|
|
Post by sayhey24 on Dec 19, 2019 16:11:16 GMT -5
Ktim - OK, you must be right. All fat people get diabetes. Oh wait, is that a fact?
HSPH’s Willett, who chairs the Department of Nutrition, said that getting Americans’ diet right can mean the difference between being healthy or ill. Studies have shown that not smoking, eating properly, and keeping a healthy weight — a body mass index of under 25 — reduces the risk of diabetes by 90 percent.
So, Walt is saying 1 in 10 people get T2 which is about the percent of people who get T2 . However we know not all T2s are fat. Look, what he says sounds great but it doesn't square with the numbers. Statements like that remind me of one of my favorite books - Freakonomics. BTW IMO - be wary of those Hardvard guys, they are fast talkers.
At the same time I am all about people being fit and taking a nice walk. Will it help reduce the body's need for insulin - sure. But, will it stop something killing off beta cells, probably not. We do for a fact that early insulin intervention can stop and sometimes reverse beta cell lose even with fat people. So, its probably not the fat.
|
|
|
|
Post by ktim on Dec 19, 2019 16:16:18 GMT -5
I agree with you on this one, and really wish MNKD had started at least a small scale study on this years ago. If they had a protocol that could be used with early prediabetics and showed it could lead to remission in some or most without causing ANY serious hypos... we would not have suffered nearly as much dilution as we have. I think that could have been much more impact than peds will be. I believe that is possible. I think A Mann believed it. Does current management? Have they vetted the idea with FDA? Is there a reason for not doing such a pilot trial? With regard to bolded, a trial is needed to show that diet, exercise plus Afrezza produces this more often than diet and exercise alone. Other STII trials would seem to indicate that should be the case. Or, we could also use real-life evidence. If there is enough real-life data to support it, FDA would accept it. Not everything has to be done via RCTs. There are many drawbacks and limitations with RCTs that do not exist in real-life. The two should compliment one another and may offset the need for xyz depending on the case and circumstances. Lucky, FDA fully supports and accepts real-life data and evidence in making such decisions!In making what decisions? We have children using Afrezza off label. Are you saying MNKD is unnecessarily spending lots of money on ped trials because FDA would have accepted the "real life data" of children not in a trial using it successfully? What real life data exists that shows that Afrezza STII with diet and exercise is more effective at inducing remission in prediabetics than diet and exercise alone? |
|
|
|
Post by sayhey24 on Dec 19, 2019 16:16:33 GMT -5
I agree with you on this one, and really wish MNKD had started at least a small scale study on this years ago. If they had a protocol that could be used with early prediabetics and showed it could lead to remission in some or most without causing ANY serious hypos... we would not have suffered nearly as much dilution as we have. I think that could have been much more impact than peds will be. I believe that is possible. I think A Mann believed it. Does current management? Have they vetted the idea with FDA? Is there a reason for not doing such a pilot trial? With regard to bolded, a trial is needed to show that diet, exercise plus Afrezza produces this more often than diet and exercise alone. Other STII trials would seem to indicate that should be the case. Or, we could also use real-life evidence. If there is enough real-life data to support it, FDA would accept it. Not everything has to be done via RCTs. There are many drawbacks and limitations with RCTs that do not exist in real-life. The two should compliment one another and may offset the need for xyz depending on the case and circumstances. Lucky, FDA fully supports and accepts real-life data and evidence in making such decisions! Mango - Aged would not approve with out the big study. Come on man, this is afrezza! Everything has to be hard! I don't think MNKD ever caught a break. India is coming for starters. The reality is however - everyone knows the ADA SoC steps are designed for failure so what have they got to lose? |
|
|
|
Post by harryx1 on Dec 19, 2019 16:22:43 GMT -5
|
|
|
|
Post by mango on Dec 19, 2019 16:30:24 GMT -5
Or, we could also use real-life evidence. If there is enough real-life data to support it, FDA would accept it. Not everything has to be done via RCTs. There are many drawbacks and limitations with RCTs that do not exist in real-life. The two should compliment one another and may offset the need for xyz depending on the case and circumstances. Lucky, FDA fully supports and accepts real-life data and evidence in making such decisions!In making what decisions? We have children using Afrezza off label. Are you saying MNKD is unnecessarily spending lots of money on ped trials because FDA would have accepted the "real life data" of children not in a trial using it successfully? What real life data exists that shows that Afrezza STII with diet and exercise is more effective at inducing remission in prediabetics than diet and exercise alone? FDA supports and accepts real-life data and evidence in making regulatory decisions. Same as with clinical trials. 🙂 You can read more at FDA website if you so desire. |
|
|
|
Post by sayhey24 on Dec 19, 2019 16:32:58 GMT -5
I think the problem here is the FDA has no impact on the ADA which is the gate keeper to the SoC and the "ultra acting" class. Once they get the new class they can ask for a label update.
