The person I was referring to is Matthew Klinker (CMC at FDA)....

The person I was referring to is Matthew Klinker (CMC at FDA). You can listen to his comments at ~2:17' https://collaboration.fda.gov/p7ugr4bkfeat/
Or page 120 of the Minutes (PM)
"DR. KLINKER: Thanks for the opportunity to bring up one other issue that we talked about earlier. I'm the primary CMC reviewer, and there was some discussion earlier in this Q&A session about the potency assay and about control of the product. We discussed this in the morning, but I just wanted to clarify and reiterate FDA's position on the utility of that potency assay. The applicant has discussed the manufacturing changes made before the 001 study was conducted, that those manufacturing changes have made a product that's more potent and have used that TNFR1 assay to justify that claim. I wanted to clarify that, based on the analyses that were in the briefing document, the associations that they showed from that pool analysis of those three studies is difficult to interpret because of the different study populations and the concomitant medications, and the fact that the significance of this connection between potency and clinical effectiveness was not observed when they looked at just the 001 study. I wanted to also point out that while the TNFR1 levels are increased using the modern manufacturing process, the clinical effect, at least in the pediatric population, the applicant is saying that that is consistent. I wanted to just clarify that. There are still some questions about whether that potency assay is really getting to effectively measuring something that is associated with the clinical effectiveness."

Actually, this might be the position of the whole CMC team and he was just speaking on behalf of his team. By which Dr Itescu and Grossman responded with this slide on the RHS, the EAP 275 is showing result from a single lot (I assume the same donor?), but the cells were grown out using either the OLD vs OPTIMISED protocol, In the SAME clinical program (to controlled any differences that may occur between different recruitment criteria - addressing the FDA's argument Bolded above). Actually, this is the exact experiment that the FDA wants Mesoblast to do!!! The only weakness is that the number for the Optimized arm (n=14) is relatively small.

"My first impression reading this the first time was that MSB had done knock out studies on TNFR1 and I thought they'd reported and show slides on inhibition of IL-2Ralpha..."
Actually, you are right, Knock-down of TNFR1 and in vitro downregulation of IL-2a has been done and were reported to the FDA (I cannot find where I read that now). But the FDA still reject this result. I remember the that source cited the FDA saying along the line of: "the artificial knockdown experiment might not be representative of patient data, and that in clinical trials, the level of TNFR1 does not correlate with increased survival" I Don't know what data is the FDA referring to, BUT the RHS graph from the EAP 275 and the 440 patients data (LSH) speak to the "in vivo" efficacy to me.

The only thing I think MSB can do is to repeat the result of EAP 275 with the single lot (Donor cell), expand the cell using 1) optimised 2) original 3) a bad protocol from the literature; then measure the level of TNFR1, then culture with activated T cells from the SAME Donor (Important). IF the optimized cells has higher TNFR1 induced the highest T cell inhibition, then it's hard to argue the effect is not due to the Optimised cells. Even better, do the Knockdown experiment in these MSC as well. If this is not enough, GOD knows what is.

Despite the 9:1 votes, if we listen carefully, Dr Walters (3:31') and Dr Bumin (3:33') actually recommend a second RCT, If possible.
Dr Henrikhs voted NO (3:08'), but the way he compares cancer PFS (a weaker endpoint compare to Overall survival) to our 28-day Overall response is non-sense. Remember, we also have day 100 & 180 Overall survival. Survival is the ultimate outcome, the only thing that beats it is "disease-free survival", which is often achieved with patients treated with Rem-L (by looking at the overall reduced dose of steroid in the Rem-L arm of 1.1 on day 28, compared to non-responder of 1.7; both started with 2mg/kg, below). "The majority of patients treated with Rem-L (except 4) were completely weaned off steroid" said Dr Grossman


The rest of the experts are not biased guys. The criticisms were relatively fair. A couple of clinicians got the efficacy of other drugs wrong (alemtuzumab, Infliximab, and ruxolitinib), and they were all corrected by Dr Grossman. He really did a fantastic job!!! too bad he is no longer with us.

I know this is taking forever, but I can only hope that we get an Acc Approval in children under 12!!! I think I am happy with that, even SI was alluding to a post approval study (from 3:35').

Good luck to US! hopefully we hear something soon