I'm glad you agree that the FDA's Graft-versus-Host Diseases: Developing Drugs, Biological Products, and Certain Devices for Prevention or Treatment Guidance for Industry (September, 2023 draft) is relevant to & may be "helpful for Mesoblast ".
I mean, it was prepared by the Division of Hematological Malignancies in the USA's Center for Drug Evaluation and Research (CDER) in cooperation with the Oncology Center of Excellence (OCE), the Center for Biologics Research and Evaluation (CBER), and the Center for Devices and Radiological Health (CDRH) at the FDA. I sure hope those guys know what they're doing - you know, read their own stuff etc.
You said: " Go to the section on "pivotal trials" and note they recommend that pivotal trials should be Randomized, Controlled and where posiible Binded. "
Well, I did that. Because you had me worried that I'd missed something.
And here's what happened: First, I went here as you suggested:
Now, this section clearly didn't apply to Mesoblast's BLA, since CEO Itescu has stated repeatedly that Remestemcel-l has NOT been sought to be marketed for first-line treatment of aGVHD - only for SR-aGVHD i.e after glucocorticoids (e.g. prednisone or methylprednisolone) have been used as treatment. GVHD-001, the pivotal trial in Mesoblast Ltd's BLA was directed solely at assessed SR-aGVHD patients.
If you're struggling with that one, this guidance from the FDA may assist:
But then, where to next? Well, the FDA was kind enough to provide this follow-on guidance:
Perhaps we should stop at line 764 i.e. if a highly effective paediatric SOC therapy is available Mesoblast Ltd should do that randomised thingy you keep banging on about. But, no.
It seems there is no highly effective paediatric SOC therapy available.
And as it turns out, there is no highly effective SOC therapy that is actually available.
In fact, we also find there is really no highly effective SOC therapy - much less an 'available' one.
Actually, on further inspection, there appears to be no effective SOC therapy. At all.
Why, why you say @whytee How can that possibly be ??!!
Well, it turns out it's simple. Really.
It's because there is NO SOC for SR-aGVHD, Much less an SOC for PAEDIATRIC SR-aGVHD.
There's just no standard of care for this specific indication in the entire world of medicine. At all.
If you or I were competent medical practitioners, then of course we would already know this, and wouldn't have wasted time or be WASTINGANYMORETIME considering this point further.
NB: I did check the opinion of Dr Paul J. Martin, of the Division of Clinical Research, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA. Dr Martin is a Board-certified oncologist & a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center as well as being University of Washington Professor of Medicine and Oncology. He was kind enough to publish his opinion and advice - you can find it here: Martin PJ. 'How I treat steroid-refractory acute graft-versus-host disease." BLOOD. 2020 May 7;135(19):1630-1638. https://ashpublications.org/blood/article/135/19/1630/452748/How-I-treat-steroid-refractory-acute-graft-versus
I'll extract from Dr Martin's comprehensive advice as published in the eminent peer-reviewed Journal Blood. In his own compelling words:
" ..Truth be told, I do not know how to treat SR-aGVHD. "
Okayyyy...not looking good.. but lets check again. I mean it's only 1 American guy, right?
Alright, here's one from Drs Malard F, Huang XJ, and Sim JPY. , in LEUKEMIA. 2020; 34(5): 1229–1240 called ' Treatment and unmet needs in steroid-refractory acute graft-versus-host disease" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192843/ . Lets see what they say. Ahem:
"...TREATMENTS FOR SR-AGVHD There is no accepted standard-of-care treatment for SR-aGVHD [11, 34]. .... "
Wow. Hey they cite this other guy - Dr Zeiser - @whytee have you ever heard of him? He does a lot of research for Novartis and Incyte, apparently. Huh. Hey, aren't they the Ruxolitinib people? Yeah. Bummer, when the randomised thingy was (almost) looking, ..well not actually 'good', but maybe 'not quite so really inappropriate', hey.
But since you and I (unlike Drs Martin & Malard et al) are totally ignorant & know nothing of medical practice, much less modern GVHD research, let's move on & look at our little diagram again. You might get lucky @whytee and have your 'gotcha' moment yet.
Well now. What do we have here at line 767?
The FDA (CBER) is willing to say a BLA "might be supported by positive results from a single-arm trial".
Alright then! Positive results from a single-arm trial - Check. Refractory disease - Check. No available (i.e. appproved) therapies - Check.
But hold on. Hold on. Hold on. They only say "might". I mean, they might, but they might not.
To get the final tick from the FDA the "sample size of the trial would need to be sufficient to show a meaningful clinical benefit & exclude an overall response rate (ORR) that is not meaningful for the intended population".
There's that word 'sufficient' again.
How fortunate MSB holders are then that CEO itescu was able to advise all attendees at & listeners to the MSB AGM held on November 27, 2023 that Mesoblast has held meetings with the OTP people at the very highest level (including Dr Nicole Verdun MD) and that the FDA has " acknowledged that the pediatric Phase III trial was an adequate and well-conducted trial and would have been sufficient for approval, but for the lack of a potency assay without variability "
I can't thank you enough for pointing all this out to me @whytee. Joking, joking. I think you're a real prick - if you want to know why, reread this post, the references & the FDA's recent Guidances in full on your own nickel.
(20min delay)