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Post by benh on May 29, 2015 3:09:22 GMT -5
I will be interested to see the abstract bodies posted, especially the one from board 96 (late breaking) on a meta-analysis of the safety and efficacy of Technosphere Insulin. My cursory search on Google Scholar found no other previous publications by Dr. Westcott, an internist, in the area of diabetes or metabolic disease. I hope he is presenting from the perspective of a clinician practicing evidence based medicine and I will be interested in his conclusions. Oddly, he is listed as being associated with Tufts Medical Center but does not appear in the clinical directory. Chris-C I am trying to temper my enthusiasm for this one. |
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Post by Chris-C on May 29, 2015 11:32:52 GMT -5
I will be interested to see the abstract bodies posted, especially the one from board 96 (late breaking) on a meta-analysis of the safety and efficacy of Technosphere Insulin. My cursory search on Google Scholar found no other previous publications by Dr. Westcott, an internist, in the area of diabetes or metabolic disease. I hope he is presenting from the perspective of a clinician practicing evidence based medicine and I will be interested in his conclusions. Oddly, he is listed as being associated with Tufts Medical Center but does not appear in the clinical directory. Chris-C I am trying to temper my enthusiasm for this one. Well, my concern is with a non-scientist trying to take on a meta-analysis of previous studies. This takes more than garden variety analytical skill to be done correctly. The problem is, if the wrong conclusion is reached because of lack of expertise, any reporter covering the event may not be erudite enough to separate the wheat from the chaff, so to speak. I trust the short interest crowd with the same degree of confidence in their collective integrity as I do Vladimir Putin and his minions for their interest in moving Russia toward democracy. Chris C |
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Post by benh on May 29, 2015 12:33:54 GMT -5
I have a more positive perspective to it. Understanding the method and understanding the results are very different skill sets. If the method is concrete, the presenter may only need to fully understand the results and present them effectively. In addition to this, Sanofi have an IR conference call relating to the ADA. en.sanofi.com/investors/events/corporate/2015/2015-06-09_IR_Seminar_Diabetes.aspxWhat I find interesting with this is it's an IR conference call. Merkel just opened their new state of the art insulin facility in Frankfurt. If the pieces to which I hope come together are to come together, this set of events would be perfect. |
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Post by bradleysbest on May 29, 2015 12:35:19 GMT -5
Wouldn't it be nice to have a major announcement (press release) with some damn good news the morning of the Goldman Sucks conference! Give it to them like they have given it to us MNKD shareholders....just saying!
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Post by notamnkdmillionaire on May 29, 2015 13:00:07 GMT -5
Wouldn't it be nice to have a major announcement (press release) with some damn good news the morning of the Goldman Sucks conference! Give it to them like they have given it to us MNKD shareholders....just saying! The only one giving anything to anyone has been management to its shareholders and not in a good giving sort of way. At least not yet. I am hoping that the ADA becomes the pivotal starting point where Afrezza finally makes inroads with the rest of the medical community. |
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Post by benh on May 29, 2015 17:16:35 GMT -5
I am trying to temper my enthusiasm for this one. Well, my concern is with a non-scientist trying to take on a meta-analysis of previous studies. This takes more than garden variety analytical skill to be done correctly. The problem is, if the wrong conclusion is reached because of lack of expertise, any reporter covering the event may not be erudite enough to separate the wheat from the chaff, so to speak. I trust the short interest crowd with the same degree of confidence in their collective integrity as I do Vladimir Putin and his minions for their interest in moving Russia toward democracy. Chris C Chris. I (again) stand corrected. Your skepticism was right. |
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Post by benh on May 29, 2015 17:45:09 GMT -5
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Post by jpg on May 29, 2015 17:55:38 GMT -5
