Ddwn - I’ll give you my take on this “complete” and “accepted” issue.
“can you explain to me why the FDA accepted the BLA resubmission then? did Mesoblast submit a Complete Response to the original CRL or not? If not, then why did the FDA accept this resubmission? I’m confused!”
The timeline.
December 2021 – potency assays will be sufficient; no trial needed.
“By demonstrating the relevance of the in vitro potency assay to clinical outcomes, Mesoblast believes it will be able to show that the remestemcel-L product used in the Phase 3 trial in pediatric SR-aGVHD was standardized as to identity, strength, quality, purity, and dosage form, and that this will address OTAT’s recommendation for an additional adequate and well-controlled study.”
October 2022 – IND updated - potency assays predict consistent outcomes.
“The submission summarizes controlled data providing further evidence of remestemcel-L’s ability to save lives” said Dr. Silviu Itescu, Chief Executive of Mesoblast. “Additionally, the improved process controls we have put in place to assure robust and consistent commercial product, together with a potency assay that predicts consistent survival outcomes, makes remestemcel-L a compelling treatment for these children.”
November 2022 – 4 year survival follow-up.
“today announced top-line long-term survival results for remestemcel-L from its pivotal Phase 3 trial (GVHD-001) in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD). The results showed durable survival through 4 years of follow-up. These new long-term survival data are a key component of the company’s BLA resubmission to the FDA.”
March 2023. – resubmission complete and accepted.
“the United States Food and Drug Administration’s (FDA) Office of Therapeutic Products (OTP) has accepted the Company’s Biologics License Application (BLA) resubmission for remestemcel-L in the treatment of children with steroid-refractory acute graft versus host disease (SR-aGVHD). FDA considers the resubmission to be a complete response and has set a Prescription Drug User Fee Act (PDUFA) goal date of August 2, 2023.”
Now ddwn … think back.
Why did MSB do the MAGIC study during the previous rolling BLA?
The reason was that the FDA had rejected the method MSB had used to generate the control group estimate from the single arm trial. MBS was asked to provide confirmatory evidence for the estimate.
According to MSB MAGIC was great success and things were apparently getting better by the day. The single arm trial had met the primary endpoint and now a “independent and unbiased” MAGIC estimate had confirmed the control group estimate.
The truth was things were going from bad (the original control group estimate had been rejected) to disastrous (the MAGIC patch to the estimate was about to be rejected). Obviously you should never be going back years after a single arm trial has completed to retrospectively calculate a control group estimate.
History repeats.
In December 2021 MSB believed the potency assays would address the need for another trial. This was rejected by the FDA after the IND was updated.
Krause puts his thinking cap on. What goes in the box where the “at least one randomised control trial” is supposed to be?
Lets try a four year updated survival analysis. The resubmission became “complete” there is the “new” clinical trial evidence. Not just potency assays predicting consistent outcomes.
But it was extremely weak. The FDA had already told MSB it wasn’t interested in survival analyses from the single arm trial because these analyses were difficult to interpret and seldom reliable. The 4 year follow-up survival data could never act as the substitute for the “at least one randomised controlled trial.
But there was nothing else (other than doing the trial which they couldn’t do because the potency assay / CMC issues hadn’t been signed off) to make the application “complete”.
It was “accepted” so that the FDA could review the potency assay / CMC issues to enable MSB to do the further trial they had requested in the first place.
It was massively confusing to link the potency assays / CMC issues with the requirement for another trial. To point where it was unclear what the approval was actually for – AA conditional on an adult trial or unconditional child approval.
If your cynical it all looks like a bit of a magic trick … create ambiguity … and then let people resolve the ambiguity incorrectly. Which is exactly what posters on this forum did.
It has taken two CRLs to get SI (almost) to the position where he accepts that he has to do an adult randomised control trial; without approval in children first.
I say “almost” because listening to the CC it appears SI still doesn’t understand that what the FDA wants. What they want is for him to demonstrate that his new “optimised” product is not the same product that failed in the previous randomised controlled trials. In other words, meaningful move the needle on the “totality of evidence”. And the only way to do that is with “at least one randomised controlled trial”. Which is what the FDA have been trying to tell him for 5 years. Perhaps the FDA need to become less “collegiate”.
But SI is right about one thing … a small, academic targeted non-randomised adult gvhd trial is probably the next step. A P2 study; building from this “new” pilot adult EAP data that has appeared. Then you move to the randomised controlled P3 trial – starting sometime later this decade.,
I’ll close by saying by saying it has been challenging at times to not get dragged into the mud on this forum. My policy (not applied perfectly by any means) is to never to respond to posts except where substantive discussion can be progressed. Not easy at times to stick to.
Social media is a great equaliser – democratiser; and it does me (and I’m sure the other contrarians on here) the world of good to be brought down to earth if our thoughts or arguments are poorly expressed.
So no complaints from me on this score - the rough and tumble is part and parcel of the deal you sign up to when participating on a stock market forum. But there needs to be a balance. I suspect on this forum that balance was lost by an idiotic minority which has been at the expense of the majority.
Perhaps today is a good opportunity to take a leaf out of Australia’s 2016 biggest biotech loser … Lang Walker. After the QRX disaster he was asked what he had learnt.
Two things he said. One was to get better at understanding the technical aspects of clinical trials. Second was to be less trusting of management. Lang paid $10m for his lesson. Hot Copper is free. Maybe you get what you pay for but maybe HC could be a bargain if only ...
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