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Post by chmith27 on Mar 29, 2014 16:38:19 GMT -5
you might be thinking about this point incorrectly. an ineffective insulin (a very bad thing) will have essentially no hypo events (a good thing, right) and an insulin that works appropriately (a very good thing) will have a higher rate of hypos (a bad thing). which one do you want to use? i can treat your DM with a wave of my wand, which will have no hypos(a good thing)- but is that going to be good for your diabetes? the primary goal of an insulin is to move glucose into the cell- if it doesn't do that then you have to call it ineffective. the reviewer should have said, "entirely consistent with the possibility that Afrezza was less effective..." i agree there seems to be some editorializing but i also have never dealt with a briefing doc so i don't know the true context and acceptable tone that is allowed for these things. You should think again about your construction: " Proposition A is entirely consistent with the possibility that Proposition B [is true]" It is a tautology, therefore meaningless. otw, kindly watch your logic. you've totally lost me. maybe you could clarify what your problem was with the reviewer's statement? my contention is that they should have worded their conclusion of poorer efficacy related to less hypos to include the possibility of causation, instead of unequivocally linking poor efficacy to less hypos. i was saying with the other more recent post, which was not quoted, that they stated the reason for less hypos was poor efficacy. my contention with that statement is that while that is a possible explanation, it is not the only explanation. but you have a different take and that's where you've lost me. do you believe that the less hypos could not possibly be explained by poor efficacy? if so then we are at an impasse.
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Post by chmith27 on Mar 29, 2014 17:01:18 GMT -5
you might be thinking about this point incorrectly. an ineffective insulin (a very bad thing) will have essentially no hypo events (a good thing, right) and an insulin that works appropriately (a very good thing) will have a higher rate of hypos (a bad thing). which one do you want to use? i can treat your DM with a wave of my wand, which will have no hypos(a good thing)- but is that going to be good for your diabetes? the primary goal of an insulin is to move glucose into the cell- if it doesn't do that then you have to call it ineffective. the reviewer should have said, "entirely consistent with the possibility that Afrezza was less effective..." i agree there seems to be some editorializing but i also have never dealt with a briefing doc so i don't know the true context and acceptable tone that is allowed for these things. You should think again about your construction: " Proposition A is entirely consistent with the possibility that Proposition B [is true]" It is a tautology, therefore meaningless. otw, kindly watch your logic. oh i see your problem with my statement. haha but you totally went straw man on us. while an argument in tautological form is redundant and unnecessarily worded, it doesn't change the actual argument into a meaningless one. you chose to leave the actual content of the discussion and point out a flaw in wording, which expresses the same idea only using a redundant phrasing. i was saying that the reviewer shouldn't have used the word "fact" when referring to afrezza as being ineffective because that's not a fact. so i put in possibility instead of fact, without changing the rest of the wording because that was the real point of contention. what i should have done is take out "entirely consistent with" and replaced it with "there remains a possibility that less hypos can be explained by poor efficacy". but you see, that is exactly what i was saying so why in the world you chose to point out a "tautology" when the actual thing we were talking about has nothing to do with the wording and everything to do with the concept that less hypos can be a result of poor efficacy? and here i thought you were just a touch misguided. you went straw man on me! i also use run on sentences and i doesn't use the right grammar or speeling at times- does that make an argument invalid?
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Post by babaoriley on Mar 29, 2014 17:37:26 GMT -5
alcc, remember when you considered not posting here cuz of me, perhaps you should consider that once again!
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Post by alcc on Mar 29, 2014 17:45:55 GMT -5
chmith27,
My problem with the reviewer's statement is his blatantly (imho) antagonistic and false assertion of a causal relationship between the "fact" that Afrezza is less effective and fewer hypos. As I said, even stipulating Afrezza is less effective than comparator in A1c reduction, which is the only "fact" that can reasonable be inferred from the data set, that causal connection is not valid when it comes to incidents of hypo events. You agree?
I can just as easily have changed his statement to "fewer hypos is entirely consistent with the fact (or possibility, if you prefer) that Afrezza has a more favorable PK profile for post prandial glycemic control."
My problem is, this reviewer twisted one "fact" to attack the one area where Afrezza outperfomed the comparator, while completely ignoring/dismissing the sponsor's pivotal claims of favorable PK. To me, that is evidence enough that he is a hostile reviewer.
My problem with your initial post is that you assumed that we (on this board) do not know that if you wave your hand at, and do nothing else for, a diabetic, he will likely never have a hypo event. That, plus the "fact" that you appear to give the reviewer a mere slap on the hand for inelegant language. I believe it is more than that. Imo he is a hostile "witness."
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Post by alcc on Mar 29, 2014 17:47:07 GMT -5
baboreily, thank you for your kind reminder. If every board member is like you, yes, I would have.
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Post by StevieRay on Mar 29, 2014 18:01:41 GMT -5
Here’s some information I found about missing data: Differential dropout and bias in randomised controlled trials: when it matters and when it may not www.bmj.com/content/346/bmj.e8668Assessing differential attrition in clinical trials: self-monitoring of oral anticoagulation and type II diabetes www.biomedcentral.com/1471-2288/7/18I’m sticking to my guns on this one and will hold all my shares until the FDA decides the fate of MannKind. I believe we clearly got the football into the end zone. When the referee extended his arms above his head in declaring a touchdown, his arms were fully extended not that it matters but to say we barely scored the winning touchdown diminishes MannKinds efforts. It’s clear the FDA reviewer has a bias that is unprofessionally expressed. I trust the AdCom meeting will be more professional and we’ll receive a favorable vote for both Type 1 and 2. We have met all of our Primary end points. Period. You either met them or you don’t.