Well, my concern is with a non-scientist trying to take on a meta-analysis of previous studies. This takes more than garden variety analytical skill to be done correctly. The problem is, if the wrong conclusion is reached because of lack of expertise, any reporter covering the event may not be erudite enough to separate the wheat from the chaff, so to speak. I trust the short interest crowd with the same degree of confidence in their collective integrity as I do Vladimir Putin and his minions for their interest in moving Russia toward democracy. Chris C Chris. I (again) stand corrected. Your skepticism was right. I would mostly be curious as to who got him to do this meta analysis... Did it say anywhere if he is being paid by BP for something related or not to Sanofi? Is he a 'hired gun' for certain BPs? Seems rather preplanned and I wouldn't be surprised in the least if a competitor to Sanofi had a hand in putting this forward. This being said I am mildly curious to how they structured their analysis. From the conclusion it's rather obvious they weren't kind to Afrezza but then again Mannkind set up all their trials in a way as to never really permit Afrezza to show what it could really do so a meta analysis of this data would by definition show Afrezza in a bad/ worst light then any one single study. It's kind of simple maths really. I am curious as to the glossing over of certain things though? I probably won't bother reading the analysis even if they do get it published but it could be interesting to look at how they evaluated certain data points (or did they simply skip over or minimize many of the positives of Afrezza? This meta analysis will be used to trash Afrezza and say it is all scientific. A bit like the pseudo reanalysis Sanofi presented a few weeks ago (and that I originally thought was new data) this meta analysis tells us nothing new. The author simply make a conclusion on all the trials we have seen so far (as you we all do) and come up with a different conclusion than most of us. Looking only at numbers can sometimes make you rather clueless to a really good thing and especially so when all the trials were designed to demonstrate non inferiority. A slightly negative signal will and did get amplified and whoever did this trail knew this ahead of time obviously... That s one of the reasons meta analysis are often received so skeptically by scientists and doctors. You often get to reach the conclusion you want by setting the goal posts where you think (know) the statisticsl will go. |
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Post by Chris-C on May 29, 2015 23:37:25 GMT -5
OK. So here is the core abstract:
Efficacy and Safety of Technosphere Inhaled Insulin: Systematic Review and Meta-analysis
The Full Poster will be available Saturday, June 6, 2015 at 10:00:00 AM Eastern.
Clinical Therapeutics/New Technology–Insulin Delivery Systems
Presented on Sunday, June 7, 2015 12:00 PM
Author(s): GREGORY P. WESTCOTT, ETHAN M. BALK, ANASTASSIOS G. PITTAS, Boston, MA, Providence, RI
Introduction: Technosphere inhaled insulin (TI) recently became available for clinical use as a non-invasive alternative to subcutaneous insulin in adult patients with diabetes. The purpose of this systematic review and meta-analysis was to determine the efficacy, safety, and patient acceptability of TI.
Methods: We searched MEDLINE, the Cochrane Clinical Trials Register, and the Food and Drug Administration review documents of TI through January 31, 2015 for randomized control trials that compared TI with placebo, subcutaneous insulin, or oral anti-diabetic drugs. Two reviewers independently assessed trials for inclusion and extracted data on study characteristics, participant baseline characteristics, efficacy, and safety outcomes.
Results: 12 trials met eligibility criteria (n=5,273, mean age range 38-61). Among patients with type 1 or insulin-requiring type 2 diabetes, hemoglobin A1c improvement from baseline favored subcutaneous insulin over TI (net difference 0.16% [95% CI 0.06, 0.25]). TI was associated with less weight gain (net difference -1.6 kg [-2.1, -1.6]) and less risk of hypoglycemia (odds ratio 0.61 [0.35, 0.92]) compared to subcutaneous insulin. There was an increased incidence of mild, transient, dry cough in patients treated with TI (odds ratio 7.82 [6.14, 10.15]) and greater decline in FEV1 (net difference -0.038 liters [-0.049, -0.026]). There was no difference in quality of life or overall patient satisfaction. Many trials were designed for non-inferiority, which may introduce bias, and most of the trials were 24 weeks duration or less, thus limiting assessment of long-term safety.
