I'm aware, as I suppose you and pretty much everyone else is, that although you are replying and tagging me, you are on a forum and knowing your post will be read by others. And they have and they've ticked and great analysis ticked.
But I'm going to respond as just me to just you.
Sorry but I am going to sound long-winded.
I've no problem with long posts as such.
This is where I think you may be wrong, @JB1975.I'm listening, I note the tag @ and I not you word "may" and infer you must have read some of my posts and find they may or might be plausible but you offer another explanation and recounting of the sequence of events as you understand it. Fair enough.
Unlike small molecule drugs, ATMPs (advanced therapy medicinal products) including CGT (cellular and gene therapies) products are harder to standardise in manufacturing for obvious reasons, and potency testing is a much bigger deal for precisely that reason.Sure. My head nods in agreement.
At the heart of the current actions being undertaken by the company is the most important and outstanding CMC issue which the FDA have identified in the first CRL and the company is trying to resolve, not so much an efficacy issue anymore, as Dr. Krause was at pains to emphasise in one conference call last year after the surprise CRL (and I don’t think it is spin, with the long term data in the resubmission corroborating the ODAC expert 9-1 opinion in 2020 and probably being weighed almost as heavily as the pivotal trial data in the FDA thinking, given the FDA’s own use of and advocacy for real world evidence).
Not sure I accept that
that is the
heart of the
current actions. But I read what you wrote. My impression is that you might be giving too much faith in Dr Krause knowing what he is talking about. I think Dr Krause isn't a mesechymal stem cell potency expert like Matthew Klinker would be in my opinion (my opinion being based on reading Klinkers papers). And Mathew Klinker is the guy MSB needs to persuade - Dr Krause is more like the guy you might hire if you wanted to understand how the FDA works and perhaps get some behind the scenes back door communication. I think Dr Klause might have been involved in updating the IND file with potency assay stuff rather than submit the BLA as was originally planned earlier.
In short I don't credit Krause as having revelent (scientific and statistical expertise) in comparison with a) Matt Klinker and (based on my prediction of the 2nd CRL failure and the reasons for it ahead of time - me). (and my "expertise" is from reading papers like those of Klinker and others specifically to do with mesenchymal stem cells etc. - I wasn't born with it - I earned it by doing the work and the reading - and I claim it not on qualifications that can't be checked but on lines of reasoning laid out in posts on this forum that can be checked and date stamped - pfeifer has summarised some of my reasoning that was long and mostly overlooked when I wrote it to make it shorter and more concise - but the reasoning through the science and stats was mine - the posts are still there (you Irene respectfully aren't engaging with the science and the stats in your analysis that I can see - so you aren't engaging in a way that would really interest me if you said I was wrong in your opinion - you are more offering an account that reads to me like a rationalisation).
This is why the company has cited the relevant FDA regulation and emphasised the issue of standardisation needing to be addressed in its public release accompanying the CRL.
Shrug. The company may have cited some regulation to sound like they are imparting information to the market and engaging with something. But I don't think that means anything different to what I thought it meant before like in the post of mine you you are replying too.
With the subsequent Type A meeting to discuss the CRL having been attended alongside the company by people from the BMT-CTN, the well regarded keeper of real world clinical trial evidence, the weight given to the long term data would, I imagine (sic), have been given a further boost compared with that which went into the drafting of the second CRL in August.
The colored bits read oxymoronically to me. The BMT-CTM may keep a lot of records based on patient histories etc - but its the FDA that is the "keeper" of "clinical trial evidence" in the way that keeping matters. They decide on what the clinical trial evidence amounts to and whether it amounts to enough. They decide on whether a potency assay is validated in their view not with a separate issuing of a THIS_IS_VALID certificate but by approving a BLA which implicitly acknowledges their acceptance of the validity of potency assay. I disagree with pfeiffers reading here. I agree with whytee take here.
I don't recall who from BMT-CTM was at the meeting. I recall Levine and Ferrara from memory as the two key guys in the MAGIC consortium with the biometrics assays. Which they have patented from memory. I recall the substance of their biometrics assays.
