$NWBO DD by sentiment_stocks post 1 Quote: S
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Posted On: 10/23/2020 11:54:52 PM
$NWBO DD by sentiment_stocks
post 1
Quote:
So there are other ways for DCVax-L to go to market. What is the chance of that happening?
I certainly think there are several pathways the company can use to file a BLA. Are they all sure fire winners? No, probably not. And each pathway's chance to gain FDA approval differs. But there are 4 RAs, and each one is going to have a choice in the process. And some of these RAs are the actual payers/payors in this process, and if they see a clear benefit for their citizens, they may be apt to make different decisions then those who are not.
There are likely other pathways to approval, but below are some of the ones that I think are possible. In the end, it'll likely be just one, but that'll be dependent upon what the unblinded data indicates. Below are those possible pathways that I think will get DCVax to market, and my explanations for each one. There are likely others, but I like knowing that the company has multiple options, and I think the rework of the SAP PRIOR TO UNBLINDING will help strengthen and define those options.
Stat Sig PFS (Primary) and OS (Secondary)
Obviously this is the grand slam home run pathway. As most of you know, I believe (I do not know) they allocated the alpha for this trial unevenly, not splitting it (.025 and .025), but giving PFS .02 and OS .03. Now, if the primary (PFS) is stat sig with .02 alpha (they need about 4 months separation between the two arms to achieve this), the .02 rolls over to OS. The trial protocol had established what is known as a "Closed Testing Procedure" (Avii had asked me to look for that terminology in the protocol quite some time back and yes, it is absolutely there in the 2013/14 versions). What that basically means is that the primary must be stat sig for the alpha allocated to it to roll over to the secondary, and if the secondary is also stat sig, all the alpha rolls over to the tertiary endpoints. But in this case, since only .02 was allocated to PFS (see August 2014 Enhancements PR), that leaves about .03 alpha to clearly put elsewhere. As I've explained several times, I think that was allocated to OS. That would allow the company to state both endpoints are independently powered (which they have stated), and they wouldn't say they split the alpha (as .02 and .03 clearly isn't split), and they haven't said that. So... this pathway would mean the data shows PFS is stat sig with about 4 months or more separation between control and treatment, so OS would be measured with a full .05 alpha then and it is stat sig, and the FDA will pretty much have to approve DCVax. With a full .05 alpha, the separation between the two arms doesn't have to be as large as it would need to be if they can't use the .02 initially allocated to PFS. And that's why I think they've spent the time and the money to adjudicate PFS rather than just abandon the endpoint. So if the unblinded data indicates stat sig PFS and OS endpoints, there will be little to nothing those who aren't invested can say to stop a pile on into this stock. I mean, they can say stuff, but no one will listen. And the pile on would likely be pretty massive.
PFS is not stat sig and OS is stat sig
This is obviously also a possibility. Most longs think PFS was messed up with pseudo progression. With adjudication using the latest immunotherapy criteria, hopefully PFS can come out stat sig, but it's also possible that may turn out to not be the case. But as explained in some detail in the previous "pathway", OS still has, IMO, a back up, and that is their "independent powering" that I suspect is something like .03 alpha. So ex and Avii have both told me that if that is how the alpha is allocated, then the separation for control and treatment needs to reflect somewhere between 6 and 8 months. That is harder to achieve, and would require a nice fat long tail. I personally suspect, but obviously do not know, that this is what LP has been gearing towards achieving - in the event that the previous pathway is not hit. I think the company hopes the first pathway is a slam dunk, but in the event that it isn't, this pathway should almost absolutely garner FDA approval.
So now, those are two pathways, both of which we have a good chance of achieving, IMO. I think that because with the first one, they will have adjudicated the PFS determinations based on the correct progression criteria. And we know that in February 2017, there were approximately 80 or so patients that hadn't even progressed, and so with such a large group of patients who were progression free still - 15 months since the last patient had been enrolled (which is 18 months from surgery) - it would seem PFS still has a good chance of being found stat sig. But in the event it isn't, by letting OS play out and the long tail develop, the math will favor a stat sig OS.
Now for more pathways....
Neither endpoint is stat sig, but there is clear separation between both arms (4 to 5 months)
Okay, here's where the pathway is still clear, but the possibility of approval is lessened. The market will likely not understand what has happened, at first glance, because it will see a very clear, appreciable separation between treatment and control, but still the trial is not stat sig. The trial will not have met what are their endpoints. Of course, that doesn't sound so great in a PR. So will there be a market pile in? Certainly not the same as there would be with the first or the second pathway I've delineated above. The pathway forward will likely be described in the SAP, and could still be presented as a randomized trial that's not stat sig, but the medical and treatment benefit is still visibly obvious and demonstrated, just not through traditional means. For the FDA not to approve this, they would likely face a great deal of public pressure and/or even outrage. So I think this pathway still has lots of promise, but the market may not see that initially.
PFS/OS not stat sig, but there are clear separations between EACH of three arms - control who never crossed over, control who crossed over, and treatment - and the separation obviously favors the later two
This is yet another pathway that the trial could request approval for based on the data. I'd suggest that the SAP will better define how this is done, and then the RAs will have to decide whether that is satisfactory enough for approval or not. Again, if the data shows very clear evidence of treatment benefit, then I think the odds of approval are still very good. Will the market get this? Maybe, maybe not. Will those not invested fight this in the market and on the blogs? Very possibly. In the end, and what's more important in terms of approval anyway, is what the RAs think of the data and this pathway.
PFS/OS not stat sig, separation between control and treatment is not as clear (2 to 3 months), but as a blended group (treatment and control combined), they beat all historical comparisons
So this represents yet another pathway forward. Is it as ideal as the first two? Maybe not. But the CAR-Ts were approved based on single arm trials, and those treatments even kill some people. DCVAx doesn't kill its patients, and for some number, it looks to extend life for a very long time when compared with all other available treatments. As a blended group, the blended data already beats Optune's, and that makes it difficult for an RA to not approve DCVax too. Still, this one could end up being fought out with an ADCom, or even in Congress, depending. I personally think the UK will still go for all of the above as I believe the prestigious UK neurosurgeons and neurooncologists there will fight tooth and nail to make that happen. And if that happens, it will look pretty bad if the FDA doesn't do the same and approve DCVax. So this scenario will likely not represent as easy a path forward, and there will likely be some fighting over the idea both in the market, and with the regulators. However, if the UK pulls approval through, then patients from anywhere will basically be able to access it via the UK. This will bring revenue into NWBO, and will, IMO, save the company, save the treatment, while the FDA and the EU decide what to do.
