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Post by mango on Nov 26, 2018 11:03:52 GMT -5
- FDA released MannKind of their postmarket requirement and commitment #4: to 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.
Released: FDA has informed the applicant that it has been released from its obligation to conduct the postmarketing study because the study is either no longer feasible or would no longer provide useful information. - Previously, it had this status and explanation:
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 - This almost identical requirement commitment #5 has a “pending” status, but I need more details to know if MannKind was released from this clinical trial in its entirety, or just from #4, and now #5 is a new protocol or study design or something that's taking its place. I don’t want to speculate, so I think we need to call FDA and ask them. Does anyone want to volunteer to do that? I will later if no one wants to.
Pending: The study has not been initiated (i.e., no subjects have been enrolled or animals dosed), but does not meet the criterion for delayed (i.e., the original projected date for initiation of patient accrual or initiation of animal dosing has not passed). What do ya'll think?
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Post by Clement on Nov 26, 2018 11:45:31 GMT -5
The descriptions of #4 and #5 appear to be exactly the same. Is there a difference in the descriptions?
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Post by mango on Nov 26, 2018 11:56:14 GMT -5
The descriptions of #4 and #5 appear to be exactly the same. Is there a difference in the descriptions? The differences are so insignificant that the descriptions are essentially the same. #4 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. #5 The trial must also include an assessment of cardiovascular risk based on prospectively defined 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.
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Post by Omega on Nov 26, 2018 12:08:48 GMT -5
The descriptions of #4 and #5 appear to be exactly the same. Is there a difference in the descriptions? The differences are so insignificant that the descriptions are essentially the same. #4 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. #5 The trial must also include an assessment of cardiovascular risk based on prospectively defined 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. If im reading this right, there are 4 additional words in #4 vs #5 (I've Bolded them above) "collected and independently adjudicated"
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Post by mango on Nov 26, 2018 12:25:27 GMT -5
The differences are so insignificant that the descriptions are essentially the same. #4 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. #5 The trial must also include an assessment of cardiovascular risk based on prospectively defined 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. If im reading this right, there are 4 additional words in #4 vs #5 (I've Bolded them above) "collected and independently adjudicated" That's the only differences I could find too. I send an email to the folks at FDA and asked about it, but someone else might want to email them too. I know you can submit a FOIA request for details about the clinical trials but if there's any proprietary info in it will have redactions or maybe not issued at all. But the previous #4 had: 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 Does anyone know if #5 has always been listed on there or if it is new?
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Post by xanet on Nov 26, 2018 13:01:10 GMT -5
If im reading this right, there are 4 additional words in #4 vs #5 (I've Bolded them above) "collected and independently adjudicated" That's the only differences I could find too. I send an email to the folks at FDA and asked about it, but someone else might want to email them too. I know you can submit a FOIA request for details about the clinical trials but if there's any proprietary info in it will have redactions or maybe not issued at all. But the previous #4 had: 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 Does anyone know if #5 has always been listed on there or if it is new? Not sure how long #5 has been listed. #4 is straight out of the NDA Approval letter: NDA Approval
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Post by mango on Nov 26, 2018 13:16:50 GMT -5
That's the only differences I could find too. I send an email to the folks at FDA and asked about it, but someone else might want to email them too. I know you can submit a FOIA request for details about the clinical trials but if there's any proprietary info in it will have redactions or maybe not issued at all. But the previous #4 had: 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 Does anyone know if #5 has always been listed on there or if it is new? Not sure how long #5 has been listed. #4 is straight out of the NDA Approval letter: NDA ApprovalYep, #4 is word for word. Maybe this PR from 11/16 is relevant? Recently, new tools for capturing data in the post-market period, including more sophisticated use of real world data and real-world evidence (RWE), are providing new approaches to address important questions about the safety and benefits of new drugs in real world settings. These approaches have the potential to do to so more rapidly and with greater efficiency than traditional methods. For example, the FDA recently announced the MyStudies app, a new mobile technology created to foster the collection of RWE via patients’ mobile devices. By releasing the open source code and technical documents, we hope that researchers will be able to customize and use the MyStudies app to collect different types of information from patients directly and more conveniently. In addition, to further advance these opportunities, the FDA will soon publish a framework for the FDA’s RWE program. This framework is intended to help evaluate the potential use of RWE to help support the approval of a new indication or to help support or satisfy post-approval study requirements. In addition, a great deal more information about the drug and the disease it treats often becomes available in the years after an approval. The FDA carefully reviews this emerging scientific information and may conclude that there are new safety concerns that warrant requiring the company to complete additional post-approval studies or changing the nature of the studies that we initially required. As a result, PMRs and PMCs may undergo modifications after they get underway. These modifications may serve an important public health purpose. But they could also extend the time required to bring them to completion. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626090.htm