For the purpose of approval any drug product obviously needs to have the intended effect, but it is more of a manufacturing or quality control/assurance issue that is being tested or considered by the FDA in the latest CRL ie. where the assay (or testing method) is administered before the product is given to the patient.
The yellow I agree with. The rest I think is comment for your own or other readers benefit - it contains nothing of interest to me - its too general and remote.
This helps resolve something that I, too, could not wrap my mind around previously, and that is, how the reverse engineering could or would work with the trial over a long time ago I went through that process a long time ago. Way ahead of both the 2nd CRL and ahead of the IND submission update. I could understand in detail how a change in antibody could produce differences and why it might be necessary to revert to a previously used antibody. An antibody might be described as a reagent. I wouldn't a reagent sounds like inorganic chemistry to me. But MSB might use it talking to the general public.
Hence, the requirements for the assay(s) to be robust and reliable, stability-indicating and able to differentiate between target and degraded product. I believe it is in the latter contexts, that the CRL can be taken as what some describe as a “soft rejection”.
Your description is too remote - too far removed and lacking detail to be of interest to me - you aren't wrong - you just aren't relevant enough specific enough about MSB actually proferred potency assay matrix. So I can't talk with you about it without teaching you a lot first - which I'm not willing to take the time to do now. But my old posts have stuff. Learn what TNFR1 does according to MSB and what IL2ralpha does according to MSB in their ODAC papers then you'll be readier to talk to me at a level I want to talk at. You can't see why I've got reasons (in my opinion) and you have rationalisation only (in my opinion) because you haven't dug into the science enough to see that yet.
I can be wrong on science and stats - but you can't show me I am unless you engage with me at that level. And from much time spent I've learned I can't take hotcopper holders that aren;t doing stats and science to do that when they don't want to go there. It wastes my time.
Then I went back to the work and substantial investment that, since 2020, the company has put into developing a matrix approach to the assay.The matrix approach - specifically involving TNFR1 and IL2ralpha goes back further than that - a long way further.
I think it was @Phaedrus who mentioned that this enhanced assay has been shown in large part to the FDA ie. not in full, and I have also read recently SI’s mention that the company can revert to the old potency assay in use during the pivotal trial. I have been trying to understand the context and reconcile the two.
When I want to read pheadrus - I read phaedrus.
I've discussed how it would have been possible to revert to an old potency assay long before 2nd CRL - I was giving MSB the benefit of just about all possible doubt - it was like I was trying to put meaningful detail to their obscure vague references to paint a picture that could possibly exist.
They've run out of room now. The science and stats pins them in now. You have to talk science and stats specifics to understand that.
Don't misunderstand - their is merit in much of what MSB have done - if they weren't hiding everything with obscurity - others could build on what they've done and if they had money they could - but they can't do the scientifically and statistical impossible - they don't possess a time machine. They need to generate more data from real patients (I'll say in my opinion - but its in my opinion much more than that its more like in my calculation (a calculation can be followed and errors pointed out if there are any)- but you have to go into science and stats to see the calculation and you haven't done that yet - you aren't and most MSB holders posting here on this forum don't engage at that level).
I remember quite distinctly Dr. Rose saying on one of the calls early in 202, shortly after he became the CMO, that the potency assay “has problems”. In retrospect, I think he was referring to that which has now been identified as a stability issue with the potency test, specifically with the reagent, itself (as opposed to the cells - this is public).
I've posted part transcripts on that. I know its public. I came up with a whole scenario to make sense of that. Its posted on this forum. But that only got them a chance at a second BLA submission - they flubbed that second BLA submission - they didn't fix enough of what needed fixing.
I'm just underlining some words in what you write below.