The ADA on the other hand is driven by politics and big money. The more they can delay and ignore the better for their base. With out the huge study they are not doing anything.
|
|
|
|
Post by ktim on Dec 19, 2019 16:37:07 GMT -5
Ktim - OK, you must be right. All fat people get diabetes. Oh wait, is that a fact? HSPH’s Willett, who chairs the Department of Nutrition, said that getting Americans’ diet right can mean the difference between being healthy or ill. Studies have shown that not smoking, eating properly, and keeping a healthy weight — a body mass index of under 25 — reduces the risk of diabetes by 90 percent. So, Walt is saying 1 in 10 people get T2 which is about the percent of people who get T2 . However we know not all T2s are fat. Look, what he says sounds great but it doesn't square with the numbers. Statements like that remind me of one of my favorite books - Freakonomics. BTW IMO - be wary of those Hardvard guys, they are fast talkers. At the same time I am all about people being fit and taking a nice walk. Will it help reduce the body's need for insulin - sure. But, will it stop something killing off beta cells, probably not. We do for a fact that early insulin intervention can stop and sometimes reverse beta cell lose even with fat people. So, its probably not the fat. You are good, or at least persistent, at the strawman argument. Implying I've asserted things I clearly have not. I'v never said everyone that is overweight gets diabetes. And I do not use what I find to be a slightly offensive term "fat people" as if it is a binary condition and at a certain point people become defined by their weight. In discussing medicine I think the proper way of referring to this when pertinent to the discussion is to say "people who are overweight" or "people with high BMI". That said, the argument strawman or otherwise isn't valid. Just like... Not everyone that gets lung cancer smokes and not everyone that smokes gets lung cancer... so smoking can't be causative factor in developing lung cancer? You are, perhaps intentionally, misrepresenting that statistic in red. What he is saying is that risk is reduced by 90%. So if overall about 10% of population gets diabetes, what he is saying is that statistics have shown people that don't smoke, eat properly and keep body mass index under 25 would have only a 1% chance of getting diabetes. |
|
|
|
Post by shawnonafrezza on Dec 19, 2019 16:55:02 GMT -5
And just to throw in the "fat" fun. There is a lot of work (on mobile, can't link) about personal fat thresholds and various genetic markers where people either can or cannot make more fat cells. The more fat cells you can create the better you're able to dispose of glucose. It's not binary at all. It's may be why we see a lot of healthy weight asian populations get T2. Genetic personal fat thresholds and the ability, or lacktherof, to create new fat cells.
|
|
|
|
Post by mango on Dec 19, 2019 16:59:57 GMT -5
Great article/interview on the implications of real-world evidence & FDA, thanks Harry! Here’s a snippet: Brenda: That’s right! As FDA Commissioner Scott Gottlieb says: “The more widespread use of RWE can make our medical product development process more efficient, and help lower the costs of development.” So, let’s talk about a few RWE uses that the 21st Century Cures Act directs the FDA to focus on – RWE to support or satisfy post-approval study requirements and RWE to support the approval of a new indication – as well as supporting new approvals of drugs to treat rare diseases. Ernest: One public example is the use of a patient registry to meet a post-marketing commitment for the drug Kalydeco®. Vertex is conducting a 3-year, single arm, observational study of all patients registered in the U.S. Cystic Fibrosis Foundation Patient Registry who have a newly designated CFTR gene mutation shown to be responsive to Kalydeco®. This study will evaluate select patient outcomes, including lung function, and select cystic fibrosis complications. When completed, the study, will meet the post-marketing commitment. Ernest: As the FDA becomes more and more comfortable with RWE for these purposes, we expect to see more examples of the use of RWE to support new approvals and new indications, satisfying post-marketing commitments, and for other uses such as determining the feasibility of certain clinical studies. Brenda: Let’s turn to a related topic for a moment. Ernest, what about promotional issues? Is there anything about RWE that companies should consider when promoting their products? Ernest: When it comes to promoting their products, I think that one area for sponsors to pay attention to is health care economic Information, or HCEI, provided to payors, formulary committees and other similar entities. The 21st Century Cures Act amended FDAMA Section 114 in some notable ways. For example, by changing the