I simply used the 5-ALA fluoresced tumor tissue as an example of something that might be deemed a manufacturing 'change'.
It might be construed as constituting a potentially 'altered' biological starting material.
Following this logically; if it was flagged up as a possible material change, then it may have resulted in a requirement for an extended real-time comparability study, thereby leading to an extended clinical hold while that exercise took place.
I'm not saying that this was the precise causation. Rather it fits the chronology of what happened, better than anything else that comes to my mind.
Equally, you might employ a new or updated piece of manufacturing kit without realising that you are actually potentially introducing something that might affect potency or safety. And again that might explain the hold.
Certainly in my mind, the hold very likely resulted from a perceived manufacturing change, even if that change or its significance (in terms of leading to a hold, if nothing else) were not realised in advance.
And a CMC issue is way more likely than a futility finding imo.
I disregard futility as a possibility.
I'll grant you that some sort of superiority conclusion was slightly more likely than a futility finding.
But I put a CMC 'issue' way ahead of both of these.
I did pose the question several months back, about whether fluoresced tumor tissue could be used in the manufacture of L.
It would be very negatively significant if it couldn't, with 5-ALA slowly being rolled out everywhere...
A onetime poster (seemingly well-informed) popped up and stated that according to his knowledge in this area and studies undertaken, it wouldn't be a problem.
Said poster hasn't posted since.
But I suspect he was well-informed and I believe him.
(Just made me think that, yes, the company do read this Board!)
So that's why I tend to think in terms of getting to a state of CMC readiness, is what is actually happening behind the scenes right now, as opposed to just devising an acceptable SAP.
You cannot submit a cell therapy BLA without demonstrating CMC readiness (which includes very clear scale-up plans).
Or if you do just that, it will be summarily rejected with one of those rude letters. Forgotten what they call them.
And similar requirements apply in the European theatre. Sawston has to be fully inspected, licensed and approved. With an identical process using identical equipment to Cognate at Memphis.
So I'm guessing that while all this takes place, there is no early imperative to lock the data.
Let it further mature, because documented and verifiable CMC readiness has to be in place, before you actually put in your BLA in the US, and your MAA in Europe.
It's about saving time to approval, not causing delay.
Why they can't tell us that this is what is going on is another question; the answer to which I can only speculate about.
But I rest easy in suspecting that this is what is going on.
Just my opinions..
