Not exactly sure how your pyramid is relevant in the case of BLA submission of evidence to the FDA that resulted in a CRL and a resubmission of new data based on collected data from the same trial/s, but looked at from a different angle that was not pre-defined.
The FDA is/was also questioning the material your pyramid is build of and Dr Rose admitted that the old potency assay used had problems, and they have now reverted to a new potency assay.
@JB1975 following up
on my post yesterday, the ODAC statements mentions a MAGIC cohort comparison:
https://www.fda.gov/media/140986/downloadWhilst you are correct, "
That study by Dr Joanne Kurtzberg was done prior to Dr Rose saying "the potency assay that we originally proposed had problems " #1 and 'we've reverted to a new potency assay'",
"Long after ODAC and the CRL was received", the data was not part of the BLA submission and was only properly analysed after the ODAC.
You can see it unfolding in the company announcements:
August 2021 Presentation
https://investorsmedia.mesoblast.com/static-files/4e340912-0cd4-4ea5-b486-faa32fa44fad31 August 2021
https://investorsmedia.mesoblast.com/static-files/a95c50ea-fe03-404c-825c-1566775f64da"attributes which we believe to be also relevant to COVID ARDS"
I found this here (source not associated with MSB) , "
A possible role for ST2 as prognostic biomarker for COVID-19":
ST2 as part of MAP formed port of [the]
"data [to] providefurther support for the proposed anti-inflammatory mechanism of action of remestemcel-L and its immunomodulatory activity [the poster called it "mechanistic evidence of immunomodulation'] in patients with SR-aGVHD, resulting in improved survival outcomes."https://www.globenewswire.com/en/news-release/2021/11/23/2340233/0/en/Operational-Highlights-and-Financial-Results-for-the-Period-Ended-September-30-2021.htmlNovember 2021 Presentation
https://investorsmedia.mesoblast.com/static-files/6ce9f92c-4d6a-44cd-b344-b2fa11df174631 December 2021
"the immunomodularity activity Mesoblast intends to measure for potency is a reasonable critical quality attribute (CQA) for the product, and the relevance of this activity to the clinical outcomes should be established"
https://investorsmedia.mesoblast.com/static-files/71f7b715-a029-47dc-af8e-8c8f09a4a96fMSB has acknowledged the FDA's input above (ODAC) and have extended the data which they believe now establishes "the relevance of the proposed in vitro immunomodulatory activity of remestemcel-L ('
potency assays currently in development appeared to be reasonable based on in vitro results provided in the briefing document, the in vitro activity of the product appears to be relatively well established') to the in vivo clinical effect of the product in the Phase 3 trial in children with SR-aGVHD, including survival and biomarkers of in vivo activity" ("
Clinically meaningful overall response and survival with remestemcel-L-treatment in pediatric SR-aGVHD are associated with changes in soluble and cellular biomarkers consistent with reduced inflammation and risk of mortality. These observed changes in biomarkers provide mechanistic evidence of immunomodulation"), which is what the FDA asked them to do ("
the relevance of this activity to clinical outcomes should be established").
Credit when credit is due. And if the potency assay(s) can be linked to ST2, Reg3alpha and MAP and can be shown to correlate with the clinical outcome of the patients (and the above ASX announcements suggest they can), then that is a job well done and should be enough in the eyes of the FDA to finally get approval (maybe even without a confirmatory trial, given the height of the hurdle that was placed in front of them).
(20min delay)