requirement that HCEI claims made to “formulary committees, payers, and other similar entities” from“directly related to the indication” to simply “related to the indication”, the Act, and the recently published guidance, seems to clear up some of the questions about the use of RWE in this type of promotion. In the past, I think sponsors were hesitant to step into this area because RWE might not always “directly” relate to the indication—I mean the patient mix in the real world is never the same as a clinical trial—but removing that “directly” language makes it clear that RWE can be an appropriate source for the development of HCEI. The examples in the guidance of what qualifies as “related to”—duration of therapy, patient subgroups, length of hospital stay—makes it clear the FDA is trying to be flexible. That being said, the agency did set some guideposts—for example, sponsors shouldn’t focus HCEI RWE on patients not found within the indicated population for the product. ————————————— As for Afrezza and RWE, one example of such an potential entity that may be poised at conducting, monitoring, gathering and storing such real-life data is VDex. If VDex greatly expanded they would have the patient base and know-how to do such a thing (think CGMs etc). Remember, physicians are constantly conducting real-life clinical trials with their patients when they manage, document, follow etc with their patients. |
|
|
|
Post by agedhippie on Dec 19, 2019 17:13:12 GMT -5
The 118 trial (aka. NCT00570687) gets mentioned a lot but I think that is due to a misunderstanding. Nowhere do they administer insulin to a fasted diabetic in either the lispro or Afrezza groups and then see what happened. What they did was a glycemic clamp. For this you have to be fasted because you are hooked to a glucose drip and that has to be your sole source of glucose. The aim is to give the person insulin and then continually adjust the glucose to keep the blood glucose level flat. A graph is plotted based on the glucose flow rates to see the activity of the insulin. For obvious reasons you will never get a hypo regardless of the quantity or type of insulin used (as was the case, neither Afrezza nor Humalog users had a hypo in this test) I have done one of these glycemic clamps (my endo needed a guinea pig for some research) and I cannot recommend the experience, it's really boring and you are staving, literally! Aged - There is no reason to speculate. Here is from the 3Q2009 quarterly call - "The basis of my (Al Mann) view was derived from the dose escalation study with meal challenges in which better glucose control was achieved with ever greater doses of AFRESA, yet without any hypos. Yet based on decades of battling these challenges of conventional insulin therapy, some physicians have questioned my suggestion. Therefore, I proposed a meal escalation study in which patients would take a fixed dose of AFRESA and then a series of meal challenges. Our clinical team designed a protocol to set a standard meal with 50 g of carbohydrates. That was the 100% challenge. This was followed by challenges at 200%, 50% and zero percent. When I heard of zero I was shocked. Surely there would be severe hypo. The remarkable thing was that with the regular prescribed dose of AFRESA regardless of carbohydrate intake between zero and 100 grams the range of excursion is only plus or minus 30-35 mg [reduction] from baseline for all of the Type II patients in the study." I can tell you at the Adcom the FDA challenged the one doctor who second dosed his afrezza patients and not his RAAs and got amazing results with afrezza. The FDA said he cheated. He was convinced he would have killed his RAA patients if he did and told the FDA they were wrong. So we can agree then that the 118 trial in no way supports the claim that Type 2 diabetics do not get hypos if they fast and take Afrezza because it was simply not tested. (Actually one Type 2 did get a hypo in the 118 trial on the original protocol and with food). The executive summary of what follows for those that don't want to plow through the whole thing is that in the trial Al Mann is talking about lots of Type 2s on Afrezza got hypos. That's probably why he phrased his comment as being the difference between carb loads rather than the number of hypos. Down to detail. Lets move on to the trial that Al Mann is talking about there and it's one I have bought up before, NCT00747006 from back in 2008 (which is why Al Mann is talking about it in 2009). Calling it a trial is a little generous since there were 5 Type 2 participants involved. This was the trial that had the overdosing of the Type 1 arm stopped where all of the Type 1 participants suffered hypos when they halved the carbs but kept the Afrezza dose the same. So what happened with the Type 2 side? The Type 2 side was split two test; an original Afrezza only test, and