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Re: What happens if 88th event occurs before the minimal event number in the pseudo-progression group?
First, I think it is important to say this is unlikely. From my simple mathmatical analysis, they need 19 events from the group of 72. The pseudoprogression group (19 event accumulation) still has at least an 18 month jump on the additional 22 events that must ultimately come from the primary group. Even though all or almost almost everyone from the pseudoprogression group will be a responder 1st to chemoradiation then more so to DCVAX-L if they are in the treatment group, the chance for the primary group to fly by the pseudoprogression group in event tallies is unlikely.
Anyway, if it does happen, I think it would be best to chart how I think the DMC will organize things if the 88th event occurs in the primary group before the (probably 19) events occurs in the pseudoprogression group.
1. The DMC already analyzed the 66 events by themselves.
2. The DMC would analyze the 88 events by themselves.
3. The DMC would then get the 19 or so pseudoprogression events and analyze them by themselves.
4. Then they would take the 19 or so events and run a statistical analysis either on the 19 plus 66 together, or the 19 +88 together. I'm not certain which, because I'm not certain if they are trying to mimic the likely percentage one might see in a random global population or not.
That last part gets to a level of detail that I think only the statisticians can wrap their brains around, but the preplanned response to this unlikely scenario, should it occur, was likely already worked out by the FDA and NWBO on or before May 17, 2012.
Those are from the Phase I/2 trials, not the phase 3 trial. The 33 are from the early part of the phase 3 trial.
Also, there are more than 2 patients alive from the phase 1/2 trials, it's a matter of when they started (plus survival) as to whether they passed the 10 year mark or not yet.
Tomorrow?
240 will be enrolled in the primary group -- 2 treated for every 1 placebo.
72 will be enrolled in the separate pseudo-progression group -- 2 treated for every placebo.
That is, if we need to reach full enrollment.
There are 2 crossover arms.
There are 6 arms.
More than 66 events occurred by December 10, 2013 because they were not including the events in the pseudo-progression group of 72 to stop.
There is no way to tell what the enrollment is right now without NWBO coughing up numbers. There is no way to tell how many total events occurred by December 10, 2013 until we are told.
EOM.
Ima gonna plugga this one-a more time.
The Ken Burns Documentary on the history of cancer will air on PBS approximately March 2015….Go figure.
In the mean time, here is the preview followed by an interview with the NIH author of the book the documentary is based upon.
"Cancer: The Emperor of all Maladies."
Ken Burns PBS Preview
http://www.emperorofallmaladies.org
……………
Interview with Siddhartha Mukherjee, author: The Emperor of all Maladies.
Ou, I think I know how to help.
Let's pretend the pseudo progression group reached their minimal event number.
1. If the primary group reached statistical significance, but the pseudo progression group did not, then NWBO only goes forward with the primary data for FDA approval.
2. If the primary group reached statistical significance and so did the Pseudoprogression group, then NWBO goes forward with combined data for approval.
The goal is to get DCVAX-L approved for the correct types of patients it can help.
Do you know how many times the FDA and EMA go separate ways on drug approval? The German decision is just that, a German decision! It cannot tell the DMC nor NWBO what they need to know for their own decision they will be faced with making.
The FDA specifically provides a means for the transfer of interim data to occur for licensing applications while a trial is still going on.
The Germans made their decision based upon all clinical trial data to date.
IMHO, I think it is more likely than not that Germany legitimately examined phase III efficacy data to arrive at their hospital exemption and reimbursement decisions. Now they have enough information to negotiate price.
Are you dubious? Yes.
I respectfully disagree. The number of events to start analysis for the 1st interim review is 66. If they reviewed that group and found statistically significant efficacy would they recommend a halt? Not yet. IMHO they would then move on to the next step. They would analyze the very critical but perhaps only tertiary pseudo-progression group. If that group reached a sufficient number of events. Remember, they are like a separate trial, with their own randomization. (We learned this from a patient blog online.) Otherwise, what a waste to come that far and force another phase 3 trial on yet another pseudo-progression group (in my estimation, literally almost half of the DCVAX-L responders). No, that's not how a trial would be designed. IMHO. It would also make people all over the world with a pseudo progression response wait that much longer for commercially available DCVAX-l.
Think of it the other way around. The Pseudoprogression group finishes their minimal number of events first. No interim analysis will be initiated until the 66 events occur in the main group. Let's pretend the recommendation is a continue in the primary group after the 1st interim review, then there is no need to analyze the pseudo progression group at the first interim.
A proper design will save people from another phase III trial.
