Ann: FDA Supports Accelerated Approval Pathway for Heart Failure, page-284

Hi @reginaldp

so $3 is the trigger for Blue Lagoon oysters, eh? Lets aim for that.

And 'ta for the light reading. Truth be told, I'd read it a while back. Gripping stuff. It seems to me that some investors in Oz have either not learned or have completely forgotten that CRLs used to be called 'approvable' letters by the FDA. A large part of the reason for the nomenclature change ( Approvable letter ---> Complete Response letter) back in 2008 was to focus on the scope of the FDA's comprehensive duty to respond & detail all hurdles to its approval & suggest what might be done about them when indicating that a NDA/BLA was approvable, although not yet approved. Let's not forget that.

Reg, I really don't think the March (Q1 '24) meeting with the FDA is just regarding 'a potency assay', no matter how much attention we may try to focus on the specifics of a particular assay & no matter that CEO Itescu has been at pains to reassure everyone that data from a second potency assay will be under consideration.

I think Mesoblast will want the meeting to entail a comprehensive review by CBER of Mesoblast's entire 'potency assurance strategy', which will include but not be confined to the release and manufacturing assays for remestemcel-l for SR-aGVHD.

What's that, you say. Well, more on that later. IMO MSB holders should remember that the FDA indicated in the September 2023 Type A meeting its willingness to consider Mesoblast’s proposed registrational trial design in adults, subject only to 'agreement' on the 'suitability' of the potency assay for the product to be used in adults.

'Suitability' is a technical term - it's not a colloquial use in any Mesoblast release to ASX. Think about 'fitness for purpose', and comparability and how that's proven in a scientific sense. And agreement can be given by the FDA at any time e.g. during a meeting. I think there's good reason to think Mesoblast will have asked for back-to-back meetings on the adult and pediatric indications, although I have no direct evidence that's so. On my analysis, it stands to reason IMO that CEO Itescu would want to submit the final adult trial protocol to the FDA before having FDA proceed to consider Mesoblast's satisfaction of the conditions for paediatric indication BLA resubmission - I believe MSB would prefer to have FDA's views (and signoff) on the suitability of the potency assays for upcoming trial product BEFORE convening the paediatric meeting.

Because the FDA really do want that adult trial run by BMT CTN. They want the data & the kudos of working collaboratively with other strategic/ major players in US national healthcare. Recall that trial protocol submission was agreed at the Type A meeting with FDA in September. Link here.

But in the context of paediatric SR-aGVHD and Mesoblast's upcoming meeting with the FDA let me just say for now that I don't think it's a mere coincidence that the FDA's proposed revised Guidance for Potency Assurance of Cellular and Gene Therapy Products was only published in December 2023. Link here. Note that the word 'risk' now appears 107 times i.e. one hundred & seven times - there were NO mentions of 'risk' at all in the previous 2011 Guidance on Potency Assays.

Or that Dr Klinker (yes, that guy), who's now Chief, Cell Therapy Branch 2 in the Office of Cell Therapy and Human Tissues CMC under OTP was given the guernsey to become the FDA's first TikTok influencer. Link here.

All MSB holders should IMO watch this video. Two of my key takeaways - and importantly from the Mouth of Matt were these:

" (at 7:01min) But testing the product is not what makes it potent. The cornerstone of an effective potency assurance strategy is a well-designed manufacturing process. Your goal should be a manufacturing process that consistently produces potent lots of drug products. " (underlining added for emphasis)

and now this:

" (at 9:40min) Now that I've explained the broader approach presented in this draft guide, i'd like to make it very clear that we do not intend for this to be more burdensome on developers. The 2011 Potency Guidance focused exclusively on the development of potency assets, and we acknowledged that developing potency assays for CGT products can be challenging.

While this new approach I've just described is certainly broader, it is also MORE FLEXIBLE.

If there are limitations in one aspect of your potency assurance, strategy, other aspects of the strategy may be able to compensate for those limitationsfor some products.

The potency-related CQAs might not be well understood, or might be difficult to measure reliably. And as a result lot-release testing may not be able to fully confirm product potency. But other aspects of the potency assurance strategy, such as process design, and control can take on increased importance in these cases, and be made more stringent and extensive.

This ADAPTABILITY is one of the key strengths of this broader approach theand it provides other tools beyond potency tests for controlling product potency. (!!!) ....." (underlining, exclamation marks and capitalising added for emphasis)

Does this sound like the situation of any particular product that you can recall?

Any therapy before the FDA for pre-approval right now?

Any bells ringing?

Now recall how many 483s we received from the FDA inspectorate during the Lonza Biologics Tuas inspection in Singapore in May 2023. DYOR on how many 483s Gamida Cell received from the FDA inspectorate for its (now-approved) processes for omidubicel.

Note in passing that Commissioner Califf dropped into Singapore very recently on an FDA world tour and said glowing things about Singapore regulators and CMOs working with the FDA.

Will we get approval during the tea break at this meeting? Not as I see things.

But, IMO Mesoblast is going to go into this Mega-meeting (or meetings) loaded for bear. On both indications.

I would not be surprised if Dr Verdun showed up at some stage, just to look over his shoulder & read Dr Matt's notes.

Cheers all
GLTAH