Neither endpoint is stat sig, the separation between the two arms is negligible, but there are 100 patients (the long tail) or about 1/3 of the patients, for whom the treatment is clearly a benefit.
Again, the pathway to approval is still possible, and likely defined, but this requires RAs to be on board with this. Again, I think the UK will be, and the FDA may have to be dragged along kicking and screaming, with some of the FDA on board with it, and others, not so much. IMO, all of the above still represent viable shots at approval because each of them still reflect a benefit to GBM patients, and that should be what's most important to the RAs.
Now this one represents yet another option that I would be remiss in not mentioning.
Methylated Subgroup Approval
Depending upon what the data shows, I think via the methylated patient data in the trial alone represent an excellent shot at approval as the treatment clearly appears to benefit this subgroup. It looks to help the unmethylated patients as well, as it certainly appears to prolong their lives, but not as many unmethylated patients made it to 36 months, so the FDA could get sticky about that. IMO, the unblinding will show whether the treatment was clearly a benefit to these patients or not, because if it is, it'll be mainly or all treatment unmeth patients who made it to 36 months.
And finally...
Neither end point is stat sig, the separation of the treatment and control arms is negligible, the overall data reflects little difference between this trial and historical comparisons
Well that outcome is unlikely to result in an approval. However, I think it's INCREDIBLY unlikely (maybe impossible) that the unblinded data will reflect this because we can already see from the blinded data back in November 2018 that there are almost 100 patients that lived to 3 years (28%), and half of them reached almost 5 years (14%).
So really, my ultimate point here is that, IMO, there are substantially more pathways available to the company than what most would consider the standard and obvious ones, such as the first and second options I've listed. These multiple options also increase the odds, again IMO, that RA approval is ultimately achieved, because even if the data doesn't work for the first pathway, there's still the second one, then the third one, and so on, and so on, with the backup pathways I've cited until we reach the last one, which I don't see as viable.
Now to be clear, it would likely just be one pathway that they ultimately move forward with, and that which one it is will depend on the data. But with so many options, I pretty much think filing a BLA is inevitable. It's the approval that will either be a clear cut yes, or it'll have to be fought over with some of the RAs.
Anyhow, these are just my thoughts on the matter of RISK, for what they are worth.
post 2
This is a post examining the new DCVax-L endpoints, likely alpha allocation, and the consideration of historical controls (same as external controls) new FDA Biological Products Guideline. The post that I’m replying to is one where I’d listed multiple pathways for DCVax-L to be successful and to get to market, and I think those may now be obsolete.
With the change in the endpoints listed on the EU GB site (https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/GB), we can now see the changes that were made to the DCVax-L trial that were set forth by the phone book-sized SAP that took about a year to write. And those endpoint changes establish new pathways forward that make most of the possible pathways I’d presented in this earlier post of mine basically irrelevant now.
So let’s look at these new DCVAx-L endpoints, and what they might mean when we receive our long-awaited top line PR, and how they might predict regulatory approval to a filed BLA (Biological License Application).
As many of us know, the previous PFS primary endpoint was to be measured applying an alpha of .02. This linked PR indicated this to be the case (https://nwbio.com/nw-bio-obtains-approvals-for-enhancements-of-phase-iii-trial-of-dcvax-l-for-gbm-brain-cancer/). Typically, most trials will use .05 alpha, and so it was my thought that the company had split the alpha allocating .02 to PFS and .03 to OS. It’s very possible the company went with the low .02 because if PFS been proven efficacious on that low .02 alpha, the FDA would have likely granted them AA (accelerated approval), and OS would have been the confirmatory trial to prove the AA was fairly granted.
Under the old protocol, had PFS been stat sig, the .02 would have then carried over to OS and OS would have been measured with the full alpha of .05. This concept of carrying over the alpha comes from the 2013 protocol for the trial which indicated that the endpoints were to be measured within the context of what’s known as a “Closed Testing Procedure”.
From 2013 and 2014 DCVax-L protocols:
Quote:
The primary, and secondary, and tertiary
endpoints efficacy endpoints will be reviewed. They should be considered
within the context of a closed testing procedure, and in the order of the
stated efficacy hypotheses, specifically the primary endpoint
(progression-free survival) first, followed by the secondary endpoint
(all-cause mortality) followed by the tertiary endpoint.).
Defining Closed Testing Procedure
This concept means that each endpoint is evaluated in the order they are stated, followed by the next endpoint, and so on. So if the first endpoint in a trial fails (under a closed testing procedure), and that endpoint had all the assigned alpha allocated first to it, then there would be no more alpha left to measure the next in line endpoint. In fact, this is exactly what happened to Dendreon in that 2007 BLA filing. Their primary of PFS failed (for whatever reason - psPD?) while the secondary OS was showing promise and I believe was indicating a few to several months difference in OS between arms. But there was no alpha left to measure that OS endpoint. I believe that is what that now infamous 2007 DNDN AdCom was set to argue… that in spite of the fact that there was no more alpha to measure OS, that DNDN’s Provenge should still be given marketing approval. And in that 2007 instance, the company lost that battle.
Now to be clear, so some people here don’t think I sound super smart with all this use of acronyms and alpha allocations, I wouldn’t know how to apply the alpha to the statistical formula, even if it could save my life (well, maybe then I could figure it out, lol). However… I do understand the concept of how alpha is applied.
So what exactly is alpha? In fancy words, alpha represents the probability of rejecting the null hypothesis (the opposite of the hypothesis) when it is true. Therefore, if a hypothesis looks to be supported by the data, and one used and alpha of .05 to determine the efficacy, that would mean that there is a 5% chance there is no difference between the data, and a 95% chance that the data indicates that there is a difference.
So what does the recently discovered change to the endpoints mean for the DCVax trial?
First, instead of measuring the previous primary endpoint of PFS at an alpha of .02, the trial will measure OS in the first position… but what is the alpha to be applied?
My thinking, and a logical assumption is, that the alpha will equal.05. So what does that extra .03 difference between the possible new .05 and previous .02 mean? If I’m correct and this is the case, it means that there is more power to successfully prove the trial’s hypothesis. The company likely had originally chosen an alpha of .02 to measure the primary endpoint (PFS at the time) for two reasons: first) to save .03 for OS in case PFS failed; and two) because the thought was likely that by using such a low alpha - .02 - and still achieving a stat sig PFS endpoint (which they thought they could do - had pseudo progression caused by DCVax not entered the picture), then the FDA granting accelerated approval (AA) would have been very likely.