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Post by mike0475 on Nov 26, 2018 13:28:25 GMT -5
5 yrs is up isn’t it..2014 released, here comes 2019 with some new and old news commentators drinking too much in nyc
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Post by agedhippie on Nov 26, 2018 13:29:43 GMT -5
That's the only differences I could find too. I send an email to the folks at FDA and asked about it, but someone else might want to email them too. I know you can submit a FOIA request for details about the clinical trials but if there's any proprietary info in it will have redactions or maybe not issued at all. But the previous #4 had: 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 Does anyone know if #5 has always been listed on there or if it is new? Not sure how long #5 has been listed. #4 is straight out of the NDA Approval letter: NDA ApprovalIt's a modification to the MACE requirements that are placed on all diabetes drugs. I think this might be more to do with the current (possibly now completed) debate in the FDA over whether or not the MACE requirements are unnecessary and simply push up costs. It looks like the FDA has simplified the MACE requirements here to allow the MACE evaluation to be completed within the lung trial rather than have the data independently handled. That's my contribution to the speculation
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Post by mango on Nov 26, 2018 14:19:36 GMT -5
Not sure how long #5 has been listed. #4 is straight out of the NDA Approval letter: NDA ApprovalIt's a modification to the MACE requirements that are placed on all diabetes drugs. I think this might be more to do with the current (possibly now completed) debate in the FDA over whether or not the MACE requirements are unnecessary and simply push up costs. It looks like the FDA has simplified the MACE requirements here to allow the MACE evaluation to be completed within the lung trial rather than have the data independently handled. That's my contribution to the speculation Maybe, but that is not what released status means. Released: FDA has informed the applicant that it has been released from its obligation to conduct the postmarketing study because the study is either no longer feasible or would no longer provide useful information.
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Post by agedhippie on Nov 26, 2018 14:23:09 GMT -5
It's a modification to the MACE requirements that are placed on all diabetes drugs. I think this might be more to do with the current (possibly now completed) debate in the FDA over whether or not the MACE requirements are unnecessary and simply push up costs. It looks like the FDA has simplified the MACE requirements here to allow the MACE evaluation to be completed within the lung trial rather than have the data independently handled. That's my contribution to the speculation Maybe, but that is not what released status means. Released: FDA has informed the applicant that it has been released from its obligation to conduct the postmarketing study because the study is either no longer feasible or would no longer provide useful information. I think what they have done is release the #4 requirement and reissue it with the relaxed MACE requirement as the new #5. Either way #5 remains and that looks like a virtually identical copy of #4 so the lung test post-marketing requirement remains.
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Post by mango on Nov 26, 2018 14:51:49 GMT -5
Maybe, but that is not what released status means. Released: FDA has informed the applicant that it has been released from its obligation to conduct the postmarketing study because the study is either no longer feasible or would no longer provide useful information. I think what they have done is release the #4 requirement and reissue it with the relaxed MACE requirement as the new #5. Either way #5 remains and that looks like a virtually identical copy of #4 so the lung test post-marketing requirement remains. Download the description data and you will see that #4 and #5 share the same annual report dates etc that MannKind files, most recent being in August. There would be no logical reason to release #4 since it never began, they could have just modified anything they wanted and updated the info. Instead, FDA released MannKind for having to do the study. Does it make logical sense to you that FDA would approve Pediatric Afrezza before this lung study ever even began? Of course not, which is why they released them from their requirement based on post-approval data and evidence via both clinical and RWE, and also probably because we already have all we need, like Dr. Kendall said. The Release status does not correlate with your assumption. What part of not feasible or not useful does what you're saying satify any condition of the release? Maybe you're right, we will find out soon just waiting on email response back.
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Post by mango on Nov 26, 2018 15:19:26 GMT -5
Do you remember when MannKind originally proposed a post-market surviellence/RWE gathering etc to satisfy this study's objectives? But FDA declined because it was not feasible back then we did not have the tools or infrastructure.
That FDA PR from the 16th is EXACTLY what MannKind proposed except now FDA has the tech and tools to allow post-market surviellence and RWE to supplement or help satisfy the Postmarket requirement/commitment clinical trial.
That makes sense to me but we'll just have to wait for FDA to shed some light on the issue.
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Post by boca1girl on Nov 26, 2018 15:53:29 GMT -5
Maybe, but that is not what released status means. Released: FDA has informed the applicant that it has been released from its obligation to conduct the postmarketing study because the study is either no longer feasible or would no longer provide useful information. I think what they have done is release the #4 requirement and reissue it with the relaxed MACE requirement as the new #5. Either way #5 remains and that looks like a virtually identical copy of #4 so the lung test post-marketing requirement remains. Hopefully MNKD management will release a PR to explain what exactly this means so we don’t have to guess.
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Post by sportsrancho on Nov 26, 2018 18:34:04 GMT -5
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