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Post by agedhippie on Nov 5, 2018 9:38:06 GMT -5
MannKind laid a solid foundation before they ever pursued FDA approval, and has accumulated a comprehensive safety profile that includes over 600 CT and MRI lung scans, hundreds of pulmonary function studies, years of use in thousands of patients, and so on. We do not need nor require the level of data you describe to establish a conclusion on Afrezza's safety simply because there is no logical reason for it. The basic science is well established, and MannKind has effectively demonstrated that their insulin does not produce any signs of pulmonary malignancy, and their inert carrier particle does not produce any signs of pulmonary malignancy. For these reasons, I do not understand your argument. Not only has Lantus been linked to cancer in 7 observational studies, but even its basic carcinogenicity studies in rodents raises major concerns for it causing cancer. Couple it with the 7 observational studies and you have yourself a legitimate concern for cancer that warrants further and immediate investigation. 600 people vs 22,000 for that Lantus study, or 8,000 for the Mannkind Lung trial? You are running into two problems there - your sample set is small, and lacking consistent medical records for patients a formal trial is the only way to get the data so the FDA has asked for that. You are making the same error that you made with the ADA - it does not matter what you believe, it matters what can be proven in a form the FDA or ADA accept if you want their approval. You bet I looked into the Lantus risk when it happened and it illustrates the problem nicely. If you have one case a year, then two cases a year is a doubling of the risk, but to me personally it's not significant - the real risk is essential unchanged. The Afrezza cancer scare is the same. The number of people getting cancer in the group is tiny, and yet the arm using Afrezza had more cancer cases, but the number is still tiny. What happens when those numbers are scaled up? Cue the FDA lung trial requirement to see if that was just statistical noise or real.
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Post by agedhippie on Nov 5, 2018 9:48:09 GMT -5
Aged - what is it you want to study; human insulin; or FDKP?
Human insulin has been working in the human body for a very long time. Do some non-diabetics who only use human insulin for BG control get cancer, sure. But I would not say human insulin is the cause. More likely a virus. ... The problem with that argument is that human insulin delivered via certain routes has been intensively studies, lungs are not one of those routes though. You cannot simply say that all delivery routes present equal risk because that is patently not true. Some drugs have to be delivered in certain ways because they cause damage if delivered in other ways. Anyway this is irrelevant to the question - why does the FDA require a lung trial. The answer is because they do not have what they view as a satisfactory data-set for Afrezza to prove safety. Whether you agree or not is utterly pointless since they are the regulator and so it is their call. If you want to sell Afrezza in the US then you do what the FDA tells you.
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Post by mango on Nov 5, 2018 11:53:51 GMT -5
MannKind laid a solid foundation before they ever pursued FDA approval, and has accumulated a comprehensive safety profile that includes over 600 CT and MRI lung scans, hundreds of pulmonary function studies, years of use in thousands of patients, and so on. We do not need nor require the level of data you describe to establish a conclusion on Afrezza's safety simply because there is no logical reason for it. The basic science is well established, and MannKind has effectively demonstrated that their insulin does not produce any signs of pulmonary malignancy, and their inert carrier particle does not produce any signs of pulmonary malignancy. For these reasons, I do not understand your argument. Not only has Lantus been linked to cancer in 7 observational studies, but even its basic carcinogenicity studies in rodents raises major concerns for it causing cancer. Couple it with the 7 observational studies and you have yourself a legitimate concern for cancer that warrants further and immediate investigation. 600 people vs 22,000 for that Lantus study, or 8,000 for the Mannkind Lung trial? You are running into two problems there - your sample set is small, and lacking consistent medical records for patients a formal trial is the only way to get the data so the FDA has asked for that. You are making the same error that you made with the ADA - it does not matter what you believe, it matters what can be proven in a form the FDA or ADA accept if you want their approval. You bet I looked into the Lantus risk when it happened and it illustrates the problem nicely. If you have one case a year, then two cases a year is a doubling of the risk, but to me personally it's not significant - the real risk is essential unchanged. The Afrezza cancer scare is the same. The number of people getting cancer in the group is tiny, and yet the arm using Afrezza had more cancer cases, but the number is still tiny. What happens when those numbers are scaled up? Cue the FDA lung trial requirement to see if that was just statistical noise or real. Well, since Lantus is associated with an increased risk of cancer in T2D, and since long-acting basal insulin is currently recommended for T2D before prandial insulin, and is required for PA before Afrezza can be used in T2D ...maybe the focus should be on what is wrong with that picture instead of diverting attention away from it. Bottom line is Afrezza has an established safety profile studied in more than 3,000 patients, not 600, and there have been no lung malignancy safety signals ever reported with Afrezza.
