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Post by mnkdfan on Mar 30, 2014 12:12:11 GMT -5
Like others, I had a chance to review the FDA briefing more thorough and am feeling much more comfortable today. I too am of the opinion we will get approval for both types I an II treatments. 1. We are all comfortable with the assessment from the reviewer's comments for the type II trial. 2. The safety profile for Afrezza, regardless of some comments about a few patients with cough issues or lung issues, the tone was not alarming and mostly comparable to the FDA approved Exubera. 3. As for the problem child, type I drop-out patients missing data, our experienced members here have already done a great job in dissecting that topic earlier. I will only add that keep in mind that the FDA stated that trial 171 did meet it's end point and that only in a "WORST CASE" sensitivity imputation scenario that Afrezza would not meet the end-point. I am sure MNKD experts could provide more details to further reduce the concern with this analysis. The goal for this post is to share with you observations I found in the recent positive outcome of Adcom vote (16:1, yes) and subsequent FDA approval of CHTP drug. Below is a link to the CHTP FDA briefing notes. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM381154.pdf1. The primary end point in one pivotal trial did not even meet the end point. 2. The trial design did not meet the FDA efficacy guideline. 3. Two of the three trials did not show improvement over placebos. 4. Safety profile was not all demonstrated and full of concerns. I could go on but you can read the 5+ pages of the FDA reviewers reasons for not approving the drug yourself for more details. As you read past the summary and see the reviewer's comments, you will see the nature/tone from the reviewer such that this drug will never see approval or be given to a family pet if the reviewer was the approver of the drug. CHTP is just one example that a drug with marginal efficacy and statistically not meeting primary end point can and was approved by the FDA. Thus, if the biggest concern MNKD has is in the worst case secondary sensitive analysis, we would not meet the end point by .08%, then I'll take that bet any day of the week for a positive ruling outcome. I know us longs are passionate about our "Afrezza baby", but if you step back and see the role of the reviewer as someone unbiased who was tasked with identifying areas of concerns for the entire FDA voting staff to mull over, than he/she is doing his job (except for some stupid commentary remarks as pointed out in earlier posts) of pointing out some "relatively minor compare to other drugs FDA have approved". I was not expecting a glorious review or rubber stamp of approval neither. I was bracing for really "bad" news that we had discover a worsen safety profile or something new that could really derail approval. If the smoking gun was just this secondary statistical worst case analysis, than I am relieved and confident we will have a positive outcome. I am holding all my position... |
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Post by StevieRay on Mar 30, 2014 12:29:03 GMT -5
I’m not sure but this may be the likely reason 171 and 009 did not perform as well. The FDA wanted the baseline HbA1c to be closer to 8.5 but it was closer to the target level. Maybe someone smarter than me can comment on this. Why did the HbA1c level drop so low so soon? Isn't this a good thing?
From Page 73
“Reviewer’s comment: At the May 2011 End of Review Meeting, FDA commented that the Sponsor should increase the baseline HbA1c for inclusion and/or actively enroll patients in the upper range of the HbA1c inclusion criterion to help ensure that the mean baseline
HbA1c will not be too low to be able to show a meaningful improvement in HbA1c over the duration of the study. FDA also stated that a mean baseline HbA1c of roughly 8.5% or above would likely be adequate. It appears that the enrollment HbA1c was closer to the FDA recommended target than was the baseline HbA1c.”
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Post by spiro on Mar 30, 2014 12:34:54 GMT -5
mnkdfan, Thanks for the interesting post, my confidence is starting to creep back. I am in the middle of a page by page analysis of the BD with a fellow investor. We are at page 80 and so far, I only have a few concerns, mostly about the PK and PD issue. I am not sure about how MNKD will address this issue and if it could be a reason for rejection. The FDA's reviewer's irrational verbosity makes the BD difficult to interpret.
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Post by savzak on Mar 30, 2014 12:59:43 GMT -5
I’m not sure but this may be the likely reason 171 and 009 did not perform as well. The FDA wanted the baseline HbA1c to be closer to 8.5 but it was closer to the target level. Maybe someone smarter than me can comment on this. Why did the HbA1c level drop so low so soon? Isn't this a good thing? From Page 73 “ Reviewer’s comment: At the May 2011 End of Review Meeting, FDA commented that the Sponsor should increase the baseline HbA1c for inclusion and/or actively enroll patients in the upper range of the HbA1c inclusion criterion to help ensure that the mean baseline
HbA1c will not be too low to be able to show a meaningful improvement in HbA1c over the duration of the study. FDA also stated that a mean baseline HbA1c of roughly 8.5% or above would likely be adequate. It appears that the enrollment HbA1c was closer to the FDA recommended target than was the baseline HbA1c.”StevieRay, I noticed exactly the same thing but I don't think that had anything to do with "performance". Rather, it had to do with the FDA's confidence level in the results. They wanted a higher baseline so that the improvement would be more obvious.
