It's all here:
https://www.fda.gov/media/143337/downloadI've put together my highlights, as follows. It's not perfect as I got over trying to make it perfect. You will get the point (or disregard as it's from me - if you don't have me on ignore - why don't you have me on ignore??!!)
ODAC meeting minutes Aug 2020. SI says:
2 In conclusion, remestemcel has a
3 well-considered consistent and robust manufacturing
4 process that uses well-defined release criteria.
5 We've identified two important product attributes,
6 TNFR1 expression and IL-2 receptor inhibition, that
7 have demonstrated a relationship to the clinical
8 performance of specific drug product lots. The
9 survival outcomes in our clinical development
10 program further inform determination of TNFR1
11 specification and IL-2 receptor inhibition in vitro
12 associated with in vivo reduction of immune
13 activation.
14 The optimization of product manufacturing
15 for remestemcel has resulted in greater potency of
16 these assays and improved clinical outcomes over
17 time. Data from our clinical development program
18 support that TNFR1 and IL-2 receptor inhibition
19 correlate with clinical outcomes and highlight the
20 importance of these clinical quality attributes to
21 ensuring the manufacturing process consistently
22 produces remestemcel lots of acceptable quality.
Then this gets said by the FDA - one of the experts - look it up to see who it was):
extremely complex,
FDA published a guidance2
document on potency tests for cell and gene therapy3
products. Ideally, the potency assay will
4 represent the product's mechanism of action.
5 However, for cellular products such as remestemcel6 L, the mechanisms of action may be very complex.
7 To test for potency of many biological
8 products,
we rely on bioassays, including in vivo
9 animal studies; in vitro organ tissue or cell
10 culture systems; or any combination of these. But
11
we can also rely on non-biological analytical
12 assays, which are methods that measure
13 immunochemical, molecular, or biochemical products
14 of the product outside of a living system. We
15 refer to these as surrogate measurements, and these
16 surrogate measurements can be substantiated by
17 correlation to a relevant product-specific
18 biological activity.
19
Our potency guidance included the use of
20 multiple potency assays also called the Matrix
21 approach. Because of the product's biological
22 complexity,
one assay may not be sufficient to
Then this:
DR. ITESCU: Look, that is an excellent
2 question. It's a very complex question. I think
3 you're suggesting that within a heterogeneous
4 cultured population there may be different levels
5 of expression from cell to cell to cell. That's
6 certainly possible. We're not analyzing single
7 cells here; we're analyzing population-based
8 analyses.
9
It's certainly possible there are10
differences, but those differences are unlikely to
11 be very large given that the population of cells
12 that we have, they're all treated the same way and
13 cultured the same way. At the end of the day, this
14 is an overall cultured process targeting the entire
15 population that's harvested.
16 MS. STORTON: And I will add to that.
17 Geraldine Storton here. I'll just add that we have
18 a specific dose per vial. So even though there may
19 be differences between cells, what we're looking at
20 is an amount per dose for the patient that has been
21 dosed based on their body weight.
22 DR. ROBEY: Right. But the point is that
1 you could have one cell in a hundred making tons
2 and the others not making very much, and
that could3
impact upon the effectiveness. It's just some food4
for thought.5 Another question that I have about your
6 presentation is that even though you've mentioned
7 colony-forming efficiency,
you don't really have8
that as one of your critical quality attributes,9
and it would seem to me that that would be a very10
important measure of the viability and11
healthfulness of the cell cultures.12 Do you actually do colony-forming efficiency
13 on a routine basis?
14 MS. STORTON: I will start and see if
15 Dr. Itescu wants to add anything. It is a measure
16 that we use as part of our extended
17 characterization panel at both the donor cell bank
18 stage.
19 Dr. Itescu, would you like to add?
20 DR. ITESCU: Yes. We certainly do routinely
21 measure see CFU-Fs, absolutely, and it's part of
22 the criteria we use to select the appropriate
FDA ODAC August 13, 2020
A Matter of Record
(301) 890-4188
102
1 donors that go through the donor cell bank stage.
2 And then of course we verify the CFU-F levels at
3 the donor cell bank stage, as well as the final lot
4 release;
a very important attribute, no doubt. We5
agree.
THE QUESTION WASN"T DO YOU AGREE, IT WAS, WHY HAVEN'T YOU YOU GOT THAT AS ONE OF YOUR CRITICAL QUALITY ATTRIBUTES???!!!
Why wasn't MSB across the FDA's potency guidelines? Why didn't MSB discuss those details to complete satisfaction during the rolling BLA? Why/how is MSB just now spending US$9.5M of shareholder's money on this? Isn't spending that money an admission of guilt or a major failing by MSB in the trial? They acted as if there was nothing left to do yet found a way to burn US$9.5M to meet the criteria within a year later as well as further meetings to fully be on the same page??
No one was up in arms after the ODAC 9-1 vote and MSB got knocked back, were they? Apart from SI.
Why are these people within MSB still holding their positions and entitlements? What would they have to do to be removed from their positions?
All IMO. Well, I've quoted others so it's not ALL IMO. Anyway, work it out yourself.
(20min delay)