The DMC would not be violating the trial design because the separate group of (perhaps 72) pseudo progression patients are analyzed separately and not used to determine the primary endpoint. Instead they would be following the statistical rules for sequential analysis in a separate group.
However, in the end, they are necessary and very critical to come to a complete halt. The evidence must be compelling.
A very accurate recap.
Ming.
Not necessarily, the DMC trial protocol is designed by the sponsor. Separate analysis is baked into clinical trials.gov already, it would make sense to complete this analysis on the minimal number of pseudo progression group events before a recommendation is given.
Ou:
I did not ask you where you read the word "firewall" in the guidelines, I asked you if you knew what one was. You just cited a subsection having to do with external data and sponsor requests for interim protocol changes [Subsection 4.4.1.4]. You completely ignored all the subsection exceptions to access that I cited to you in my previous post on this matter.
For instance, let's go over section 6.5 and see where a "firewall" is recommended without using the word firewall.
Please pay special attention to the passages placed in bold.
6.5." Sponsor Access to Interim Data for Planning Purposes
Often, sponsors wish to have access to unblinded interim data for the purpose of planning product development, e.g., designing/initiating further trials or making decisions regarding production facilities. This interest is understandable, but such access is problematic for reasons already discussed. In general, sponsors are advised to avoid seeking information about unblinded interim data because of the significant possibility that they may wind up impairing trial management or even making the trial results uninterpretable by doing so. Further, plans or decisions based on statistically imprecise interim data may often be suboptimal. Where the sponsor nonetheless has a compelling need to review such information, certain approaches may lessen, although they do not eliminate, risks to the trial:
"….Identification of those sponsor employees with a critical "need-to-know" and restriction of such information to those individuals only.
Ensuring that individuals with access to the information avoid any subsequent role in the management of the trial and minimize interactions with others in that role.
Ensuring that individuals who have access to such information make every effort to avoid taking actions that will assist others in inferring what the information is.
Ensuring that reports of study findings describe any access to interim data by individuals involved with study management, and steps taken to prevent such access from potentially biasing the study results."
Now what would that fire-walled employee be allowed to do with that information? IMHO.
Section 6.5
"Often, sponsors wish to have access to unblinded interim data for the purpose of planning product development, e.g., designing/initiating further trials or making decisions regarding production facilities. " While this is "understandable" it is often "undesirable," however, if the sponsor has a "compelling need" they can use the firewall sections just mentioned to prevent problems. IMHO Another proactive step to avoid misstep is the following:
"Discussion of such an action with FDA in advance. This is particularly advisable when the sponsor intends to use the study in support of a licensing [Germany?] or marketing application."
Now how do you think NWBO is going to work with the FDA to make certain its licensing in Germany is properly handled. You got it, the PEI-FDA Commitment previously posted by Staccanni.
(Note: So the section you cited is protocol modification specific.)
Cancer: The Emperor of all Maladies
Ken Burns PBS Preview
http://www.emperorofallmaladies.org
……………
Interview with Siddhartha Mukherjee, author: The Emperor of all Maladies.
Sigh….do you know what a "fire-wall" is? I encourage you to read the guidelines all the way through.
As far as making sense….please read posts from the time the German announcement was made until now. There are multiple sensible reasons Germany would come before the DMC decision.
I suggest you might combine section 6.5 licensing parameters within the Guidelines with the FDA-PEI commitment. Combine that with the hospital exemption statutes and reimbursement contingencies and one can easily (IMHO) make the case that FDA and fire-walled NWBO people could legally facilitate the exchange of information for "licensing" purposes. It's just my opinion though.
Actually, it appears there are access paths for the FDA to access DMC data beyond safety. "Urgent concern" might at first sound like a catch-all for safety, but it is clearly delineated in the DMC Guidelines written by the FDA.
7.2.2. IMHO
"In rare cases, we may wish to interact with a DMC of an ongoing trial to ensure that specific issues of urgent concern to FDA are fully considered by the DMC or to address questions to the DMC regarding the consistency of the safety data in the ongoing trial to that in the earlier trials, to optimize regulatory decision-making."
Section 6.5 provides yet another avenue, IMHO
"Often, sponsors wish to have access to unblinded interim data for the purpose of planning product development, e.g., designing/initiating further trials or making decisions regarding production facilities…. Where the sponsor nonetheless has a compelling need to review such information, certain approaches may lessen, although they do not eliminate, risks to the trial:
Discussion of such an action with FDA in advance. This is particularly advisable when the sponsor intends to use the study in support of a licensing [Germany?] or marketing application…."
