Hi
@PhaedrusAny study whether it be a superiority study or non-inferiroirty study must be an adequate and well controlled study for the FDA to consider it for approval, its pretty clearly stated in
21CFR314.126It seems the FDA have an issue with the adequacy of the study conducted by MSB, the announcement in Sep23 (Type A Meeting) specifically speaks to this clause in the CFR.
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(d) For an investigation to be considered adequate for approval of a new drug, it is required that the test drug be standardized as to identity, strength, quality, purity, and dosage form to give significance to the results of the investigation."
Interestingly the FDA appears to accept that it is a well controlled study, after all the debate around the control for this study. Its just the adequacy that seems to be lacking (as defined by the FDA).
I think Mesoblast are hoping that the new potency assay data will address any specific concerns the FDA have identified in the latest BLA review.. though they went at lengths to get assurance from OTAT that they were on the right track before they did the resubmission last time, will they be asked to do the same before another resubmission and how much confidence will the market have in the process?
It is almost at the point where it is better to focus management's time and effort on the adult SR-aGVHD trial, as well as the potential AA's on offer for HF which are fast becoming the 'closest to market' potential, especially if the pediatric SR-aGVHD is going to require further clinical data before another BLA is submitted.
Whilst Ryoncil has been front and centre when it comes to approvals ... my attention, has well and truly shifted to heart failure. If Rex starts making progress through the FDA, the ramifications will be massive.
The first big hurdle has been cleared, which was to convince the surrogate endpoints may support a reasonable likelihood of clinical benefit, which is all they need for accelerated approval. Keeping in mind, that this is all new terriroty (establishing the relationship between inflammation and heart failure). I believe MSB needed all the data on hand (including those from the larger Dream HF trial) to get the FDA across the line on this one. MSB essentially took the 'failed' phase 2 LVAD trial, where the primary endpoint was not achieved .. but a pre-defined subset of ischemic HF paitents (narrowed arteries) saw massive benefits (those highlighted in the AA announcement). SOC for coronoary heart disease has been focused on drugs that open up the arteries (ACE inhibitors and ARBs) or by-pass surgery, but non have ever targeted inflammation. If this is approved, it will be a paradigm shift on how to treat coronary heart disease. Inherent in all this, is that by recommending AA .. the FDA have signalled that they are now convinced of the MOA i.e. IL-6 / inflammation. Its taken them this long to come around to it (trial finished in 2018/2019). Having cleared that massive hurdle, we can see what hurdles remain to be cleared in a BLA..
The LVAD trial was a randomised placebo controlled trial, so the same kerfuffle with Ryoncil on single-arm trial is not an issue here .. there are no confounding historical trials to muddy the waters, safety is not an issue, manufacuting facility has been FDA inspected (for the Ryoncil BLA), and statistical significance has been achieved for ischemic patients. MOA should be very clear, or else AA would not have been recommended IMO.
Now MSB need another trial to get into the much large CHF market, and what did they learn from that trial? Those patients with high levels of inflammation were the ones that benefitted most. Big pharma dots are connecting, the FDA just opened up a new treatment paradigm for heart failture (via treating inflammation) ... suddenly a confirmatory trial targeting CHF patients with high inflammation markers (CRP) sounds like a pretty good idea, don't you think?
goodluck
(20min delay)