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Post by tomtabb on Nov 5, 2018 16:13:07 GMT -5
When is MNKD planning on starting the actual safety study the FDA wants? As I recall, there's a deadline at some point.
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Post by mango on Nov 5, 2018 16:26:44 GMT -5
When is MNKD planning on starting the actual safety study the FDA wants? As I recall, there's a deadline at some point. It's status is Delayed and its reason is in "good cause" w/ FDA.
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Post by mnkdfann on Nov 5, 2018 16:36:12 GMT -5
When is MNKD planning on starting the actual safety study the FDA wants? As I recall, there's a deadline at some point. You can do a search at www.accessdata.fda.gov/scripts/cder/pmc/index.cfmI believe this is the trial in question (the 'good cause' bit is in the last bolded section): Requirement/Commitment Number: 4 Required Under: FDAAA Section 505(o)(3) Original Projected Completion Date: 12/31/2023 Description: Conduct a 5-year, randomized, controlled trial in 8,000-10,000 patients with type 2 diabetes to assess the serious potential risk of pulmonary malignancy with Afrezza use. The primary objective of the trial should be to compare the incidence of pulmonary malignancy observed with Afrezza to that observed in the standard of care control group. Secondary endpoints should include mortality due to pulmonary malignancy and all-cause mortality. Randomization to Afrezza or standard of care should be 1 to 1. The patient population should be enriched with respect to lung cancer risk (i.e., predicted incidence of no less than 200/100,000 patient-year). The potential for detection bias should be adequately addressed in the trial design. Subjects who discontinue randomized intervention due to lack of efficacy or tolerability issues should continue to be followed for the outcomes of interest and prospective measures to encourage subject retention and capture outcomes in patients who withdraw or are lost to follow-up should be in place. Glucose control and glycemic rescue should be per standard of care. The trial must also include an assessment of cardiovascular risk based on prospectively defined, collected and independently adjudicated major adverse cardiovascular events or MACE (i.e., cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). Also include as part of the trial a substudy (also with 1 to 1 randomization to either Afrezza or standard or care) to evaluate the long-term effect of Afrezza on pulmonary function. Patients in the substudy should have pulmonary function tests at baseline and every 6 months until end of treatment. Current Status: Delayed
Explanation of Status: The Final Protocol Submission milestone was missed because of ongoing discussion with FDA regarding the study design and FDA determined that the applicant demonstrated “good cause” for the delay. FDA agreed with the applicant on a final protocol in February 2017.
I'm not at all sure what has happened since February 2017. Still delayed? if so, why?
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Post by mango on Nov 5, 2018 17:07:10 GMT -5
When is MNKD planning on starting the actual safety study the FDA wants? As I recall, there's a deadline at some point. You can do a search at www.accessdata.fda.gov/scripts/cder/pmc/index.cfmI believe this is the trial in question (the 'good cause' bit is in the last bolded section): Requirement/Commitment Number: 4 Required Under: FDAAA Section 505(o)(3) Original Projected Completion Date: 12/31/2023 Description: Conduct a 5-year, randomized, controlled trial in 8,000-10,000 patients with type 2 diabetes to assess the serious potential risk of pulmonary malignancy with Afrezza use. The primary objective of the trial should be to compare the incidence of pulmonary malignancy observed with Afrezza to that observed in the standard of care control group. Secondary endpoints should include mortality due to pulmonary malignancy and all-cause mortality. Randomization to Afrezza or standard of care should be 1 to 1. The patient population should be enriched with respect to lung cancer risk (i.e., predicted incidence of no less than 200/100,000 patient-year). The potential for detection bias should be adequately addressed in the trial design. Subjects who discontinue randomized intervention due to lack of efficacy or tolerability issues should continue to be followed for the outcomes of interest and prospective measures to encourage subject retention and capture outcomes in patients who withdraw or are lost to follow-up should be in place. Glucose control and glycemic rescue should be per standard of care. The trial must also include an assessment of cardiovascular risk based on prospectively defined, collected and independently adjudicated major adverse cardiovascular events or MACE (i.e., cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). Also include as part of the trial a substudy (also with 1 to 1 randomization to either Afrezza or standard or care) to evaluate the long-term effect of Afrezza on pulmonary function. Patients in the substudy should have pulmonary function tests at baseline and every 6 months until end of treatment. Current Status: Delayed
Explanation of Status: The Final Protocol Submission milestone was missed because of ongoing discussion with FDA regarding the study design and FDA determined that the applicant demonstrated “good cause” for the delay. FDA agreed with the applicant on a final protocol in February 2017.