Section 7.2 also might necessarily give the FDA access, IMHO
7.2. Accessing Interim Data
"As discussed above, accessing interim data by the sponsor carries many risks, not all of which may be fully appreciated by the sponsor. We recommend that sponsors contact FDA before initiating communication with the DMC regarding access to interim data from a trial likely to be an important part of a regulatory submission. While FDA permission is not required, a discussion regarding the potential risks and implications of that action and of methods to limit the risks may contribute to informed decision making."
7.2.1 Terminating for efficacy also may give the FDA significant inroads to interim info, IMHO
"We recommend that sponsors of trials that could potentially be terminated early for efficacy reasons discuss these issues with FDA prior to implementing the trial….Sponsors are encouraged to revisit these issues with FDA when considering DMC recommendations for early termination if new issues have arisen and/or if the regulatory implications of early termination were not adequately clarified at the outset of the trial."
"[P]re-decisional information"
In the current context, that seems like the key phrase from the PEI-FDA Commitment.
(From Post #6332.)
Smith on Stocks has a good article exposing short-selling deception. It is subscriber only, but it does mention Cramer and AF. It seems to me the SEC may take another look at tactics used by those who can control the landscape via powerful media distribution. I know the SEC gets little respect from anyone anymore, but there is that old adage, when you least expect it….
Afford,
Please do not judge yourself. There are several different types of intelligence, and as you get older, you may start to recognize how valuable (beyond just monetary) your various gifts of intelligence are. We are raised to only grasp one or two types of intelligence, when the world needs another 5 to 50 more. Don't not discard your gifts. Wealthy or not, your money is not the only thing that defines you, and it may not define you at all. Thanks for everything you add to this board and the world around you.
Nice review. I knew that would be a ton of information, but I'm glad you found it worthwhile.
Happy St. Patrick's Day to one and all!
I agree Ou. I just added an automatic signature line to my new posts. See below.
Well articulated. It's possible both scenarios are in play.
It's mostly reeducation. No need to read, as you know almost all of it.
OK. My reason is that within the Pseudo-progression group, the events (aka: real progression or death) took longer than expected.
In my opinion, no one would dare go forward without completing a certain number of events in this Pseudoprogression subgroup that is basically its own trial.
Why is this?
Several years ago, pseudoprogression was not recognized as it is today. Previously, it was confused with true progression (and still can be early on), and the fact that it represented a response to chemoradiation treatment going on was slowly accepted in the field. Pseudoprogression is a visible way to see that the chemoradiation is working (it's not a necessary observation but it is a clear indication). Moreover, after phase I/II trials with DCVAX-L, it was determined that dendritic therapy even boosted this already responding pseudo progression group to unimaginable responses above and beyond the chemoradiation which was already helping. (I'm intentionally leaving out bogging this down with info overload re: the 4 subtypes).
Now, because there really is no confusion, once pseudo progression is accurately distinguished from true progression, this group will need to be treated with DCVAX-L.
So look at how the trial protocol changed over the years, particularly the changes in 2011.
The pseudo Pseudo-progression group is now in the trial, but it does not include the prior thirty three patients, so it got a late start, and it probably only draws from the 72 patients added in 2011 along with the pseudo progression protocol changes found in clinical trial.gov.
Even though they are not part of the primary endpoint, think about ending the trial before events in the pseudo progression group occurred. You go to the FDA with less ammo? No way! You go with both groups.
If you did not do this you might also lose the ability to treat this subgroup, which I think makes up almost half of the responding patients (in a normal population), until another trial was completed. Think NWBO would do that??? No way!
Waiting for the pseudo progression group to reach their # event point (which I calculate to be about 19 patients) is absolutely necessary.
It's taking longer because I'm almost certain 90% of the true progression or death events has to come from the placebo group. Pseudo-progression patients are likely the very same type of DCVAX-L patients that are still alive today that were treated 10 years ago. But remember, the placebo group still receives chemoradiation, which means that those patients are even responding to the SOC treatment better than average! So getting approximately 19 events from this group takes time.
During your vacation of sorts. Read the patent on direct, the Triozzi (Human less potent form of Direct) study and conversation on this board about both. See you on the other side.
I meant (inoperable and ultimately operable). I had them reversed.
One year, and it can start before phase 2a is complete.
There are some who believe the current phase I and II will be enough for FDA and EMA approval. This is because of the incredible results expected and the terrible position these patients find themselves in. I'm open minded on this optimistic projection, but I'll simply wait to see phase 1 results roll in before taking a solid position.
You answered my question correctly, as you already know. The trial was planned just this way. I cannot devise a better trial to avoid including SOC (chemo), get approval for all solid tumor cancers (operable and ultimately inoperable) and move it through a series of very fast trials so that it gets to the world in the shortest amount of time. Cheers to NWBO.
