banter and General Discussion, page-4650

Baz, if you were in the FDA's position of being asked to approve a specific product as was the case at 13 August 2020, but you had data in front of you which had caused you to have doubts, (we know this, that the FDA had doubts, from their statements see below for two examples from then) and then afterwards, after receiving a CRL, Dr Rose acknowledged problems with the potency assays, wouldn't that make you think in the FDA's shoes, hey those guys were going to go ahead if we'd let them back in August 2020 even with potency assay problems, so perhaps we'd better not cut them too much slack now? Perhaps we better insist on seeing a rock solid potency assay before not after granting a BLA with a phase 4 to confirm?

Wouldn't you think (in the FDA shoes) that when MSB comes to need more Donor Cell Banks to be generated beyond those they'd already had at 13 August 2020, that perhaps they'll go with a potency assay on new DCB's that isn't really good enough on the assumption that hey the product is nonetheless safe even if we aren't sure that its potent? And perhaps because they may have business pressures to ship product to get revenue?


1) "When unmanipulated lots of remestemcel-L( i.e. lots not treated with SiRNA/shRNA to reduce TNFR1) are used in similar experiments, TNFR1 levels do not correlate with in vitro inhibition of T cell proliferation" (page 7 FDA AM session briefing paper)

and

2) "Although studies in early product development showed that knockdown of TNFR1 expression in the product reduced in vitro immunomodulatory activity, similar knockdown studies using the current version of the product found that inhibition of T cell activation was not affected by TNFR1 knockdown.

There new results suggest the in vitro modulatory activity of the product is largely independent of TNFR1 expression. Also, TNFR1 levels of the product lots without knockdown do not correlate with in vitro immunomodulary activity"


I can see some possibility of the FDA being persuaded just barely if they get a plausible story on the TNFR1 expression problems (sorting out their above concerns) and data to corroborate what went wrong that maybe they could allow a post BLA confirmatory phase 4, but the problem with that is that MSB has very strong incentives to pump out product without a better potency assay in that scenario than they have currently if they do that. TNFR1 on its own (which is pretty much what they have as IL2Ralpha is poor) and on just 3 donors is very threadbare. And better potency assays (broader more reliable, multifactor potency assays) certainly seem possible. But they are likely to be comparatively more expensive.