Now let’s take this discussion of alpha further and apply it as it would likely be applied to the newly discovered endpoints for this trial. The primary endpoint is:
Quote:
The primary objective of this study is to compare overall survival (OS) between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma. This endpoint will be assessed using 3 different analyses
As stated, it’s logical to think that they’ve applied the full .05 to the primary as I can’t see any reason to just use half of it - like .02 or .03, especially given that they’ve picked an easy, IMO, to achieve endpoint so better to use the whole .05.
It’s also important to note that it’s the DCVax-L treatment arm which will be measured against the control arms of the three historical trials. I stress this because in the past, some stat people here have compared the blended trial data to the treatment arms of other GBM trials to see how DCVax compared - like to like. Some have hypothesized what the treatment arm data for DCVax-L might look like, but these comparisons were hypothetical, and not based on any actual data.
So it’s difficult to see where the DCVax-L treatment arm doesn’t compare extremely well against other comparable GBM trial control arms. To that point, the UCLA Phase 1 trial in newly diagnosed GBM using DCVax had a mOS of 35 months. The current DCVax-L trial’s protocol had assumed a mOS of at least 25.3 (from randomization, so about 3 months from surgery) therefore, that’s about a 28.3 mOS from surgery.
By the way, I’m only using the mOS measurement of survival as it’s an easier metric to discuss comparisons. I’m not suggesting that this trial will use mOS as the final measurement of efficacy, as medians are not what the trial measures.
Moving on, if this trial is still using the same “closed testing procedure” that the trial used in the earlier protocol, then should the primary end point be stat sig, then the full alpha (I’m suggesting .05) carries down to the following end point - the secondary endpoint:
Quote:
The first secondary objective is to compare overall survival (OS) between patients randomized to placebo who received DCVax-L treatment following disease recurrence and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.
Frankly, the company can project that this endpoint has a strong likelihood to be proven stat sig simply by looking at the blended data. I’m not going to go into great detail on that point at this time because I don’t want to wade into the weeds on that for now.
But I’d like to again point out a few things.
With the former endpoints, had PFS been stat sig using an established alpha of .02, it was my theory that this alpha (under the rules of the “closed testing procedure”) would have then passed on to measure OS. The alpha of .02 that had measured PFS would have been added to the missing .03 alpha to equal .05 to measure OS. The problem, as I saw it, was that if PFS had not been stat sig, then OS would have only had .03 left to measure the secondary endpoint. This concept is somewhat detailed in the post that I’ve responded to (which has been up in the yellow sticky section for some time now).
The beauty of this endpoint change is that this secondary endpoint will now, likely (remember, I am guessing here, but this seems logical, to me anyway), be able to access the full .05 alpha to measure this recurrent GBM OS endpoint. This endpoint is really similar to the earlier secondary endpoint from the original trial, EXCEPT, that the control arm will be historical arms, and not the control arm for this trial. And my bigger point is that this endpoint will likely be measured by the full .05 alpha.
I love that part.
Now, should this secondary endpoint be stat sig (which is likely), then the full alpha of .05, theoretically, would move down to the endpoint that follows:
Quote:
The second secondary endpoint, confirmed progression-free survival (cPFS), is confirmed disease progression (cPD) compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
This endpoint is very much like the original primary endpoint, except that now, all of the patients have had their progression adjudicated by a team of radiology experts that have (it’s already done) closely determined, on a blinded basis, when the patient actually progressed, and this endpoint will use that date. That’s why they’re calling it “confirmed progression-free survival”. This endpoint is hoping to remove the pseudo-progression problem, and to look at the real progression events for the trial patients.
Now… this may likely be very clear to some, and may be becoming clear now to others, this particular endpoint would now also be measured, not with that puny .02 alpha, but with the full .05 alpha. And to note, this is the alpha almost every trial uses to measure their endpoints.
And if this third in the line up of endpoints is also stat sig… and to my thinking, it would now have been measured using the additional .03 alpha to help ensure a better outcome - and that was not going to be used previously. So again, if I’m correct, then full .05 alpha would then move on to the next endpoint… and please note that this endpoint represents the original (let us call it the problem primary endpoint) primary endpoint measuring the trial’s actual arms from the previous trial protocol.
Quote:
The third secondary endpoint, PFS, is progression-free survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
And to drive home the point I’m trying to make here, if I’m correct, then instead of measuring the old primary with the originally intended .02 alpha, the old primary endpoint of PFS will now be measured with the full .05 alpha. See how that works?
Now I really love that part.
And finally, if this new endpoint (which was the former primary endpoint) is stat sig, and it would now also be measured using the full .05 alpha (and not the .03 I believe would have been used). In other words, the original OS endpoint will have now have more alpha to measure it now. then the full .05 alpha moves on to the next endpoint… which is exactly the former secondary endpoint of OS - comparing the actual arms in the trial. More alpha means it’ll be much easier to reach a stat sig reading.
Quote:
The fourth secondary objective, OS, is overall survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
Then there’s the final endpoint, the 5th secondary endpoint, which, under my theory, would be also be measured with the full .05 alpha if the 4th secondary endpoint of OS just discussed is stat sig.
Quote:
The fifth secondary objective is tumor response compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
To wrap up on the topic of these new endpoints, alpha, and closed testing procedures, I’d think most of us realize that these new endpoints are much more achievable, which takes away a great deal of risk from the trial. The former endpoints were a much greater hurtle to achieve a stat sig reading, meaning that on a fail, the company may have had a bigger mountain to climb to convince the regulatory agencies to approve DCVax-L.
That mountain has been trimmed down, IMO, more to like a little mole hill now.
Of course, this is all again, my own opinion. I haven’t seen the latest protocol… I doubt anyone outside has… and the only reason I had the others is that they were… conveniently (to the naysayers)… publicly leaked. So I don’t know that the alpha now being used to measure the primary is .05.
Now I’d like to make a quick examination at the recent December 2019 guidance that points to why these changes to the endpoints are likely to be acceptable to the FDA.
The guidance is entitled, “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products Guidance for Industry.”
https://www.fda.gov/media/133660/download
I’d like to do this because I know that there have been some naysayers, especially on Twitter, that seem to think that using a historical comparison in this trial will never work.
Let’s look first look at the FDA’s recent guidance pertaining to the concept of using “historical comparisons” in a trial that one hopes to use in order to obtain a marketing approval for a treatment.
