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Post by esstan2001 on Apr 7, 2014 13:47:03 GMT -5
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IMO, Senior Execs also have to balance taking the potential opportunity of a partnership and all it's wild gains against the risks down the road that there is some confounding event- if they can not solidly quantify that event with high degree of certainty, many will just decide to wait for more clarity, & pay up so as not to loose out on all those executive perks. No one wants to be associated with a costly partnership that went south (not that I believe this to be the case here with Mannkind) Hence, why we are here where we are today.
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Post by esstan2001 on Apr 7, 2014 8:34:15 GMT -5
rockyp- I vote for reason 1) also :-)
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Post by esstan2001 on Apr 7, 2014 8:32:10 GMT -5
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Al Mann in so much as told the FDA this right to Peggy Hamburg's face (there is a 4-5 year old youtube clip of a 56+ minute presentation from a panel discussion about the FDA drug approval process)
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Post by esstan2001 on Apr 7, 2014 8:27:53 GMT -5
A one month delay would have given them 6 weeks to work out the label details, which should have been enough time. IMO, it is possible that they have to call on their best in house diabetes expert(s) to resolve in committee the difference between the A1C metric having been used and the FBG excursion data (and who know knows what, & how much new data was provided by Mannkind)- I was hopeful that a 1 month delay would suffice; but after all, this is our government we are dealing with...
Good suggestion from silentbob to write our congress people to keep on the pressure.
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Post by esstan2001 on Apr 4, 2014 10:44:52 GMT -5
savak,
you've made a very reasoned assessment and I can not add other than to speculate that the reviewers will take their (adjusted for the Adcom) recommendation to the supervisors, which make the decision.
The only comment I can add, from watching 4 AdComs and a reading a lot of review and commentary is that: there has been a lot of staff turnover at the FDA. The experienced old salts are mostly gone. In their place, mostly green kids. A lack of continuity of knowledge about drug history in reviews due to the dearth of experienced staff. A mandate to protect the public from risk of ... [fill in the blank]
The evolved purpose of the AdCom has become (IMO) to provide a blanket of cover for the FDA. Having said all this, I still do believe we do get the nod (even after Al gave Margaret Hamburg a hard time a few years ago on how FDA aversion to risk has entirely been blown out pf proportion).
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Post by esstan2001 on Apr 3, 2014 17:41:31 GMT -5
brentie, that is it
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Post by esstan2001 on Apr 3, 2014 15:58:34 GMT -5
... I hate how all these articles say it is less effective than current treatment... then add at lowering A1C!! When it potentially is vastly superior in managing glucose levels.
OTOH, I could not find anything glaringly wrong with the politics on that page.
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Post by esstan2001 on Apr 3, 2014 14:01:02 GMT -5
The point of prandial insulin to cover the meal only... when you bolus at mealtime, it adds to the existing insulin in the system that is meant to be "basal" insulin. So there is a layering affect of existing ... basal, with the tail of the bolused insulin from a prior meal. This [stacking] creates the havoc for type 1's or parents of type 1's. Afrezza is going to isolate the mealtime insulin need, leaving basal insulin to do its thing, keeping the body steady for the other 20 hours of the day. Diabetics, their parents and their endo's are going to be able to be more aggresive, more accurate with both the basal and bolus insulin regiment because the two issues will be more clearly separated. This could very well mean more basal insulin. ...more important than that, the highs will be less high and the lows will be less low. Parents of type 1's such as myself are terrified of lows (death) and back of the mind worried about ongoing highs. DKA yes, but more so, the long term affects on the body (life expectancy) of continuously running high. An A1c of 8 with limited excursions above 250 or below 70 will-be-life-changing.typeonedad- count yourself among the so many brilliant people on this board: IMO your statement above is the clearest, most succinct, almost 'soundbite like' reason advocating for Afrezza. This should be sent to Mannkind and used everywhere as their clarion call to the FDA for approval.
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Post by esstan2001 on Apr 3, 2014 7:41:41 GMT -5
By plcfischer in comments section of Brian Orelli MF article this AM: this captures what AL has been trying to convey for all these years and what the FDA seems dense as wood about regarding Afrezza-
The FDA fell into the HbA1c trap. What is the HbA1c (A1c) trap? It is the trap that is created when a proxy measure (A1c) is treated as more important than the direct measurement (plasma glucose). This is very easy to do with diabetes treatment. A1c is a measure of average plasma glucose over three months. A direct plasma glucose measurement shows a point in time. Because plasma glucose changes rapidly, point in time measurements are not very useful in the clinic. Because in a clinical environment A1c is the better measurement the American Diabetes Association (ADA) and other professional societies use A1c in their treatment guide lines.
The FDA, using well established methods used A1c as a measure of how well Afrezza worked to treat diabetes. The problem is they took it to far, way to far. Looking on page 50 of the briefing document you will see where the FDA is stating that the superior reduction in Fasting Plasma Glucose (FPG) in the Afrezza arm is due to the increase in basal insulin used in that arm. I have no argument with that statement, but it is incomplete. I will argue that the increase in basal insulin is made possible because Afrezza is better for glucose control than the current prandial (meal time) insulins. If you look on page 55 you will find more evidence that Afrezza is not an effective basal insulin, nor is it intended to be. Afrezza did not have a significant effect on FPG when not taken with treatments that cause a decrease in FPG. This should have been expected. Looking on pages 90 and 91, you will find evidence of Afrezza's superior glucose control in preventing hypoglycemia. Afrezza patients had less than half of the hypoglycemic events where blood glucose dropped below 37 mg/dL compared to current prandial insulin patients. As would be expected your Afrezza patients did have more hypoglycemic events than placebo patients.