a second test split into Humalog users and Afrezza users. The result? One Type 2 on Afrezza in the original Afrezza only groups has a severe hypo, and 6 out of the 8 get a non-severe hypo. What about the head to head group? The good news is that nobody had a severe hypo in either the Afrezza or RAA groups, however 2 out of 3 people in the Afrezza group, and 1 out of 2 people in the RAA group had non-severe hypos. I suspect by this point it was clear that you got similar results with both RAA and Afrezza when you did dumb things so this got spun as a delta story and not a hypo story. Anyway the data is all there in the trial filing. A Type 2 most definitely can get a hypo from from Afrezza and, with the disclaimer about the sample size, it looks as if the results are about the same as a Type 2 on RAA. I put the severe hypo down to the person taking Afrezza, not eating and then getting drunk at a wine tasting and essentially passing out rather than a real severe hypo. |
|
|
|
Post by prcgorman2 on Dec 19, 2019 20:33:40 GMT -5
When discussing severity of a hypoglycemic event, is the definition based on how little glucose was measured, or is there a time component? It would seem like there needs to be some language around how to describe severity. Is under 90 for 3 hours as severe as below 70 for 30 minutes? (And please don’t bash me too hard for not remembering what blood glucose measurements count as a “hypo”. I have no idea from memory what the threshold is.)
|
|
|
|
Post by shawnonafrezza on Dec 19, 2019 21:47:28 GMT -5
Typically under 70 is hypo, under 55 is severe. Time does not matter.
|
|
|
|
Post by sayhey24 on Dec 20, 2019 7:50:12 GMT -5
Aged - its the holiday season and sure we can agree. In addition to the NCT00747006 I think Al was talking about the NCT00570687.
I think what we can agree to is its not really worth trying to zapruder these studies at this point. Why can't we just take Al at his word? This guy put his money where his mouth was and ran over 60 studies to answer every question and doubter. Another thing I know is Al was a really smart guy.
I think Bill from VDex showed similar results in one of his papers where he did not eat and took afrezza. The thing is we really don't need a study to do this. It works and it repeatable. In fact Bill did it with a non-diabetic. The key is the "other meds". Every time we see issues its because of subq insulin, TZD, or sulfonylureas in the mix. When we get them out things are predictable because afrezza is predictable.
Take the T2 off the other meds including metformin and just give them the afrezza. I just saw a commercial for GOLO and their diet to reduce insulin resistance. As I have said a zillion times, there is nothing wrong with dieting and a good walk but we do know if we get the sugars under control, insulin resistance decreases. If GOLO wants a better plan all they need to do is add the afrezza.
|
|
|
|
Post by lennymnkd on Dec 20, 2019 8:19:46 GMT -5
And a CGM 😀
|
|
|
|
Post by agedhippie on Dec 20, 2019 9:18:50 GMT -5
Aged - its the holiday season and sure we can agree. In addition to the NCT00747006 I think Al was talking about the NCT00570687. I think what we can agree to is its not really worth trying to zapruder these studies at this point. Why can't we just take Al at his word? This guy put his money where his mouth was and ran over 60 studies to answer every question and doubter. Another thing I know is Al was a really smart guy. I think Bill from VDex showed similar results in one of his papers where he did not eat and took afrezza. The thing is we really don't need a study to do this. It works and it repeatable. In fact Bill did it with a non-diabetic. The key is the "other meds". Every time we see issues its because of subq insulin, TZD, or sulfonylureas in the mix. When we get them out things are predictable because afrezza is predictable. Take the T2 off the other meds including metformin and just give them the afrezza. I just saw a commercial for GOLO and their diet to reduce insulin resistance. As I have said a zillion times, there is nothing wrong with dieting and a good walk but we do know if we get the sugars under control, insulin resistance decreases. If GOLO wants a better plan all they need to do is add the afrezza. NCT00570687 is MKC-TI-118 and it cannot be that trial because that was not what was tested in the trial, it was a crossover with glucose clamps. You have to be fasted for a clamp, and varying the meal would invalidate the crossover. I still think it was the earlier trial. Either way there is no evidence. Why can't we take Al at his word? Well I don't think that is what he said, he was talking about variances and not hypos, but chiefly because that's not how medicine works or clinical trials for approvals would not be necessary and every drug would just work because really smart people work on them. |
|