The new guidance first addresses the risk versus benefit used in making an approval determination.
beginning at line 86:
Quote:
The finding of substantial evidence of effectiveness is necessary but not sufficient for FDA approval. The approval decision also requires a determination that the drug is safe for the intended use. As all drugs have adverse effects, evaluating whether a drug is “safe” involves weighing whether the benefits of the drug outweigh its risks under the conditions of use defined in labeling. Uncertainties regarding benefits and risks are considered when making an approval determination; a drug with greater risks may require a greater magnitude and certainty of benefit to support approval.
We can pretty much count on DCVax-L passing this “safety” criteria with flying colors. What that means, IMO, is that when the FDA looks at the evidence of efficacy, risk to safety will not weigh against any efficacy because there basically is no risk to safety.
Next, let’s look at how the FDA’s guidance approaches the concept of using a historical control as a basis for determining the effectiveness of a treatment.
In the guidance, the FDA points out that historical controls (also called “external controls”) have been included in the earliest descriptions of adequate and well-controlled trials (AWC).
beginning at line 179:
Quote:
Although randomized double-blinded, concurrently controlled superiority trials are usually regarded as the most rigorous design, as discussed further below, five types of controls are described in section 314.126:10 placebo concurrent control, dose-comparison concurrent control, no treatment concurrent control, active treatment concurrent control, and historical control (a type of external control).11 Of note, when the first version of the rule was published in 1970, historical controls and active treatment controls were included.12 Thus, from its earliest description of adequate and well-controlled trials, FDA included trial designs (as discussed below) that may be more difficult to interpret, which reflected FDA’s recognition that different trial designs (including choice of control) may be appropriate in different disease settings.
And here’s the footnote providing more extensive detail as to what is a historical or external control arm:
Quote:
11 The regulation uses the term “historical control,” which is a subset of “external control.” FDA also accepts other types of external controls. An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the trial, rather than to an internal control group consisting of patients from the same trial population assigned to a different treatment. The external control can be a group of patients, treated or untreated, at an earlier time (historical control) or a group, treated or untreated, during the same time period but in another setting. An important subset of externally controlled trials are “baseline controlled trials,” where there is not a specific external control group but assurance, based on experience, that no change could occur (e.g., tumors are known not to shrink spontaneously or patients not given general anesthetic remain awake). See International Conference on Harmonisation E10 guidance on Choice of Control Group and Related Issues in Clinical Trials (ICH E10). This guidance uses the term “external control,” except when referring to section 314.126.
This guidance then addresses using “external controls” - which, as noted above, historical controls are a subset of.
at line 221
Quote:
Externally controlled trials differ in several important ways from the other trial designs identified in 21 CFR 314.126. Most notably, random assignment is not a feature of external control designs. As a result, there may be differences in patient characteristics or concomitant treatments in the trial population compared to the external control population that lead to differences in outcomes that are unrelated to the investigational treatment. In addition, the lack of blinding could introduce bias. For these reasons, external control designs are usually reserved for specific circumstances, such as trials of diseases with high and predictable mortality or progressive morbidity (e.g., certain malignancies or certain rare diseases) and trials in which the effect of the drug is self-evident (e.g., general anesthetics).
In this passage the guidance states that problems with using external controls are that these types of trials usually don’t use “random assignment” (however, we know that the DCVax trial did use random assignment), and lack of blinding (and we know that the DCVax trial was quadruple blinded - quite literally). However, one will note that when these two stated problems (which this trial DOES NOT HAVE), these types of externally controlled designs are reserved for diseases with “high and predictable mortality… in which the effect of the drug is self-evident” (which one will also note, describes the GBM disease very accurately).
To that point, this guidance goes on to state,
beginning at line 231
Quote:
Despite the limitations of externally controlled trials compared with concurrently controlled trials, strong support for effectiveness can emerge from externally controlled trials, especially when
(1) the natural history of a disease is well defined,
(2) the external control population is very similar to that of the treatment group,
(3) concomitant treatments that affect the primary endpoint are not substantially different between the external control population and the trial population, and
(4) the results provide compelling evidence of a change in the established progression of disease.
Such results could include partial or complete response in a disease where spontaneous regression is not observed, or stabilization or improvement in function in a disease where progressive functional decline is well documented to occur over the duration of the treatment period in the trial. Another example of where there is strong evidence of drug effectiveness is reversal of clinical signs and symptoms following a toxic exposure or overdose after administration of a drug antidote. In all such circumstances, a detailed understanding of the full range of possible clinical outcomes, with a well-documented natural history of the disease in the absence of treatment, is essential to interpreting trial results and, therefore, drawing a conclusion about the effectiveness of the drug.
We should note that the guidance is quite literally stating that “strong support for effectiveness can come from these types of externally controlled (using historical controls) trials, especially when:
(1) The history of the disease is well defined - as is absolutely the case with GBM
(2) The external control group is similar to the treatment group - most historical arms will be similar, although some of them will have included pseudo-progressors from chemo/radiation (these are the typical longer livers in GBM) in their trial, whereas the DCVax-L trial did their level best to screen these types of pseudo-progression longer livers out of the trial.
(3) Concomitant treatments used are not substantially different between the treatment group and the external control groups - most GBM trials used the same SOC treatment (radiation and temozolmide; and some crossovers may have used Avastin ) that DCVax used.
(4) The results provide compelling evidence of a change in the established progression of the disease - even the blended data (including using even 30 or so non-crossed over controls) still shows compelling evidence that adding DCVax to the treatment mix has increased the life span by a greater percentage for many of the trial participants. The top 100 were showing a mOS of almost 5 years, for goodness sakes!
And the last part that I highlighted about evidence of drug effectiveness is when they see a reversal of clinical signs and symptoms following a toxic (toxicity is not a concern - but definitely after a dosing of DCVax, this trial may see a some possible clinical outcomes that can only be attributed to the effectiveness off the drug - e.g. pseudo-progression).
beginning line 247
Quote:
For example, compelling results may overcome challenges associated with less rigorous trial designs, such as those with an external control. As discussed above, a small externally controlled trial with an outcome markedly superior to the well-established natural history of a disease may provide a compelling case for drug effectiveness.
And in making the above stated point, the FDA guidance is signaling that compelling results - such as what we expect to evidenced in the DCVax-L results - should be enough to overcome any challenges to having used external controls to measure against the treatment arm in their new endpoints.