For my theory to work, Afrezza patients must have no more hyperglycemia than current treatments. Looking on page 67 you will find that the rate is the same. On page 72 you will find that Afrezza is superior versus placebo (as expected).
In conclusion, I find that the FDA's assertion that Afrezza's patients took more basal insulin or other treatments to lower A1c to be true. But unlike the FDA, I consider this to be a positive. The evidence is strong that the ultra fast action of Afrezza lowers the excursion of blood glucose levels better than current prandial treatments. This lowering of excursions allows for more aggressive treatments for lowering A1c without an increased risk for hypoglycemia. The FDA got it wrong, but the panel got it right. Lets hope for the sake of diabetes patients and for our retirement accounts that the FDA sees the light and follows the panel's advice.
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Post by esstan2001 on Apr 1, 2014 15:52:58 GMT -5
congrats and thanks to all!!!
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Post by esstan2001 on Mar 31, 2014 15:55:51 GMT -5
On a brighter note:
I listened to this AdCom meeting from ~3PM on for approval of their antibiotic today... sounded very iffy when the FDA lady spoke regarding efficacy and safety. Then at about 4PM the vote occurred- was 12 0 to approve.
Go figure. Sure hope that is how tomorrow goes. GLTA
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Post by esstan2001 on Mar 31, 2014 14:02:38 GMT -5
jpg, you already posted a good response to this- however I kept it alive, dredging it up here and there. My bad :-)
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Post by esstan2001 on Mar 31, 2014 10:32:10 GMT -5
Do not recall Mannkind's take on dosing in their document. (Was the first thing I downloaded from FDA site, sped thru it, and thought the FDA was in love... next, I then saw the FDA's BrfDoc...)
Assuming tomorrow's presentations go well, and the vote is not bad What gates do we need to get thru for approval? 1. FDA has to be willing to allow Mannkind to go back to the dosing used in Gen2 trial... can this be accomplished just via discussion & labeling? 2. FDA (begrudgingly) accepts endpoints in trials 3. FDA looks at data measuring of glycemic levels in patients / deems value to the limited excursions... this in conjunction with the totality of A1C data gets them over the hurdle for both indications....
1- I can see happening without requiring another CRL... Opinions? 2- Plausible this can happen for T2, not sure about T1 trial (50/50). 3- So was such data collected? Was it submitted in the filing? If not, will be presented tomorrow?
1 & 3 are gnawing at me... all thoughts from anyone are welcome
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Post by esstan2001 on Mar 30, 2014 20:15:19 GMT -5
jpg, alcc, liane, mnkdfan, thanks for a lot of valuable input.
jpg, is it likely that the Mannkind presenters succeed in convincing the FDA on such matters as how irrelevant this dose conversion to IA is (beyond providing a fair dosing start point) and can they get the FDA reviewers to weight the other benefits that are not covered using the standard metrics for A1C, PK, PD etc? More weighting needs to come in on the benefits to outweigh the risks, and the FDA has seemed unusually conservative and risk averse the past 4 years.
I'm pretty comfortable on T2, I'm even getting a little less agitated on T1; I just keep reviewing the dosing section and wonder how stubborn the FDA decision makers will be on this, given it is their job to highlight the concerns...
not necessarily expecting an answer, but I do welcome your opinions.
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Post by esstan2001 on Mar 30, 2014 20:05:54 GMT -5
The problem is they were testing a new device and if they gave to much they probably feared hypoglycemia and if they give a bit less they probably figured that dosing will simply be adjusted upwards (which it was) and that every patient is different and what counts are the glucose readings anyway. We treat to glucose levels based on rough understandings of PK/PD anyway. Who really cares about 3/10 or 4/10 in a long run clinical scenario? It is like arguing about fentanyl to morpine or hydrocortisone to solumedrol potency equivalences. A ballpark figure is necessary but past a cerain level it is not clinically relevant (not to say the FDA won't care but I doubt the panel members will). I did see 2 pharmacology students argue once if fenanyl to morphine was 1/80 or 1/100 for a surpisingly long time. They didn't ask my input but I would have laughed as it is a meaningless argument because the half lives are different with different age groups, the peak and redistibution are different and more impotantly it doesn't make any clinical difference in these ranges. The same could be said for prandials and Afrezza. 3/10 or 4/10 at what time? 10 minutes? 60 minutes? 100 minutes? 3 hours? If anyone comes up with a uniform potency answer to all these time points the are simply wrong and not thinking it through. The whole non linear thing is also kind of a theoretical argument and has to do with the same exact arguments as above and a massively complicated second set of variables that have to do with stuff we don't know a lot about yet because there has never been an insulin like Afrezza to study all this stuff. And no MNKD could not have done all these studies since we are talking of 100s of studies that will be done like was done when prandials first came out. I do know the non linear thing being said to be due to a faulty design of the Gen2 inhaler is wrong and simplistic. There will be many academic careers built around understanding a few of these topics. As another poster here or on another board pointed out: look at the original understanding (andI would add clinical interest or lack of) of the first prandials to come out. We know a lot more about Afrezza then we did about those first meal time insulins already but we will hopefully get to another level with an approval and the right partner. JPG
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