IMO, this is the biggest risk MNKD faces in it's NDA. Despite the 171 PR stating that a bridge was established between the inhalers, I remain skeptical that the FDA will see it the same way (MNKD said it achieved bio = in a trial on 11/15/10, but FDA the FDA rejected bio = two months later).
Q&A #2 admitted a .08 mean change A1c difference between the two inhalers (I am assuming MT did better than DB inhaler).
PR 171 stated "there was an insignificant difference of 0.01 L in mean change in FEV1 between the two AFREZZA groups (p=0.5364)." (I am assuming DB did worse vs. MT)
PR 171 also stated "over the same 24-week treatment period, the decrease in FEV1 seen in the AFREZZA-Gen2 group was slightly greater than that seen in the aspart group (0.03 L)."
Reading between the lines (since they refuse to tell us) it appears that the Dreamboat inhaler may have had a greater decrease in FEV1 vs. the Medtone inhaler, yet did 0.8% worse in A1C vs. the Medtone inhaler.
If this indeed happened, it is a very VERY bad sign for the safety bridge. This means the Dreamboat inhaler was less effective at lowering BG levels, but still had a greater decrease in lung function. Clues for this happening include the lower A1c in DB vs 117, the greater cough in DB vs. Medtone in 171 and the new 30U single dose DB trial. (it appears Dreamboat may catch more insulin in the lungs than Medtone which would explain the lower efficacy and greater decrease in lung function).
This is not a good sign for MNKD. For Dreamboat to equal Medtone's efficacy and establish a safety bridge, it may push the FEV1 decrease in lung function to a level higher than what the FDA considers acceptable.
If this happens, there may be no bridge. With no bridge, no approval.
You wrote, "Reading between the lines (since they refuse to tell us) it appears that the Dreamboat inhaler may have had a greater decrease in FEV1 vs. the Medtone inhaler, yet did 0.8% worse in A1C vs. the Medtone inhaler."
Which is which Rapps? Was the difference between inhalers .8% or was it .08%
This makes a big difference.
Now the real question is whether the .08% difference is considered as being significant with respect to NOT what the difference between each of the 2 inhalers but rather between each of the 2 inhalers vrs aspart or normal healthy humans. Supposed the data on Medtone showed that its FEV1 score was 10% below that of aspart while the data for Dreamboat was same as aspart would you then conclude that every non diabetics be prescribed Medtone?
Let's say the same person starts out with an HbA1c of 7.5 at the beginning of the trial. Using DB, his HbA1c drops to 6.9 by the end of the trial. Now, assuming that same person used MT and ended the trial with a 0.08% better HbA1c, what would that person's HbA1c be at the end of the trial?
elder, I'm no mathematician or statistician, so I could be wrong, but first I'd need to know if your example above means a .08% better A1c from the baseline (of 7.5) or does it mean .08% better than the 6.9 final DB A1c. Your example isn't clear so I can't assume what you mean, but knowing what the .08% A1c is "better" than would be a good start.
Once that it known, I'd also need you to clarify if your 7.5 or 6.9 are represented as %'s or absolute values. Your example above doesn't clarify. In other words, I don't think it's as simple as subtracting .08 from 6.9 and getting a 6.82. Rather, if 6.9 is an absolute # and .08 is a % (which it appears it is), you may need to do conversions and find out how much .08% of 6.9 is and then subtract that number from 6.9 (assuming .08% is "better" than DB's final reduction and not .08 better than baseline). If the former, it would be, what, .552 and you'd subtract that from 6.9 and get 6.348?
Beats me. Why I'm attorney and not a math teacher. It appears you are a brilliant attorney and mathematician. I wasn't so lucky. I get paid to argue facts to law in a courtroom, not do math equations. My posts on MNKD gives analysis of the issues I see based upon my 20 year experience as a T1, my research of MNKD and my background in biochemistry. I have admitted before that I don't know stats and could be wrong on the numbers. I used single variable differential and integral calculus w/ chemistry, but otherwise tried to stay away from too many calculations. The effects of molecular and chemical processes is what intrigues me with science. The quantitative analysis of those effects is the necessary evil.
What's interesting is that even MNKD's own statisticians could get the .40% threshold question right in their 009 analysis. They use a methodology that the FDA outright rejected. They thought the upper level of 95% CI was .38. The FDA disagreed and said it was .401. Same thing happened in 175 w/ .5. v .4.
What do you think the FDA does? Go back and look at MNKD's 11/15/10 press release where they claimed to prove bio equivalence. Then consider why the FDA rejected their bio = "proof" two months later.
You don't think the FDA doesn't look at this stuff with a fine tooth comb?
Put more simply, if dreamboat patients are inhaling less overall powder yet are experiencing a greater decrease in lung function, a bridge may not be established.
Or, if dreamboat requires more overall powder just to equal medtone's efficacy, a bridge may not occur.
The reported data suggests one of these two scenarios happened in 171.
What part of statistical significance can't you understand? A .08 difference in A1c between dreamboat and medtone is NOT statistically significant. No additional powder needs to be added to equal the efficacy no matter how much you harp on it, they are EQUAL statistically - meaning the variance could have been due differences in the subjects in the trial groups, etc.
0.01l difference between the groups is roughly a difference od 10cc of FEV over a 1 second interval. in a 6 foot 40 year old FEV1 could be as much as 4.2 liters. A 10cc difference is miniscule!
•FEV1 greater 80% of predicted= normal
• FEV1 60% to 79% of predicted = Mild obstruction
•FEV1 40% to 59% of predicted = Moderate obstruction
•FEV1 less than 40% of predicted = Severe obstruction
For diminished FEV1 even to be considered mild, a difference of several 100cc would have to be observed. differences of 10cc could easily be attributed patient effort.
There are lies, damn lies, and then there are statistics. Your use of the statistics places you in the middle.
Dreamboat and Medtone had a ".08" difference (the PR did not specify better or worse), not "0.8" difference as you wrote, both of which are statistically insignificant., and statistical significance is all the FDA cares about.