So anyone that is emphatically stating otherwise, must not be aware, or does not understand specifically what this new approach to historical or external controls that the new FDA guidance on Biologic Products is now signaling they're willing to accept.
post 1
Quote:
So there are other ways for DCVax-L to go to market. What is the chance of that happening?
I certainly think there are several pathways the company can use to file a BLA. Are they all sure fire winners? No, probably not. And each pathway's chance to gain FDA approval differs. But there are 4 RAs, and each one is going to have a choice in the process. And some of these RAs are the actual payers/payors in this process, and if they see a clear benefit for their citizens, they may be apt to make different decisions then those who are not.
There are likely other pathways to approval, but below are some of the ones that I think are possible. In the end, it'll likely be just one, but that'll be dependent upon what the unblinded data indicates. Below are those possible pathways that I think will get DCVax to market, and my explanations for each one. There are likely others, but I like knowing that the company has multiple options, and I think the rework of the SAP PRIOR TO UNBLINDING will help strengthen and define those options.
Stat Sig PFS (Primary) and OS (Secondary)
Obviously this is the grand slam home run pathway. As most of you know, I believe (I do not know) they allocated the alpha for this trial unevenly, not splitting it (.025 and .025), but giving PFS .02 and OS .03. Now, if the primary (PFS) is stat sig with .02 alpha (they need about 4 months separation between the two arms to achieve this), the .02 rolls over to OS. The trial protocol had established what is known as a "Closed Testing Procedure" (Avii had asked me to look for that terminology in the protocol quite some time back and yes, it is absolutely there in the 2013/14 versions). What that basically means is that the primary must be stat sig for the alpha allocated to it to roll over to the secondary, and if the secondary is also stat sig, all the alpha rolls over to the tertiary endpoints. But in this case, since only .02 was allocated to PFS (see August 2014 Enhancements PR), that leaves about .03 alpha to clearly put elsewhere. As I've explained several times, I think that was allocated to OS. That would allow the company to state both endpoints are independently powered (which they have stated), and they wouldn't say they split the alpha (as .02 and .03 clearly isn't split), and they haven't said that. So... this pathway would mean the data shows PFS is stat sig with about 4 months or more separation between control and treatment, so OS would be measured with a full .05 alpha then and it is stat sig, and the FDA will pretty much have to approve DCVax. With a full .05 alpha, the separation between the two arms doesn't have to be as large as it would need to be if they can't use the .02 initially allocated to PFS. And that's why I think they've spent the time and the money to adjudicate PFS rather than just abandon the endpoint. So if the unblinded data indicates stat sig PFS and OS endpoints, there will be little to nothing those who aren't invested can say to stop a pile on into this stock. I mean, they can say stuff, but no one will listen. And the pile on would likely be pretty massive.
PFS is not stat sig and OS is stat sig
This is obviously also a possibility. Most longs think PFS was messed up with pseudo progression. With adjudication using the latest immunotherapy criteria, hopefully PFS can come out stat sig, but it's also possible that may turn out to not be the case. But as explained in some detail in the previous "pathway", OS still has, IMO, a back up, and that is their "independent powering" that I suspect is something like .03 alpha. So ex and Avii have both told me that if that is how the alpha is allocated, then the separation for control and treatment needs to reflect somewhere between 6 and 8 months. That is harder to achieve, and would require a nice fat long tail. I personally suspect, but obviously do not know, that this is what LP has been gearing towards achieving - in the event that the previous pathway is not hit. I think the company hopes the first pathway is a slam dunk, but in the event that it isn't, this pathway should almost absolutely garner FDA approval.
So now, those are two pathways, both of which we have a good chance of achieving, IMO. I think that because with the first one, they will have adjudicated the PFS determinations based on the correct progression criteria. And we know that in February 2017, there were approximately 80 or so patients that hadn't even progressed, and so with such a large group of patients who were progression free still - 15 months since the last patient had been enrolled (which is 18 months from surgery) - it would seem PFS still has a good chance of being found stat sig. But in the event it isn't, by letting OS play out and the long tail develop, the math will favor a stat sig OS.
Now for more pathways....
Neither endpoint is stat sig, but there is clear separation between both arms (4 to 5 months)
Okay, here's where the pathway is still clear, but the possibility of approval is lessened. The market will likely not understand what has happened, at first glance, because it will see a very clear, appreciable separation between treatment and control, but still the trial is not stat sig. The trial will not have met what are their endpoints. Of course, that doesn't sound so great in a PR. So will there be a market pile in? Certainly not the same as there would be with the first or the second pathway I've delineated above. The pathway forward will likely be described in the SAP, and could still be presented as a randomized trial that's not stat sig, but the medical and treatment benefit is still visibly obvious and demonstrated, just not through traditional means. For the FDA not to approve this, they would likely face a great deal of public pressure and/or even outrage. So I think this pathway still has lots of promise, but the market may not see that initially.
PFS/OS not stat sig, but there are clear separations between EACH of three arms - control who never crossed over, control who crossed over, and treatment - and the separation obviously favors the later two
This is yet another pathway that the trial could request approval for based on the data. I'd suggest that the SAP will better define how this is done, and then the RAs will have to decide whether that is satisfactory enough for approval or not. Again, if the data shows very clear evidence of treatment benefit, then I think the odds of approval are still very good. Will the market get this? Maybe, maybe not. Will those not invested fight this in the market and on the blogs? Very possibly. In the end, and what's more important in terms of approval anyway, is what the RAs think of the data and this pathway.
PFS/OS not stat sig, separation between control and treatment is not as clear (2 to 3 months), but as a blended group (treatment and control combined), they beat all historical comparisons
So this represents yet another pathway forward. Is it as ideal as the first two? Maybe not. But the CAR-Ts were approved based on single arm trials, and those treatments even kill some people. DCVAx doesn't kill its patients, and for some number, it looks to extend life for a very long time when compared with all other available treatments. As a blended group, the blended data already beats Optune's, and that makes it difficult for an RA to not approve DCVax too. Still, this one could end up being fought out with an ADCom, or even in Congress, depending. I personally think the UK will still go for all of the above as I believe the prestigious UK neurosurgeons and neurooncologists there will fight tooth and nail to make that happen. And if that happens, it will look pretty bad if the FDA doesn't do the same and approve DCVax. So this scenario will likely not represent as easy a path forward, and there will likely be some fighting over the idea both in the market, and with the regulators. However, if the UK pulls approval through, then patients from anywhere will basically be able to access it via the UK. This will bring revenue into NWBO, and will, IMO, save the company, save the treatment, while the FDA and the EU decide what to do.
