one. Would have saved me 10 minutes.
I will say PFS is hard to talk about, being both the event count and the duration!
No you're confused.
I said, "My point is that TTP will be lower than PFS. Do you disagree on this?"
And you reply, "And, yes, I absolutely disagree by light years that TTP would be longer than PFS. How can it not?"
So which is it? I believe you simply wrote it wrong from context, since the rest of your post deals with your objection.
Here's my example. Let's say TTlP (time to local progression) is around 9 months. TTdP (distant) is 11 months. TTexP (ex-hep) is 14. And death is about 30 months.
So TTP might be 12 months but PFS (including all components) would be extended out becuase of the (admittedly few) events triggered by death without tumor progression.
As you say, GOOD GRIEF.
Your reasoning is flawed when you say,
"(1) There's lots of ways a PFS can happen.
(2) There's only one way a TTP can happen.
Therefore PFS is far more likely to happen -- and SOONER -- obviously!"
The sooner is incorrect.
Yes PFS EVENTS will occur more frequently than TTP events. But the actual VALUE of PFS can be pushed out by the non-TTP events.
Regarding the other two posts you made after the one I'm replying to, why on earth do you keep talking about general HCC stats? I am talking about the population for HEAT. I am ignoring those because they say nothing about our central disagreement.
Again, from the 2Q12 cc, "In our target population, median time to progression is 12 months..."
Your point:
"(1) TPS does not equal PFS."
I'm assuming you mean TTP - time to progression?
So you are correct, they are not equal. My point is that TTP will be lower than PFS. Do you disagree on this?
"(2) Since the survival stats of 30 months matches their previous stats for general HCC, it's not what you think it is. Target population is HCC. It's a target POPULATION."
I concede the possibility. But I maintain since he talks about the trial AND Thermodox right before and after that commment, when he says population he means the trial population.
"OUR population" definitely connotes that he is talking about what TDox would affect, not a general HCC population.
We disagree on RFA-only PFS... but we both think it will succeed. That's good enough for me.
"(2) Mgmt NEVER said to "expect 12 months PFS" -- YOU did. You cannot show me a single link, image, CC quote, absolutely NOTHING that says 12 months and PFS. You're still running around in circles with the local recurrence only estimate that has NEVER been expressed as a PFS estimate by management. Just you."
In the first link you provided, the 2Q12 cc (http://seekingalpha.com/article/807791-celsion-management-discusses-q2-2012-results-earnings-call-transcript?part=single)
in MT's opening remarks he says,
"In our target population, median time to progression is 12 months with median time to death 30 months"
Pretty clear he says "our target population" - you agree that will be the HEAT population?
He does say TTP and not PFS. Since he does NOT break out local vs distant, that has to be meant as mgmt's assumptions FOR THE HEAT POPULATION.
TTP does not include death. But since death should occur after progression, using TTP as a proxy within the trial should be fine for our purposes.
IOW, if TTP (which is local AND distant) is 12 months, and death is 30 months, you are safe to say 12 months at best. It probably will be longer than that.
I repeat, yes the term used was TTP and you seemingly want to find an exact quote for PFS. But I fail to see how a worse TTP than other-event time can cause TTP to be less than 12.
OK - 9 v 28. I hope you're right.
"What we, and CLSN management, are rerferring to is statistics for LARGE tumors. You made the same silly argument Adam F made. You're both dead wrong."
*sigh*
1) So now you are speaking for CSLN mgmt.
2) Is that the royal we? Or who else are you speaking for?
3) My claim wrt management is simply that when they address the placebo patient population that is exactly what they are doing - talking about ALL the placebo patients, globally, in HEAT. So when they say they expect 12 months PFS from this group, they are NOT singling out the patients who will event from local progression. Otherwise every time they said it, every analyst on the calls would immediately ask, "well what do you expect from distant mets?" Contrary to your assertations that distant has been somehow missed, that question has been asked quite a few times.
4) Keep in mind for LARGE tumors (5-7cm) they still have to qualify for RFA being the correct initial treatment. This means a "perfect" patient elsewise - not near veins, probably 0 or 1 other tumors, etc. So a large tumor patient in HEAT probably will not have the terrible prognosis as the typical large-tumor patient in the regular world.