Conclusions: Until long-term safety data are available, TI should be reserved for non-pregnant, non-smoking, adult patients with diabetes, free of pulmonary disease, who are needle-phobic and would otherwise delay initiating or intensifying insulin therapy. For patients who are needle-tolerant, subcutaneous insulin appears to be a better option.
The abstract has a negative-neutral spin; not as bad as I feared but not enthusiastic and argues for maintaining the status quo (injected insulin).fsqPittas appears to be the only investigator with experience in the method, having published a meta analysis of incretin mimetics 8 years ago that was more favorable to their use than this analysis is to TI. Although CONFLICT DISCLOSURES are denied by the authors, Tufts has a cultural history of tolerating payments for research by BPs. The question then arises as to who funded the study? Meta analytical studies are, of themselves, easy ways to manufacture conclusions quickly if one wishes to do so, and despite the absence of any new data or findings (only data from existing studies are available); reviewers are free to set their inclusion criteria and endpoints,which could make such studies convenient methods for fostering a particular agenda behind veil of legitimacy.
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Post by jpg on May 30, 2015 2:51:56 GMT -5
The abstract has a negative-neutral spin; not as bad as I feared but not enthusiastic and argues for maintaining the status quo (injected insulin).fsqPittas appears to be the only investigator with experience in the method, having published a meta analysis of incretin mimetics 8 years ago that was more favorable to their use than this analysis is to TI. Although CONFLICT DISCLOSURES are denied by the authors, Tufts has a cultural history of tolerating payments for research by BPs. The question then arises as to who funded the study? Meta analytical studies are, of themselves, easy ways to manufacture conclusions quickly if one wishes to do so, and despite the absence of any new data or findings (only data from existing studies are available); reviewers are free to set their inclusion criteria and endpoints,which could make such studies convenient methods for fostering a particular agenda behind veil of legitimacy. I said I would even read the study when it came out but I couldn't resist doing some digging... As much as I find mechanical extraction and interpretation of data scientifically displeasing if done poorly it is the way medicine now works and 2 of the 3 authors have done a lot of this stuff. We will only be able to (subjectively and personally obviously) tell if they have done a good job when we read the full meta analysis. This being said the abstract is not to me (subjectively and personally) encouraging. The non inferiority bias thing is a big deal and didn't make it into their conclusion. Bad biased data is the weakness of meta analysis and few things can bias as much as combining a bunch of non inferiority studies that were specifically designed not to show superiority but simply to get past the goalpost. What I found on the 3 authors (no smoking gun and certainly no evidence of 'BP contract workers'): Anastassios G. Pittas has published extensively and mostly non commercial stuff. He has done a few drug reviews and has been a paid consultant to GlaxoSmithKline. He has done a previous meta analysis on inhaled insulin in which the discussion was rational and well though out and he was much kinder to Exubera (article and abstract) than he was to Afrezza (abstract only available): 7 November 2006 Meta-Analysis: Efficacy and Safety of Inhaled Insulin Therapy in Adults with Diabetes Mellitus Lisa Ceglia, MD; Joseph Lau, MD; and Anastassios G. Pittas, MD, MSc Ann Intern Med. 2006;145(9):665-675. doi:10.7326/0003-4819-145-9-200611070-00009 He also seemed very kind and positive towards Thiazolidinediones (but was working for GSK (Avendia)) when he wrote this article...: Expert Opinion on Pharmacotherapy Monthly Focus: Cardiovascular, Renal, Endocrine & Metabolic Thiazolidinediones in the treatment of Type 2 diabetes Anastassios G Pittas & Andrew S Greenberg His review of incretins (which I didn't read) did not have any stated conflicts: Review | July 11, 2007 Efficacy and Safety of Incretin Therapy in Type 2 DiabetesSystematic Review and Meta-analysis Renee E. Amori, MD; Joseph Lau, MD; Anastassios G. Pittas, MD, MSc ETHAN M. BALK is also well published and has done numerous non commercial reviews and does not seem to have any obvious conflicts. Most of his work seems to be 'by the book data meta analysis' and one of his reviews of meta analysis is actually worth a read as it is critical of the type of meta analysis that they did using the type of data the Afrezza non inferiority studies produced: Correlation of Quality Measures With Estimates of Treatment Effect in Meta-analyses of Randomized Controlled Trials by Lau, Joseph; Moskowitz, Harry; Bonis, Peter A. L; Schmid, Christopher H; Balk, Ethan M; Wang, Chenchen; Ioannidis, John P. A I couldn't find any publications by GREGORY P. WESTCOTT? Kind of strange but maybe this is his first publication or he spelled his name differently in the past or I am simply tired of thinking of Mannkind and can't do simple searches anymore? All in all no obvious conflicts except for the growingly cautious attitude of Dr. Pittas over the years and some hyperbolic optimism for a GSK drug a while back (maybe he got burnt on that and decided to become a skeptic!)... |
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Post by Chris-C on May 30, 2015 12:04:11 GMT -5
jpg-
Nice sleuthing. I tend to agree with your observations. I'm still curious about the timing on this one and the motivation of the writers. I'm also curious to see if/where it appears in print.