Neither endpoint is stat sig, the separation between the two arms is negligible, but there are 100 patients (the long tail) or about 1/3 of the patients, for whom the treatment is clearly a benefit.
Again, the pathway to approval is still possible, and likely defined, but this requires RAs to be on board with this. Again, I think the UK will be, and the FDA may have to be dragged along kicking and screaming, with some of the FDA on board with it, and others, not so much. IMO, all of the above still represent viable shots at approval because each of them still reflect a benefit to GBM patients, and that should be what's most important to the RAs.
Now this one represents yet another option that I would be remiss in not mentioning.
Methylated Subgroup Approval
Depending upon what the data shows, I think via the methylated patient data in the trial alone represent an excellent shot at approval as the treatment clearly appears to benefit this subgroup. It looks to help the unmethylated patients as well, as it certainly appears to prolong their lives, but not as many unmethylated patients made it to 36 months, so the FDA could get sticky about that. IMO, the unblinding will show whether the treatment was clearly a benefit to these patients or not, because if it is, it'll be mainly or all treatment unmeth patients who made it to 36 months.
And finally...
Neither end point is stat sig, the separation of the treatment and control arms is negligible, the overall data reflects little difference between this trial and historical comparisons
Well that outcome is unlikely to result in an approval. However, I think it's INCREDIBLY unlikely (maybe impossible) that the unblinded data will reflect this because we can already see from the blinded data back in November 2018 that there are almost 100 patients that lived to 3 years (28%), and half of them reached almost 5 years (14%).
So really, my ultimate point here is that, IMO, there are substantially more pathways available to the company than what most would consider the standard and obvious ones, such as the first and second options I've listed. These multiple options also increase the odds, again IMO, that RA approval is ultimately achieved, because even if the data doesn't work for the first pathway, there's still the second one, then the third one, and so on, and so on, with the backup pathways I've cited until we reach the last one, which I don't see as viable.
Now to be clear, it would likely just be one pathway that they ultimately move forward with, and that which one it is will depend on the data. But with so many options, I pretty much think filing a BLA is inevitable. It's the approval that will either be a clear cut yes, or it'll have to be fought over with some of the RAs.
Anyhow, these are just my thoughts on the matter of RISK, for what they are worth.
post 2
This is a post examining the new DCVax-L endpoints, likely alpha allocation, and the consideration of historical controls (same as external controls) new FDA Biological Products Guideline. The post that I’m replying to is one where I’d listed multiple pathways for DCVax-L to be successful and to get to market, and I think those may now be obsolete.
With the change in the endpoints listed on the EU GB site (https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/GB), we can now see the changes that were made to the DCVax-L trial that were set forth by the phone book-sized SAP that took about a year to write. And those endpoint changes establish new pathways forward that make most of the possible pathways I’d presented in this earlier post of mine basically irrelevant now.
So let’s look at these new DCVAx-L endpoints, and what they might mean when we receive our long-awaited top line PR, and how they might predict regulatory approval to a filed BLA (Biological License Application).
As many of us know, the previous PFS primary endpoint was to be measured applying an alpha of .02. This linked PR indicated this to be the case (https://nwbio.com/nw-bio-obtains-approvals-for-enhancements-of-phase-iii-trial-of-dcvax-l-for-gbm-brain-cancer/). Typically, most trials will use .05 alpha, and so it was my thought that the company had split the alpha allocating .02 to PFS and .03 to OS. It’s very possible the company went with the low .02 because if PFS been proven efficacious on that low .02 alpha, the FDA would have likely granted them AA (accelerated approval), and OS would have been the confirmatory trial to prove the AA was fairly granted.
Under the old protocol, had PFS been stat sig, the .02 would have then carried over to OS and OS would have been measured with the full alpha of .05. This concept of carrying over the alpha comes from the 2013 protocol for the trial which indicated that the endpoints were to be measured within the context of what’s known as a “Closed Testing Procedure”.
From 2013 and 2014 DCVax-L protocols:
Quote:
The primary, and secondary, and tertiary
endpoints efficacy endpoints will be reviewed. They should be considered
within the context of a closed testing procedure, and in the order of the
stated efficacy hypotheses, specifically the primary endpoint
(progression-free survival) first, followed by the secondary endpoint
(all-cause mortality) followed by the tertiary endpoint.).
Defining Closed Testing Procedure
This concept means that each endpoint is evaluated in the order they are stated, followed by the next endpoint, and so on. So if the first endpoint in a trial fails (under a closed testing procedure), and that endpoint had all the assigned alpha allocated first to it, then there would be no more alpha left to measure the next in line endpoint. In fact, this is exactly what happened to Dendreon in that 2007 BLA filing. Their primary of PFS failed (for whatever reason - psPD?) while the secondary OS was showing promise and I believe was indicating a few to several months difference in OS between arms. But there was no alpha left to measure that OS endpoint. I believe that is what that now infamous 2007 DNDN AdCom was set to argue… that in spite of the fact that there was no more alpha to measure OS, that DNDN’s Provenge should still be given marketing approval. And in that 2007 instance, the company lost that battle.
Now to be clear, so some people here don’t think I sound super smart with all this use of acronyms and alpha allocations, I wouldn’t know how to apply the alpha to the statistical formula, even if it could save my life (well, maybe then I could figure it out, lol). However… I do understand the concept of how alpha is applied.
So what exactly is alpha? In fancy words, alpha represents the probability of rejecting the null hypothesis (the opposite of the hypothesis) when it is true. Therefore, if a hypothesis looks to be supported by the data, and one used and alpha of .05 to determine the efficacy, that would mean that there is a 5% chance there is no difference between the data, and a 95% chance that the data indicates that there is a difference.
So what does the recently discovered change to the endpoints mean for the DCVax trial?
First, instead of measuring the previous primary endpoint of PFS at an alpha of .02, the trial will measure OS in the first position… but what is the alpha to be applied?
My thinking, and a logical assumption is, that the alpha will equal.05. So what does that extra .03 difference between the possible new .05 and previous .02 mean? If I’m correct and this is the case, it means that there is more power to successfully prove the trial’s hypothesis. The company likely had originally chosen an alpha of .02 to measure the primary endpoint (PFS at the time) for two reasons: first) to save .03 for OS in case PFS failed; and two) because the thought was likely that by using such a low alpha - .02 - and still achieving a stat sig PFS endpoint (which they thought they could do - had pseudo progression caused by DCVax not entered the picture), then the FDA granting accelerated approval (AA) would have been very likely.