5) Please don't lump me in with AF.
6) I'd love to be wrong if it means you are right. The ONLY way I see you being correct though is if we have an abnormally large number of incomplete second ablations, meaning there's > ~15% of placebo patients who show a PFS = 0. And that will have its own set of problems if we go in front of the FDA with a large set of patients who did not go thru a complete ablation.
Again, I'm calling for about 14v24, with probably a month wrong either side.
Please tell me exactly what you are predicting, then?
Rawnoc,
You asserted that placebo PFS in HEAT will be "way under" 12 months. You provide nothing to back this up except saying mgmt has only spoken of local progression wrt 12 months.
I provided a section of the recent cc where MT says 12 months when talking about the expected placebo PFS in the HEAT trial. NO he did not specify "the overall placebo", but he's talking about the overall trial and he did NOT say "only local" in that section. Since he did NOT modify the wording in any way, I'm going to continue to believe mgmt is talking about overall stats, including local and distant, ex-hep mets, and death.
When challenged all you do is change the argument to what percentage recur. I'm not arguing that.
If you want some company provided stats on that, by the way, look at page 5 from the 'Presentation at the 2012 Annual Congress of the Cardiovascular and Interventional Radiological Society of Europe by Professor Ronnie T.P. Poon "Thermosensitive Liposome in Combination with Thermal Ablation"', available at http://investor.celsion.com/events.cfm.
This shows seven studies of RFA, with local recurrence averaging around 11% after an average of about 21 months follow up. Nothing here shows actual time to recurrence, but if only 7-15% recur after 21 months follow up, I hardly see where you can argue 50% in HEAT will recur in less than 12 months.
So what IS your prediction? It'd be nice to see a number rather than your "Way Under 12!!!!!" bravado.
"As to the rest of you post, it's just plain wrong. In one interview by one of the investigators he gave the example of a pancreatic cancer drug that only improves the mean progression by 3 weeks yet the FDA still approved it. 33% is not a "softball" since it stil represents months."
And pancreatic cancer is even worse than lung cancer. I'd be very willing to bet that approval you spoke of was for third line or further out? FDA always has to balance efficacy with safety, and we're talking a first line treatment here that could be in store for 12.5 to 35% of liver cancer patients worldwide. Better believe we'll be judged with a different eye.
Yeesh, every time I engage to try to counter some wild optimism I end up sounding bearish. Again, if its "way under 12 months" for placebo as you claim I'll be jumping up and down AND frst in line to congratulate you.
Any thoughts as to the enrollment issue?
WRT your #2 - the distant mets....
That has actually been the subject of almost all debate in the last 2 weeks on Ymb, SA, and IVmb.
Biotech Sage is basically a plant, just a large short trying to get out, on SA. But lots of awesome comments on the two bear articles. The issue is what other studies to use to try to compare results from - NOTHING is apples to apples.
If you look for roseny on the Ymb, a lot of his posts address the local v distant mets issue.
My own opinion is that distant will occur later on average than local, and so using local as a proxy is fairly conservative. As you say, death and ex-hep are even more rare.
I agree with some caution on your points.
RFA alone *is* curative.
In other words, if the ablation is successful, the patient walks out of the clinic with no (detectable) cancer.
As we all know, it is in the margins of the ablation zone that some micromets or actual tumorous tissues remain. And if those are not caught on the follow up visit, then those patients will almost certainly recur and pretty darn soon.
Adding TDox is 3x the ways effective. It lowers the surrounding temperature, making the ablation more effective. Heat increases the effectiveness of dox. And the dox obviously also helps kill cancer (and healthy) cells.
So either arm, if it doesn't happen in 12 months, it won't for QUITE awhile.
Agree on first line use with all RFA.
My second largest quibble with "much less" than 12 months (again #1 is getting the timeline to work with enrollment and interim/final event dates) that that we have an SPA. No way FDA would have given us such a free pass as to softball the placebo PFS. They work with the same data and trying to get 80% powered with 33% improvement ... just won't happen at <11 months or so.