I'm not at all sure what has happened since February 2017. Still delayed? if so, why? Still delayed. Looks like a final protocol was approved in 2017, but its submission has been Delayed for good cause according to FDA.
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Post by agedhippie on Nov 5, 2018 17:41:37 GMT -5
Bottom line is Afrezza has an established safety profile studied in more than 3,000 patients, not 600, and there have been no lung malignancy safety signals ever reported with Afrezza. Which trial did Mannkind do with 3,000 patients, and how long did it last?
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Post by mango on Nov 5, 2018 18:13:52 GMT -5
Bottom line is Afrezza has an established safety profile studied in more than 3,000 patients, not 600, and there have been no lung malignancy safety signals ever reported with Afrezza. Which trial did Mannkind do with 3,000 patients, and how long did it last? The clinical trial data reflects exposure of over 3000 patients to AFREZZA.
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Post by sayhey24 on Nov 5, 2018 19:42:26 GMT -5
Aged - what is it you want to study; human insulin; or FDKP?
Human insulin has been working in the human body for a very long time. Do some non-diabetics who only use human insulin for BG control get cancer, sure. But I would not say human insulin is the cause. More likely a virus. ... The problem with that argument is that human insulin delivered via certain routes has been intensively studies, lungs are not one of those routes though. You cannot simply say that all delivery routes present equal risk because that is patently not true. Some drugs have to be delivered in certain ways because they cause damage if delivered in other ways. Anyway this is irrelevant to the question - why does the FDA require a lung trial. The answer is because they do not have what they view as a satisfactory data-set for Afrezza to prove safety. Whether you agree or not is utterly pointless since they are the regulator and so it is their call. If you want to sell Afrezza in the US then you do what the FDA tells you. Aged - you are conflating two different things. The discussion was the cancer causing possibilities of RAA vs human insulin once in the blood. The one thing we have are thousands of years of experience of human insulin in the blood.
RAAs not so much and introducing Frankenstein molecules into the blood is a risky business. Moreover, why would anyone want a Frankenstein insulin when they can take a human insulin and have better results? Why the ADA has not already updated the standards of care is mind boggling. Another 2 or 3 year delay is just hurting the PWDs. IMO, they should be ashamed of themselves.
The FDA approved compassionate use of afrezza in 2007. At this point MNKD has over 10 years of safety information on lung function including patients commenting they have seen improved lung function. In that time I am not aware of any lung scarring issues or other safety issues. I am sure if there were all the MNKD bashers would have reported them by now. I am sure that is not the case with injection sites. Lots of issues.
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Post by agedhippie on Nov 5, 2018 20:31:33 GMT -5
... Anyway this is irrelevant to the question - why does the FDA require a lung trial. The answer is because they do not have what they view as a satisfactory data-set for Afrezza to prove safety. Whether you agree or not is utterly pointless since they are the regulator and so it is their call. If you want to sell Afrezza in the US then you do what the FDA tells you. ... The FDA approved compassionate use of afrezza in 2007. At this point MNKD has over 10 years of safety information on lung function including patients commenting they have seen improved lung function. In that time I am not aware of any lung scarring issues or other safety issues. I am sure if there were all the MNKD bashers would have reported them by now. I am sure that is not the case with injection sites. Lots of issues. My original point stands. The FDA has a very clear understanding of what they need, and does not consider the currently existing data usable. It's their game, it's their rules. You can either play or pack up and go home - those are the options.
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Post by agedhippie on Nov 5, 2018 20:47:34 GMT -5
Which trial did Mannkind do with 3,000 patients, and how long did it last? The clinical trial data reflects exposure of over 3000 patients to AFREZZA. You cannot simply adding up everyone who has ever taken Afrezza in a trial does not work as the protocols all differ. The FDA is very specific about the trial; it's for five years, it's 8,000 to 10,000 Type 2 diabetics, and most importantly the patient population should be enriched with respect to lung cancer risk (i.e., predicted incidence of no less than 200/100,000 patient-year). Why not make lemonade from the lemons? This trial has to be run so add secondary endpoints around HbA1c (I would say TIR but for this size group that would be horrifically expensive) and hypoglycemia. There is a lot you could mine from the resulting data-set if you constructed the protocol well.