Now let’s take this discussion of alpha further and apply it as it would likely be applied to the newly discovered endpoints for this trial. The primary endpoint is:
Quote:
The primary objective of this study is to compare overall survival (OS) between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma. This endpoint will be assessed using 3 different analyses
As stated, it’s logical to think that they’ve applied the full .05 to the primary as I can’t see any reason to just use half of it - like .02 or .03, especially given that they’ve picked an easy, IMO, to achieve endpoint so better to use the whole .05.
It’s also important to note that it’s the DCVax-L treatment arm which will be measured against the control arms of the three historical trials. I stress this because in the past, some stat people here have compared the blended trial data to the treatment arms of other GBM trials to see how DCVax compared - like to like. Some have hypothesized what the treatment arm data for DCVax-L might look like, but these comparisons were hypothetical, and not based on any actual data.
So it’s difficult to see where the DCVax-L treatment arm doesn’t compare extremely well against other comparable GBM trial control arms. To that point, the UCLA Phase 1 trial in newly diagnosed GBM using DCVax had a mOS of 35 months. The current DCVax-L trial’s protocol had assumed a mOS of at least 25.3 (from randomization, so about 3 months from surgery) therefore, that’s about a 28.3 mOS from surgery.
By the way, I’m only using the mOS measurement of survival as it’s an easier metric to discuss comparisons. I’m not suggesting that this trial will use mOS as the final measurement of efficacy, as medians are not what the trial measures.
Moving on, if this trial is still using the same “closed testing procedure” that the trial used in the earlier protocol, then should the primary end point be stat sig, then the full alpha (I’m suggesting .05) carries down to the following end point - the secondary endpoint:
Quote:
The first secondary objective is to compare overall survival (OS) between patients randomized to placebo who received DCVax-L treatment following disease recurrence and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.
Frankly, the company can project that this endpoint has a strong likelihood to be proven stat sig simply by looking at the blended data. I’m not going to go into great detail on that point at this time because I don’t want to wade into the weeds on that for now.
But I’d like to again point out a few things.
With the former endpoints, had PFS been stat sig using an established alpha of .02, it was my theory that this alpha (under the rules of the “closed testing procedure”) would have then passed on to measure OS. The alpha of .02 that had measured PFS would have been added to the missing .03 alpha to equal .05 to measure OS. The problem, as I saw it, was that if PFS had not been stat sig, then OS would have only had .03 left to measure the secondary endpoint. This concept is somewhat detailed in the post that I’ve responded to (which has been up in the yellow sticky section for some time now).
The beauty of this endpoint change is that this secondary endpoint will now, likely (remember, I am guessing here, but this seems logical, to me anyway), be able to access the full .05 alpha to measure this recurrent GBM OS endpoint. This endpoint is really similar to the earlier secondary endpoint from the original trial, EXCEPT, that the control arm will be historical arms, and not the control arm for this trial. And my bigger point is that this endpoint will likely be measured by the full .05 alpha.
I love that part.
Now, should this secondary endpoint be stat sig (which is likely), then the full alpha of .05, theoretically, would move down to the endpoint that follows:
Quote:
The second secondary endpoint, confirmed progression-free survival (cPFS), is confirmed disease progression (cPD) compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
This endpoint is very much like the original primary endpoint, except that now, all of the patients have had their progression adjudicated by a team of radiology experts that have (it’s already done) closely determined, on a blinded basis, when the patient actually progressed, and this endpoint will use that date. That’s why they’re calling it “confirmed progression-free survival”. This endpoint is hoping to remove the pseudo-progression problem, and to look at the real progression events for the trial patients.
Now… this may likely be very clear to some, and may be becoming clear now to others, this particular endpoint would now also be measured, not with that puny .02 alpha, but with the full .05 alpha. And to note, this is the alpha almost every trial uses to measure their endpoints.
And if this third in the line up of endpoints is also stat sig… and to my thinking, it would now have been measured using the additional .03 alpha to help ensure a better outcome - and that was not going to be used previously. So again, if I’m correct, then full .05 alpha would then move on to the next endpoint… and please note that this endpoint represents the original (let us call it the problem primary endpoint) primary endpoint measuring the trial’s actual arms from the previous trial protocol.
Quote:
The third secondary endpoint, PFS, is progression-free survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
And to drive home the point I’m trying to make here, if I’m correct, then instead of measuring the old primary with the originally intended .02 alpha, the old primary endpoint of PFS will now be measured with the full .05 alpha. See how that works?
Now I really love that part.
And finally, if this new endpoint (which was the former primary endpoint) is stat sig, and it would now also be measured using the full .05 alpha (and not the .03 I believe would have been used). In other words, the original OS endpoint will have now have more alpha to measure it now. then the full .05 alpha moves on to the next endpoint… which is exactly the former secondary endpoint of OS - comparing the actual arms in the trial. More alpha means it’ll be much easier to reach a stat sig reading.
Quote:
The fourth secondary objective, OS, is overall survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
Then there’s the final endpoint, the 5th secondary endpoint, which, under my theory, would be also be measured with the full .05 alpha if the 4th secondary endpoint of OS just discussed is stat sig.
Quote:
The fifth secondary objective is tumor response compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.
To wrap up on the topic of these new endpoints, alpha, and closed testing procedures, I’d think most of us realize that these new endpoints are much more achievable, which takes away a great deal of risk from the trial. The former endpoints were a much greater hurtle to achieve a stat sig reading, meaning that on a fail, the company may have had a bigger mountain to climb to convince the regulatory agencies to approve DCVax-L.
That mountain has been trimmed down, IMO, more to like a little mole hill now.
Of course, this is all again, my own opinion. I haven’t seen the latest protocol… I doubt anyone outside has… and the only reason I had the others is that they were… conveniently (to the naysayers)… publicly leaked. So I don’t know that the alpha now being used to measure the primary is .05.
Now I’d like to make a quick examination at the recent December 2019 guidance that points to why these changes to the endpoints are likely to be acceptable to the FDA.
The guidance is entitled, “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products Guidance for Industry.”
https://www.fda.gov/media/133660/download
I’d like to do this because I know that there have been some naysayers, especially on Twitter, that seem to think that using a historical comparison in this trial will never work.
Let’s look first look at the FDA’s recent guidance pertaining to the concept of using “historical comparisons” in a trial that one hopes to use in order to obtain a marketing approval for a treatment.