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Post by liane on Mar 29, 2014 18:10:25 GMT -5
At least the 1st reference used the term "missing data" - common in the statistical analysis circles, but to the layman, it sounds like the sponsor is hiding something.
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Post by alcc on Mar 29, 2014 18:16:31 GMT -5
Thanks for the links. Interesting: 20% or greater dropout rates in 18% of P3 trials. Confirms Afrezza dropouts on the high side. Plus Afrezza rates are 2x that of Exubera, which should be a good comp. Does company's choice of venues affect dropout?
At this point, I am still reasonably comfortable with adcom outcome. But much less so re FDA outcome, given the bias expressed and multiple assertions of statistical inferiority.
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Post by chmith27 on Mar 29, 2014 21:08:09 GMT -5
chmith27, My problem with the reviewer's statement is his blatantly (imho) antagonistic and false assertion of a causal relationship between the "fact" that Afrezza is less effective and fewer hypos. As I said, even stipulating Afrezza is less effective than comparator in A1c reduction, which is the only "fact" that can reasonable be inferred from the data set, that causal connection is not valid when it comes to incidents of hypo events. You agree? I can just as easily have changed his statement to "fewer hypos is entirely consistent with the fact (or possibility, if you prefer) that Afrezza has a more favorable PK profile for post prandial glycemic control." My problem is, this reviewer twisted one "fact" to attack the one area where Afrezza outperfomed the comparator, while completely ignoring/dismissing the sponsor's pivotal claims of favorable PK. To me, that is evidence enough that he is a hostile reviewer. My problem with your initial post is that you assumed that we (on this board) do not know that if you wave your hand at, and do nothing else for, a diabetic, he will likely never have a hypo event. That, plus the "fact" that you appear to give the reviewer a mere slap on the hand for inelegant language. I believe it is more than that. Imo he is a hostile "witness." i agree that the tone of the reviewer seems over the top. but i also don't know what is acceptable limits for a reviewer. are they supposed to be like a devil's advocate, poking holes in theories and postulating? what sort of statements are fair game for them to make? if i did know this then i would feel authority to make more definitive comments on their tone and give more than a slap on the wrist. they do seem a little hostile to me too and definitely should not have used "fact" in their assessment. i would think it's okay for them to interject some opinion, such as to postulate that less efficacy could be the cause of less hypos. then again, if it were that ineffective as an insulin, we would have seen more dka cases in 171 and we did not see any in 171, so they don't get to keep their cake and eat it too. best of luck.
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Post by alcc on Mar 29, 2014 21:56:18 GMT -5
There were no new cases of DKA in 171, but the doc refers to higher frequency (4.8x) of DKA from Afrezza arm in earlier trials. The reviewer made a comment about this as well, but that comment stayed close to facts, not out of line imo. See attached: Attachment DeletedBtw, your detailed and careful reads & considerations are helpful and appreciated.
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Post by harshal1981 on Mar 29, 2014 23:00:02 GMT -5
I believe DKA narratives suggest they were non-issue. Remember that it is reviewer's job to state all the facts. For approval, AEs that are due to improper use are not considered a threat. DKAs should be controlled fine with basal insulin itself (as stated in the document by reviewer). Especially when basal insulins were titrated higher, these events will be safely assumed to be the cause of patient neglect, improper device use or non-compliance.
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Post by alcc on Mar 30, 2014 0:02:00 GMT -5
I agree. Just pointing out that DKA was noted in the document, which is fine. I understand it is the job of the FDA to do a critical analysis of the data; I expect and want them to. But I am not ok with some of the over the top, overreaching, antagonistic editorializing. That's unprofessional imo.
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Post by esstan2001 on Mar 30, 2014 9:59:04 GMT -5
I too agree that a decidedly biased tone comes thru from the reviewer; and also noted the extensive use of 'I' in the statistician's section, leading me to believe this person has an ego. I think there are enough questions on T1 to impact the panel vote but I think T2 should pass if the presentations are good. What concerns me are the dosing discrepancies highlighted by the FDA- 1. Must they be resolved as part of the label (regarding the rough equivalence to IA; I do not see why this would have to be mandated before appvl- I am hoping that it gets considered more as a 'nice to know' to help you understand where you are in terms of Afrezza dosing relative to SC injectables.. ) 2. Are there issues that need to be resolved regarding the inconsistent selection of PK vs PD data during the clamp dosing study? 3. If they need resolution, what is the vehicle to do that between now and an approval, or can this just be 'addressed' as some post marketing approval follow up? Not sure how we weather another 6-12 months before the AOK.
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Post by liane on Mar 30, 2014 13:04:06 GMT -5
esstan,
That area bothered me too. Nothing that cannot be resolved - but that is the big question - will it cause a delay?
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Post by alcc on Mar 30, 2014 14:22:50 GMT -5
The discrepancy re PD/PK re GIR/dosing is a concern to me as well. Putting my wishful thinking hat on, I imagine FDA could leave this as a fine-tuning exercise between physician and patient, especially given the observed individual variability. Putting my worse case hat on... never mind.
You would think that between the 2 CRLs the company had plenty of time to sort through and work out these known issues. Very sloppy. Grrr.
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