The applicant developed Temcell in Japan, by in-licensing the technology of Prochymal developed by Osiris.
PMDA asked the applicant to explain quality differences between Temcell and Prochymal, based on the results of process evaluation and characterization studies performed on the transfer of the technology from Osiris, the US
The applicant’s response:
After the in-licensing of the technology from Osiris, the manufacturing process was changed 4 times until
Process D was established. Since comparability was demonstrated after process changes, the manufacturing process changes would not cause differences in quality attributes between Temcell and Prochymal. The results of in-process tests and specification tests were also similar between Temcell and Prochymal, thus demonstrating the comparability of Temcell to Prochymal.
Change control has been performed after the in-licensing of the technology and comparison of the results of in-process tests and specification tests indicated no apparent differences in quality attributes between Temcell and Prochymal. Nevertheless, it is difficult to conclude from these findings alone that Prochymal is comparable to Temcell manufactured through different processes by another manufacturer, because no adequate analysis of quality attributes has been performed for bone marrow aspirates as the raw materials of Temcell, nor have any sources of process variability been identified [see Section 3.4.2.].
Report on the Deliberation Results, September 2015 (pages 26 and 27).
https://www.pmda.go.jp/files/000215658.pdfOn pages 40-43 you will find studies 280 and EA 275 under "'8.4. Reference data (Foreign studies with Prochymal)".
These references can also be found on Ken Sakushima's (MD, MPH, PhD, Medical Reviewer,Advanced Review with Electronic Data Promotion Group, PMDA, Japan) presentation, "Regulatory Trends Regenerative Medicine in Japan", March 2017 pages 13-16.
https://www.pmda.go.jp/files/000226750.pdfPotency
Comparing the Report on Deliberation Results (referenced above), "3.1.4.2. Characterization of ex-vivo cultured hMSCs":
"The results of T-cell proliferation inhibition assay showed that ex-vivo cultured hMSCs inhibit human peripheral blood T-cell proliferation induced by anti CD3/CD28 stimulation and that the presence of a PGE2 synthesis inhibitor or an inhibitor of indoleamine 2,3-dioxygenase (IDO) reduces the suppression of T-cell proliferation by ex-vivo cultured hMSCs. These results indicated that at least the secretion of PGE2 or the induction of IDO production is involved in the suppression of T-cell proliferation by ex-vivo cultured hMSCs. The addition of IFN-γ, a Toll-like receptor (TLR) 3 agonist, poly (i:c), or a TLR4 agonist, lipopolysaccharide (LPS) resulted in concentration dependent increases in IDO1 expression, which had been hardly observed before the addition of these agonists,"
with a reference of Danilkovitch's work (Osiris. 2006), one of scientists developing the original Potency assay, outlining "Potency Markers Selected for Screening",
a few things look quite similar to say the least.
This led to the Osiris hMSC Key Characteristics for potency:
The above can be found on the PMDA website, "Potency Assays for Cell Therapy Products":
https://www.pmda.go.jp/files/000211291.pdf.
It was part of a presentation by Anthony Ridgway, P.hD., Senior Regulatory Scientist, Biologics & Genetic Therapies Directorate, Health Canada.
With the above in mind, when Makoto Murata MD PhD, who was also involved in the clinical development of Temcell, says, "Temcell®, an equivalent manufactured MSC product to remestemcel-L", "[Temcell], its real-world efficacy was found to be equivalent to that observed in a prospective study of remestemcel-L with strict eligibility criteria," and "Temcell, which has no generic name, is the equivalent manufactured MSC product to remestemcel-L, derived from unrelated adult bone marrow," (
https://www.sciencedirect.com/science/article/pii/S0006497119728249), I tend to believe him that the products aren't all that different.
Therefore, coming back to the information
@doctorwho2 has asked for, "efficacy data [from Japan] to improve our confidence", I think the data is comparable for reasons stated above and the fact that Murata notes that Temcell's real-world evidence is equivalent to data generated in a (targeted) prospective study of remestemcel-L should give confidence that the cells work and that the only thing missing now is to generate the data in the US in a format the FDA has been requesting since at least 2020.
The FDA didn't request MSB to resubmit the BLA when they did. The first CRL back in 2020 asked for demonstration of the relationship of potency to the product's activity in addition to "at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness." When MSB fixed up the potency assay (which forms part of the product development stage and generally doesn't get done via post-hoc analysis, trying to find an explanation why the cells did what they did when they did it in the sub-group of patients that they did it), they could have started the study as requested by the FDA, but opted to use post-hoc analysis instead. And with enough data on hand, that could have been enough to get the product approved. But apparently there wasn't enough data available according to the second CRL, or as
@JB1975 called it, without "confounding data."
(20min delay)