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Post by mango on Nov 5, 2018 21:56:02 GMT -5
... The FDA approved compassionate use of afrezza in 2007. At this point MNKD has over 10 years of safety information on lung function including patients commenting they have seen improved lung function. In that time I am not aware of any lung scarring issues or other safety issues. I am sure if there were all the MNKD bashers would have reported them by now. I am sure that is not the case with injection sites. Lots of issues. My original point stands. The FDA has a very clear understanding of what they need, and does not consider the currently existing data usable. It's their game, it's their rules. You can either play or pack up and go home - those are the options. There is no factual basis for what you are arguing. I'd suggest taking it up with this fellow below, as he seems well qualified on the matter and also disagrees with you, taboot. John Bruce Bode, MD, PhD, FACE (Chair, MannKind Scientific Advisory Board)- Verne S. Caviness Distinguished Professor
- Chief, Division of Endocrinology
- Director, Diabetes Center
- Director, NC Translational and Clinical Sciences Institute
- Formerly held the position of President, Medicine & Science on the board of the American Diabetes Association.
“The problem is most people (ENDOs) out there, never give this (AFREZZA) an option. They worry about the pulmonary safety opinion. They never worried about pulmonary safety, but that's their job. Their job is to make sure that whatever medication you give that that it's safe. And there's clearly, from Lung Biologists and Pulmonologists and Oncologists, the (AFREZZA) is safe". "As far as I know, there's no reported (cases). The ones' who had lung cancer, there were a total of four, 2 during and 2 afterwards. These people - 2 of them had long standing history of smoking. One person only used it (AFREZZA) a very short time, less than a few weeks. So you know, obviously, so many people think this rate of lung cancer of these 4 cases is so unexpected. They also showed that when they looked at the Chest xRay, 2 out of the 4 had changes on their xRay that was misdiagnosed unfortunately. So there's no way that inhaled insulin can cause cancer within. You know, 10 weeks, 20 weeks, and this thing (AFREZZA) doesn't hang out in the lungs. There's no activity in the lungs. So it just either gets absorbed. If your's silly, bring it back up and cough it out when you swallow".
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Post by mango on Nov 5, 2018 22:27:38 GMT -5
Hypocritical Irony
ADA evidence-grading system for “Standards of Medical Care in Diabetes”
Level of Evidence E : Expert consensus or clinical experience
• ADA uses the lowest form of evidence, opinion, in the construction of the Standards of Medical Care in Diabetes.
Demonstrable Fact
No scientific evidence exists to support a pulmonary malignancy risk in humans nor lower mammals with exposure to Afrezza.
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Post by sellhighdrinklow on Nov 5, 2018 22:47:29 GMT -5
MannKind laid a solid foundation before they ever pursued FDA approval, and has accumulated a comprehensive safety profile that includes over 600 CT and MRI lung scans, hundreds of pulmonary function studies, years of use in thousands of patients, and so on. We do not need nor require the level of data you describe to establish a conclusion on Afrezza's safety simply because there is no logical reason for it. The basic science is well established, and MannKind has effectively demonstrated that their insulin does not produce any signs of pulmonary malignancy, and their inert carrier particle does not produce any signs of pulmonary malignancy. For these reasons, I do not understand your argument. Not only has Lantus been linked to cancer in 7 observational studies, but even its basic carcinogenicity studies in rodents raises major concerns for it causing cancer. Couple it with the 7 observational studies and you have yourself a legitimate concern for cancer that warrants further and immediate investigation. 600 people vs 22,000 for that Lantus study, or 8,000 for the Mannkind Lung trial? You are running into two problems there - your sample set is small, and lacking consistent medical records for patients a formal trial is the only way to get the data so the FDA has asked for that. You are making the same error that you made with the ADA - it does not matter what you believe, it matters what can be proven in a form the FDA or ADA accept if you want their approval. You bet I looked into the Lantus risk when it happened and it illustrates the problem nicely. If you have one case a year, then two cases a year is a doubling of the risk, but to me personally it's not significant - the real risk is essential unchanged. The Afrezza cancer scare is the same. The number of people getting cancer in the group is tiny, and yet the arm using Afrezza had more cancer cases, but the number is still tiny. What happens when those numbers are scaled up? Cue the FDA lung trial requirement to see if that was just statistical noise or real. Agedhippie-. You work hard here on this message board and quite honestly, I'm not convinced you are a Type 2. I am convinced however that you are here for FUDster extraordinairre (sP?). Please respond to Mango. TYIA.
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