MSB (ASX) Silviu Itescu The Legend

Originally posted by stockrock ↑

Thanks for the response, though you seem selective in what you respond to.

Any analysis outside of the primary endpoint of that trial will encounter the same multiplicity problem. The data they are presenting is using HF MACE as the null, instead of repeat hospitilisations. Something the FDA has accepted (and as pointed out before, it was actually the initial primary endpoint of the trial). So by running analysis on an endpoint other than the primary endpoint of that trial, they only need to adjust for one additional null which would mean the statistical significance would need to be adjusted to 9.75% (0.95 x 0.95) of a type 1 error instead of 5%.

What you are implying is that Mesoblast have run all their analysis using another endpoint other than HF-MACE... my question is how do you know that? All we can see is one additional null being presented... how did you come up with 5? Ah thats right, you did it for your desired effect... knowing that it was not entirely accurate.. but you just wanted to emphasise your point right?

The data presented to the FDA is for regulatory approval, so will need to be adjusted for multiplicity (its part of the FDA guidance) as they are using a different endpoint to seek approval. But for external presentations outside the FDA, Mesoblast chose to present the data as if HF MACE were the primary endpoint and not adjusted for multiplicity. Adjusting the data for a different audience is common practice, like you just did above, it is done to maximise awareness or impact of the point you are trying to get across to that particular audience.

By doing so in this setting (outside of FDA approval) requires them to advise the audience that the data has not been adjusted for multiplicity so the audience is aware that an adjustment is required to be made before it is submitted to the FDA.

So the fact they mentioned multiplicity implies that Mesoblast are well aware of multiplicity and that any data submitted to the FDA is in fact adjusted for multiplicity... yet the FDA still find the data compelling enough to ask for further analysis to find the highest risk group, for what we believe to be a chance of a single trial approval.

So in the absence of actual trial data where you are able to do any analysis, again.. how did you conclude that any significance would dissapear? What other null are you aware of that is being presented to the FDA outside of HF MACE?

I don't have the data and I can't adjust for multiplicity, so all I have to work off is what I've seen (only one other null presented by Mesoblast) and the FDA response to the data presented (which would have been adjusted for multiplicity). But I'd be happy for you to demonstrate that by adjusting the type 1 error to 9.75% instead of 5% makes all the statistical significance dissapear as you claim. Or if you think there is more than one null, can you tell me what the other null is.. where did you see it being analysed or presented? If you can't, then I'd ask that you stop repeating the same argument over and over again..

But all of what we are doing is conjecture... is there nothing to garner from what the FDA response has been to this data? Rather than reject it, it looks like they've embraced it and are looking at an expediated pathway for approval.

While you are responding to me, why did the FDA ask Mesoblast to identify the highest risk group?

And what do you think is the most clinically meaningful endpoint out of reduction in repeat hospitilisations and reduction in HF-MACE?

In other words is a surrogate endpoint for the primary endpoint intended for that treatment more important, or is the primary endpoing for that treatment more important than the surrogate endpoint?

It would be greatly appreciated if you showed the courtesy to respond to the above.

Expand

With 30 secondary outcome measures, it's almost inconceivable that they couldn't find something to claim as a success. Even then it took Dr Perin a year to come up with that one.

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