Taken from the guidance above, it appears Mesoblast need to demonstrate a few things before a single trial approval can be granted based on it being unethical to conduct a second trial:
a) Clinically meaningful and statistically very persuasive effect on mortality, severe or irreversible morbidity , or prevention of disease with potentially serious outcome.
b) Large multi-centre adequate and well-controlled trial c) Effect size and statistical analysis are both persuasived) Finding consistent, and clinically meaningful effects on distinct prospectively specified endopints (with actual examples used by the FDA guidance being heart attack and stroke).So what results from our CHF phase 3 trial are being presented to the FDA to consider if a second trial is unethical?
a) Now the only reason we are having this discussion with the FDA is because we met 1) above, that is the phase 3 trial demonstrated a significant benefit to a clinically meaningful endpoint (being the 3 point MACE; stroke, heart attack and cardiac death), as well as data demonstrating the ability of Revascor to significantly reduce mortaility in Class II patients by delaying disease progresion (from earlier analysis).
b) In terms of assessing whether our phase 3 trial is 'large', Mesoblast's phase 3 trial 537 treated patients (across 59 study locations in US and Canada), should be considered a large multi centre trial because Giapreza was approved on a single trial back in 2017 with only 321 patients (across 128 centres, in US, EU, AU and NZ).
https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-giapreza.
c) Effect size is 19.4% (39.0%-19.6%), and statistical analysis is p=0.003 This is really up to the FDA to determine if a 19.4% effect size is very persuasive or not, but as the FDA has asked for this high risk analysis after bing presented with the AHA data where the effect size was only 13.4% (32.4-19.0%) for 3 ponit MACE where CRP > 2 (i.e. also includes non-diabetics and non ischemics), and the p value was p=0.012, then the effect size of 19.4% and p value of p=0.003 are signifciantly better (i.e. more persuasive). But I believe that anything with a p value < 0.01 would be considered very persuasive, so p=0.003 is well below that.
d) One of the key things I took away from Dr Perin's AHA presentation is how proud he was of his the trial .. called it a beautiful trial I believe, and his comment that if nothing else.. the data was very very consistent. I'm sure Mesoblast have much more data to provide the FDA, but here are a few slides that could demonstrate consistency across multiple analysis, reducing the risk that it was by chance... with the last one below, probably the most convincing... as it very very clearly demonstrates the mechanism of action of Revascor across treated patients.
If you look at just stroke or heart attack... 65% reduction from treated vs control, p=0.001 across all 537 patients
We looked at how Mesoblast demonstrated that CRP>2 patients benefited most, and I'll repaste it below.. to show how the mechanism of action is so clearly demonstrated in treated patients...
You can see above that where CRP < 2, there is literally no benefit in using Revascor. Even still, if it were CRP naive.. we'd still see a 37% reduction in ischemic and/or dibetic p value = 0.019. But looking at how CRP impacts the data, is a very clear demonstration that these cells need inflammation to work.
An even more persuasivie data set can be seen below..
For class II patients, CRP naive there is a 57% reduction and a respectiable 11.8% effect size on a p value of 0.044. But look at the CRP <2 patients, no difference in effect size at all. So all the benefit was for patients who have CRP > 2.
Just to round out data consistency... data on IL-6 was captured by Mesoblast (IL-6 in the liver is a what produces CRP) and it correlated perfectly with CRP readings... so if the FDA ever doubted why the data was so great for high CRP patients... maybe it was chance, well Mesoblast have the perfect data set in IL-6 to demonstrate that both IL-6 and CRP readings correlate, so unless the readings were wrong across both IL-6 and CRP for the entire trial, then the FDA can have some more confidence that the results with CRP >2 patients are not seen due to chance.
But I guess going back to the slide below... where Mesoblast have outperformed the best of the already approved drugs in terms of risk reduction of 3 point MACE by 386% (0.54/0.14).. may be the most compelling data, and lets not forget the impeccable safety profile of this treatment. Well it sure explains why the FDA asked Mesoblast to go reanalyse their data to find the highest risk group... so I think this trial has definitely captured their attention and they are taking it very seriously... though the market doesn't quite appear to be on the same page.
(20min delay)