@Phaedrus has said in one recent post that it had taken the company almost 18 months to track down the source of the instability of the reagent but that the issue has, it seems only recently, been addressed - unfortunately it was not before the resubmission in early 2023. Perhaps this explains why the company started developing the (likely more expensive but) enhanced assay* but now, in order to address the FDA’s concern of a lack of an effective potency assay during the trial, SI is talking about the old approach again - I am guessing because they have resolved the issue with the test reagent. If in the company’s view, both assays work, then it should have a good chance of being able to produce consistency results in “comparability” studies in their “parallel strategy” because it opens up the possibility of (i) having a last shot at near term approval for kids’ GVHD by addressing the quality or standard of the trial product and (ii) paving the way for the current inventory to be used in the adults’ GVHD trial. I have done some research and now understand what they are trying to use to get the extra data, at a high level, to be a “bridging” analytical method. It is something that is normally used in the context of manufacturing changes to ensure that batches after the changes are still usable despite the changes, and it normally applies to already licensed products.
(Me now - "by high level" I think you mean at a remote lacking detail level. I want you to get to lower level of detail if you want to engage my interest to talk with your I think I got there a long time ago frankly - you are fairly new to MSB as I understand - a holder of a couple of years or so and a commenter here for about that long)
However, the concept seems now to be used by the company with the potency assay, in order to show that the commercial inventory is the same as the trial product, and can be used either to launch the kids’ product, or to be used in the adult trial. (This is where Dr. Krause has no doubt been adding a lot of value,
(excuss the blowing of raspberries from me - Krause has been wrong on everything that mattered since he joined when it comes to getting results. If I wanted to engage on a trivial analytic level I should scoff you should have hired Klinker the scientist not Krause - you should have hired the guy that knows rather the guy you hoped would help game the system)
and if you have been following my thinking so far,
(I have)
perhaps the reason why he has participated in the capital raising recently.)
(Yeah he got it wrong buying shares, he is getting good money for being there - pledge is closer to right on this - but sometimes too cynical imo)
They are attempting to link the product (likely to be retained samples) when the old assay was in use during the trial (to directly tackle the FDA’s issue with the lack of an effective product potency assay or test during the clinical trial, now that they have found the source of the problem) to the current inventory they initially prepared for commercial release using the enhanced assay and pending the approval they were betting on but did not come in August 2023.
I feel like you are putting together stuff like dachopper did - but doing it later. And like dachopper you are missing stuff because you don't dig deep enough in the science and stats. You rationalise what you want to be true rather than reason dispassionately form axioms and build up what you actually can know. Science facts can be known, but a person has to learn them.
The main reason, as I see it, for going down the adult trial, is a commercial one, as SI explained before.In the ODAC papers there is a statement from SI responding to questions from panelists about MAGIC biomarker data - that there is no difference shown
in that data from pediatrics to adults.
Previously, I got a sense that the company was reluctant to target Inctye**, the manufacturer of Rux, directly.
I didn't.
I never though it mattered one way or the other.
Unless they feel they have a fair chance to gain approval for children, they won’t have started thinking about activating this pre-conceived strategy of going for the adult market as well.
Wrong (imo) they have to go adult market to get data they can't get in the kids market because they've burned that bridge with all their statements and long association with Dr Joanne Kurtzburg - they've argued they can't do it in kids - thats its unethical and physicians won't do it - they are going to adults (if they can) reluctantly because they have to do it - ot because they want to - they would have gone kids first adults later and got ophan drug approval and protection if they could - they could not.
If, however, the FDA knocked back the potency data they are working on, pursuing a parallel strategy has the advantage of building further on (some may say, not having to write off) the value of the kids’ GVHD work.
@Pfeiffer1982 mentioned that the FDA does not validate potency assays.
And I disagree. They do implicitly when they approve a BLA. I understand what he is saying and why I think. But I think whytee's take is better. But thats better discussed by me with them.
In case don't get around to it though - Matt Klinker (and team at the FDA) will effectively validate (though not with a separate certificate) or keep failing to validate the potency assay (in its detail and iterations) on the basis of their assessment of its scientific and statistical merit --- in my opinion.
(20min delay)