Regards
Chris C
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Post by jgv on May 30, 2015 12:33:37 GMT -5
FYI to all here. I am a physician at a major academic center (so you know where this perspective is coming from).
The abstract is of mere interest and should not be weighted in either direction pro or con. As it is just an abstract and has not gone through ANY form of peer review its value is limited. The purpose of the "abstract display" is to give other researchers an opportunity to see what you are doing and to weigh in with enthusiasm, potential collaboration, and to pick the piece a part. I've published many papers and have had many papers not make it through the peer review process. I have also reviewed many papers for publication. The abstract is literally an idea with direction. A published manuscript has gone though the initial round of peer review (it was reviewed by a group of reviewers with expertise in that field, was sound, and the reviewers felt it contributes to the body of knowledge on the subject. The manuscript is then tested by many other published manuscripts which either support or refute the findings. It's a long process. It's a very small % of abstracts that will ever even make it to the manuscript stage. They (abstracts) are important to the author more so than the medical or research community. It's like the person who says "hey, I've got this song, want to hear it?!" It's literally at that stage of the game.
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Post by doubleo7 on May 30, 2015 12:37:47 GMT -5
So we have less hypo and less weight gain vs the a1c number. We also know that more hypo lowers the a1c number. It can't be that hard to calculate some sort of correction factor in order to have a fair assessment. Is there one out there and if not, why?
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Post by jpg on May 30, 2015 13:53:01 GMT -5
So we have less hypo and less weight gain vs the a1c number. We also know that more hypo lowers the a1c number. It can't be that hard to calculate some sort of correction factor in order to have a fair assessment. Is there one out there and if not, why? For many endos it's only about the A1C and nothing else. If the A1c is good enough the rest doesn't matter. For many anything that justifies the status quo is what will work intellectually for them. As for your question: without CGM the correlations are not that great and would probably not help Afrezza. Like I keep on mumbling: CMGs are our best friend.,, |
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Post by Chris-C on May 30, 2015 14:37:54 GMT -5
FYI to all here. I am a physician at a major academic center (so you know where this perspective is coming from). The abstract is of mere interest and should not be weighted in either direction pro or con. As it is just an abstract and has not gone through ANY form of peer review its value is limited. The purpose of the "abstract display" is to give other researchers an opportunity to see what you are doing and to weigh in with enthusiasm, potential collaboration, and to pick the piece a part. I've published many papers and have had many papers not make it through the peer review process. I have also reviewed many papers for publication. The abstract is literally an idea with direction. A published manuscript has gone though the initial round of peer review (it was reviewed by a group of reviewers with expertise in that field, was sound, and the reviewers felt it contributes to the body of knowledge on the subject. The manuscript is then tested by many other published manuscripts which either support or refute the findings. It's a long process. It's a very small % of abstracts that will ever even make it to the manuscript stage. They (abstracts) are important to the author more so than the medical or research community. It's like the person who says "hey, I've got this song, want to hear it?!" It's literally at that stage of the game. Hi jgv: Thanks for posting and welcome to the board. Here is my disclosure so you know the perspective I'm coming from: I'm a "recovering academic" clinical scientist and senior administrator who held tenured appointments at US and Canadian academic health centers. I have many publications in scientific journals, but I am not an expert in endocrinology, internal medicine, or diabetes. In the scientific meetings I've attended, posters generally represent the results of studies that have been