Be well.
Welcome to the board! I'm sorry you are leaving so soon.
Aha! Now you know why the running back makes the 20 yard pass.
Look at ClinicalTrials.gov. DCVAX-Direct. Do you see any standard of care immediately preceding or concurrent with treatment? Look at DCVAX-L on ClinicalTrials.gov and see how it looks when chemoradiation is added as part of the protocol.
Now you get it!
Ask yourself this question. Why are they foregoing Standard of Care? Why did the FDA allow them to forgo standard of care?
Why then am I suggesting Direct will charge more? I'll answer that one. Because they know it won't need to be combined with expensive chemotherapy.
NWBO won't release any planned protocol for the pivotal (i.e.. phase IIB/III) on Direct at least until we pass ASCO. It will be by (initial) direct tumor injection however, because in this technology, method of administration is as critical to efficacy as the treatment itself.
Pyrr, I only responded to part of your post last time. If you believe Direct only treats the injected tumor, and you believe Direct has no place in metastasized cancers, I humbly encourage you to read the on-and-off discussion about the Triozzi study this board had at the end of last year and the beginning of this year. Keyword: Triozzi Keyword: Patent
I think you'll be pleasantly corrected and happily surprised.
You also need to look at NWBO's past presentations regarding the maurine studies on direct, with special emphasis on long term immunity and Direct's effects on non injected tumors.
No, you were not necessarily right about the Germans not having access to the blinded data. There are firewalls set up in biotechnology companies so that the person speaking to the public usually does not have access to Section 6.5 details, FDA and PEI workings, and the like. Linda's comment is so carefully worded that it precisely fits the statements one would make on the blinded side of the firewall, and yet it still allows room for the alternative. This is to maintain the blind effect, enrollment potential and data integrity until the trial is officially unblinded.
IMHO, quick does not mean a couple years for each extension trial on Direct (perhaps on L which will become unnecessary IMHO -- and there will be no need for extension trials on Direct -- only post approval trials). The "discussion shifted," because as I have said before, their is an order to things. These 2 treatments are intimately related in NWBO's strategy.
Let me humbly present a homely analogy. Provenge is the blocking fullback. ICT-107 is the tailback.
DCVAX-L is the running back. Percy Harvin is DCVax Direct.
Provenge fakes getting the handoff and makes a critical block, the quarter-back pitches to the tail-back who does a reversal hand-off to the running-back who makes the 20 yard throw down field to Percy Harvin, Percy Harvin outruns everyone on the field. TD.
Let me suggest to you that Direct is already used on what you probably consider operable cancer. Go to clinicaltrials.gov and see how they broadly define "inoperable." Now ask yourself, is there a biotherapeutic difference in treatment response to DCVAX-Direct based upon whether the tumor is "inoperable" or not? Having answered "no", take it one step further. When both are on the market, Which one would you pick to save your life?
Also, if it's insurance you are concerned about with multiple cancer type treatment with DCVAX-L, let me suggest to you that all of Europe, Japan, Great Britain and many other countries already have the equivalent to " Germany's 4b hospital exemption" statute, and the United States is contemplating this in the very near future -- albeit having to work it through a different regulated insurance system.
Perhaps there is a happy medium. "Ethics" trumps "perfection" -- that's true -- but ethics must also weigh whether tens of thousands of people will have to wait for a second phase 3 trial versus waiting a little longer before unblinding this trial, and thus getting through the FDA and EMA based upon just one phase 3 trial.
They likely will not need to. First, there is off label use in the United States. Secondly, if you simply reject off-label use is an option before more DCVAX-L studies are completed on different cancer types, let me suggest that the Direct platform will beat any such post-approval label extension studies to the finish line. While safety is the primary endpoint in the phase I/II trial in Direct, Tumor regression and/or lack of progression is the secondary outcome measure. In any IIB/III pivotal trial for Direct, tumor regression would be the primary endpoint/outcome. This is the fastest route to approval there is in cancer trials. The events happen at lightening speed, and unlike the first phase of the Direct trial, there will be no first-in-human bottleneck protocol to slow it down -- and remember, direct is for all solid tumors.
I think it is important to point out that one cannot lump all members of NWBO on one side of the firewall or the other. In practice, from all the general rules, guidance and so forth i've read, some people within NWBO would likely be in the know regarding certain matters (i.e.., PEI and FDA conversations about data), and therefore screened off from the public (and other NWBO personnel), and others would be intentionally in the dark, so they can continue making public statements.
This is all done to preserve trial enrollment, the blinded study and data integrity. Thus, Linda Power's comment about what Germany based their decision upon is appropriately naive, while leaving room for other possibilities.