The new guidance first addresses the risk versus benefit used in making an approval determination.
beginning at line 86:
Quote:
The finding of substantial evidence of effectiveness is necessary but not sufficient for FDA approval. The approval decision also requires a determination that the drug is safe for the intended use. As all drugs have adverse effects, evaluating whether a drug is “safe” involves weighing whether the benefits of the drug outweigh its risks under the conditions of use defined in labeling. Uncertainties regarding benefits and risks are considered when making an approval determination; a drug with greater risks may require a greater magnitude and certainty of benefit to support approval.
We can pretty much count on DCVax-L passing this “safety” criteria with flying colors. What that means, IMO, is that when the FDA looks at the evidence of efficacy, risk to safety will not weigh against any efficacy because there basically is no risk to safety.
Next, let’s look at how the FDA’s guidance approaches the concept of using a historical control as a basis for determining the effectiveness of a treatment.
In the guidance, the FDA points out that historical controls (also called “external controls”) have been included in the earliest descriptions of adequate and well-controlled trials (AWC).
beginning at line 179:
Quote:
Although randomized double-blinded, concurrently controlled superiority trials are usually regarded as the most rigorous design, as discussed further below, five types of controls are described in section 314.126:10 placebo concurrent control, dose-comparison concurrent control, no treatment concurrent control, active treatment concurrent control, and historical control (a type of external control).11 Of note, when the first version of the rule was published in 1970, historical controls and active treatment controls were included.12 Thus, from its earliest description of adequate and well-controlled trials, FDA included trial designs (as discussed below) that may be more difficult to interpret, which reflected FDA’s recognition that different trial designs (including choice of control) may be appropriate in different disease settings.
And here’s the footnote providing more extensive detail as to what is a historical or external control arm:
Quote:
11 The regulation uses the term “historical control,” which is a subset of “external control.” FDA also accepts other types of external controls. An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the trial, rather than to an internal control group consisting of patients from the same trial population assigned to a different treatment. The external control can be a group of patients, treated or untreated, at an earlier time (historical control) or a group, treated or untreated, during the same time period but in another setting. An important subset of externally controlled trials are “baseline controlled trials,” where there is not a specific external control group but assurance, based on experience, that no change could occur (e.g., tumors are known not to shrink spontaneously or patients not given general anesthetic remain awake). See International Conference on Harmonisation E10 guidance on Choice of Control Group and Related Issues in Clinical Trials (ICH E10). This guidance uses the term “external control,” except when referring to section 314.126.
This guidance then addresses using “external controls” - which, as noted above, historical controls are a subset of.
at line 221
Quote:
Externally controlled trials differ in several important ways from the other trial designs identified in 21 CFR 314.126. Most notably, random assignment is not a feature of external control designs. As a result, there may be differences in patient characteristics or concomitant treatments in the trial population compared to the external control population that lead to differences in outcomes that are unrelated to the investigational treatment. In addition, the lack of blinding could introduce bias. For these reasons, external control designs are usually reserved for specific circumstances, such as trials of diseases with high and predictable mortality or progressive morbidity (e.g., certain malignancies or certain rare diseases) and trials in which the effect of the drug is self-evident (e.g., general anesthetics).
In this passage the guidance states that problems with using external controls are that these types of trials usually don’t use “random assignment” (however, we know that the DCVax trial did use random assignment), and lack of blinding (and we know that the DCVax trial was quadruple blinded - quite literally). However, one will note that when these two stated problems (which this trial DOES NOT HAVE), these types of externally controlled designs are reserved for diseases with “high and predictable mortality… in which the effect of the drug is self-evident” (which one will also note, describes the GBM disease very accurately).
To that point, this guidance goes on to state,
beginning at line 231
Quote:
Despite the limitations of externally controlled trials compared with concurrently controlled trials, strong support for effectiveness can emerge from externally controlled trials, especially when
(1) the natural history of a disease is well defined,
(2) the external control population is very similar to that of the treatment group,
(3) concomitant treatments that affect the primary endpoint are not substantially different between the external control population and the trial population, and
(4) the results provide compelling evidence of a change in the established progression of disease.
Such results could include partial or complete response in a disease where spontaneous regression is not observed, or stabilization or improvement in function in a disease where progressive functional decline is well documented to occur over the duration of the treatment period in the trial. Another example of where there is strong evidence of drug effectiveness is reversal of clinical signs and symptoms following a toxic exposure or overdose after administration of a drug antidote. In all such circumstances, a detailed understanding of the full range of possible clinical outcomes, with a well-documented natural history of the disease in the absence of treatment, is essential to interpreting trial results and, therefore, drawing a conclusion about the effectiveness of the drug.
We should note that the guidance is quite literally stating that “strong support for effectiveness can come from these types of externally controlled (using historical controls) trials, especially when:
(1) The history of the disease is well defined - as is absolutely the case with GBM
(2) The external control group is similar to the treatment group - most historical arms will be similar, although some of them will have included pseudo-progressors from chemo/radiation (these are the typical longer livers in GBM) in their trial, whereas the DCVax-L trial did their level best to screen these types of pseudo-progression longer livers out of the trial.
(3) Concomitant treatments used are not substantially different between the treatment group and the external control groups - most GBM trials used the same SOC treatment (radiation and temozolmide; and some crossovers may have used Avastin ) that DCVax used.
(4) The results provide compelling evidence of a change in the established progression of the disease - even the blended data (including using even 30 or so non-crossed over controls) still shows compelling evidence that adding DCVax to the treatment mix has increased the life span by a greater percentage for many of the trial participants. The top 100 were showing a mOS of almost 5 years, for goodness sakes!
And the last part that I highlighted about evidence of drug effectiveness is when they see a reversal of clinical signs and symptoms following a toxic (toxicity is not a concern - but definitely after a dosing of DCVax, this trial may see a some possible clinical outcomes that can only be attributed to the effectiveness off the drug - e.g. pseudo-progression).
beginning line 247
Quote:
For example, compelling results may overcome challenges associated with less rigorous trial designs, such as those with an external control. As discussed above, a small externally controlled trial with an outcome markedly superior to the well-established natural history of a disease may provide a compelling case for drug effectiveness.
And in making the above stated point, the FDA guidance is signaling that compelling results - such as what we expect to evidenced in the DCVax-L results - should be enough to overcome any challenges to having used external controls to measure against the treatment arm in their new endpoints.
So anyone that is emphatically stating otherwise, must not be aware, or does not understand specifically what this new approach to historical or external controls that the new FDA guidance on Biologic Products is now signaling they're willing to accept.
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