completed, with all the elements expected in a study. They are often exploratory studies, small sample size "pilot studies" and similar contributions that are worthy of review and discussion with the authors, but perhaps either not sufficiently rigorous or compelling to be assigned a regular scientific session. The posters I've seen are most often expanded abstracts (summaries) of a study rather than "ideas about studies." Poster sessions I've attended are ideal for dialogue with the investigators (often early stage or emerging) and quite good as venues for providing mentoring and feedback. I've never attended an ADA conference, so perhaps the tradition is different there. I have a colleague who is a former research director at ADA, so I'll query him to see if that is the case. The "late breaking" label is interesting, and it's not clear to me if that means it was just completed and not submitted in time for a full peer review (my educated guess) or that "late breaking" confers some notion of importance or urgency. Of course, the trouble with posters that present "preliminary" findings from meta-analytical studies is that the conclusions presented by the authors get "broadcast", whether tentative or not, and if the study is revised (an uncommon occurrence, in my experience) and the conclusions are revised, it is unlikely that the members of the "original audience" will ever get wind of those revisions/corrections. This is the game played by political misinformation in modern day electoral politics (and in stock market manipulation, by the way). My question still stands. What motivates a clinical practitioner -internist (perhaps not an endocrinologist) without a scientific track record in diabetes research to do a meta analysis of a new inhaled insulin and to submit it as a lead author at this particular ADA meeting at this particular time? And why does the abstract seem to stand silent on the issue of pharmaco-kinetics and dynamics, since even non medical informed observers (many on this board) know that this is a distinguishing feature of Afrezza and that traditional approaches to measuring efficacy in glycemic control may not be ideal? If I were a peer reviewer for papers and posters submitted at ADA, even acknowledging my biases as an investor and a health professional concerned about the obesity and diabetes epidemics (pandemics), I'd welcome a paper (poster) that simply discussed traditional measures of efficacy in diabetes care and joined the chorus of informed commentators who note that for ultra fast acting insulin (inhaled) A1c might not reveal the value of the Rx in controlling glycemic excursions. Based on this abstract, I'd at the very least expect informed scientists to acknowledge that a limitation of the study might be that traditional measures could potentially understate the full benefit of the treatment, given that the damage caused by uncontrolled spikes may be the critical factor in understanding how those excursions lead to secondary consequences such as peripheral nerve damage. As an idealistic "scientific boy scout", one of the hardest lessons I had to learn in science was that scientific data can be (and are) manipulated as propoganda for "political reasons" that range from advancing (or preserving) the careers and reputations of scientists, supporting existing reigning theories", which often have religious adherents, to manipulating perceptions of value for economic gain. To an idealist, it is disturbing to acknowledge that a method of knowing (science) that prides itself on observable objectivity still has "subjective" components— the human element cannot be removed entirely, and the degree of weakness that this represents depends entirely on the integrity of the investigator(s). As a health care provider who still believes in ethical behavior, I am also adamant that if any treatment results in harm that, on balance, exceeds its benefits, then that treatment should be discontinued. Primum non nocere. And, even though I have a six figure stake in MNKD, I think that if studies show it causes harm that outweighs its benefits, it should not be prescribed. I also believe that interventions that have not been shown to help nor harm patients are unethical; simply because they consume valuable resources (payments from patients or insurors; and they falsely or cruelly inspire unwarranted hope where it is otherwise unjustified. jm2cw ChrisC |
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