My copy is highlighted and I have a big question mark next to the statement "It appears that the enrollment of HbA1c was closer to the FDA recommended target than was the baseline HbA1c." When you look at the HbA1c line on the table on page 72 you see that the mean and median baseline ranged between 7.90 and 8.00. I just don't know what can be done to improve that baseline for study purposes (which would mean they need participants with higher HbA1c). They have to take the participants as they come. The comment suggests that the study results would be more convincing if more perfect participants were registered. I'm sure that's true with any scientific study. And where the input is easily manipulated, the study can be set up in the best way possible to ensure that the results are clear. But they have to deal with reality in a study of humans. They have to take the participants as they come. In reality, I assume there were insufficient numbers of participants with the higher HbA1c levels to conduct a statistically accurate study.
In short, this is reads like another of those snarky reviewer comments. It reads as though he's saying "we told the sponsor we'd like to have a baseline of 8.5 to make sure the results are as clear as possible but the sponsor didn't do it". I'm saying that the sponsor was dealing with reality. The study had to be done and it was done with the participants that were available. If MannKind waited to get sufficient numbers of participants with an 8.5 baseline we might still be waiting for the study to start.
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Post by StevieRay on Mar 30, 2014 13:29:29 GMT -5
Savzak, It sounds like you’re saying the FDA actually wanted to see a superiority study not a non-inferior study. When you’re trying to prove treatment A is just about as good as treatment B you’re not going to see data that is wildly different. But if you’re trying to prove superiority then you would expect to see very significant deltas and the protocol would be much different so you can easily amplify the deltas. I’m sure we will see a superiority study in the future post approval. I guess my point is the study design would be much different if we were tasked with proving superiority. But also see the FDA's point in requesting a much higher starting point but don't know why we (MannKind) did not follow their advice. Maybe there's a reasonable explanation. |
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Post by liane on Mar 30, 2014 13:39:05 GMT -5
StevieRay,
I believe that you cannot do a superiority study in the T1s (correct me if I'm wrong, any of you who are more up on study design). Since the T1s have an absolute requirement for insulin, you can only compare 2 treatments and not compare to a placebo. Thus the non-inferiority study.
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Post by notamnkdmillionaire on Mar 30, 2014 13:39:11 GMT -5
Savzak, It sounds like you’re saying the FDA actually wanted to see a superiority study not a non-inferior study. When you’re trying to prove treatment A is just about as good as treatment B you’re not going to see data that is wildly different. But if you’re trying to prove superiority then you would expect to see very significant deltas and the protocol would be much different so you can easily amplify the deltas. I’m sure we will see a superiority study in the future post approval. I guess my point is the study design would be much different if we were tasked with proving superiority. But also see the FDA's point in requesting a much higher starting point but don't know why we (MannKind) did not follow their advice. Maybe there's a reasonable explanation. Al has stated that he would like to do superiority studies after approval to prove Afrezza is what he says it is, a superior product. Let's first get approval across the board. |
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Post by jpg on Mar 30, 2014 13:58:35 GMT -5
StevieRay, I believe that you cannot do a superiority study in the T1s (correct me if I'm wrong, any of you who are more up on study design). Since the T1s have an absolute requirement for insulin, you can only compare 2 treatments and not compare to a placebo. Thus the non-inferiority study. You can do a superiority study with standard medication like whatever insulin a type 1 is on and comparing it to Afrezza. An interesting study that will or could be done using continuos glucose monitoring would look at variability (highs and lows) of glucose, HbA1c and orher clinical outcomes (hypoglycemia or more complex longer term outcomes) using basal (daily or BID or by pump) and Afrezza in one arm and basal (daily or BID or by pump) and prandial sc. in the other arm. The possibilities for doing outcome studies with Afrezza with hard meaningful outcomes are huge. I am not even talking of how useful these studies would be for marketing purposes. Yet... JPG |
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Post by jpg on Mar 30, 2014 14:00:44 GMT -5
Like others, I had a chance to review the FDA briefing more thorough and am feeling much more comfortable today. I too am of the opinion we will get approval for both types I an II treatments. 1. We are all comfortable with the assessment from the reviewer's comments for the type II trial. 2. The safety profile for Afrezza, regardless of some comments about a few patients with cough issues or lung issues, the tone was not alarming and mostly comparable to the FDA approved Exubera. 3. As for the problem child, type I drop-out patients missing data, our experienced members here have already done a great job in dissecting that topic earlier. I will only add that keep in mind that the FDA stated that trial 171 did meet it's end point and that only in a "WORST CASE" sensitivity imputation scenario that Afrezza would not meet the end-point. I am sure MNKD experts could provide more details to further reduce the concern with this analysis. The goal for this post is to share with you observations I found in the recent positive outcome of Adcom vote (16:1, yes) and subsequent FDA approval of CHTP drug. Below is a link to the CHTP FDA briefing notes. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM381154.pdf1. The primary end point in one pivotal trial did not even meet the end point. 2. The trial design did not meet the FDA efficacy guideline. 3. Two of the three trials did not show improvement over placebos. 4. Safety profile was not all demonstrated and full of concerns. I could go on but you can read the 5+ pages of the FDA reviewers reasons for not approving the drug yourself for more details. As you read past the summary and see the reviewer's comments, you will see the nature/tone from the reviewer such that this drug will never see approval or be given to a family pet if the reviewer was the approver of the drug. CHTP is just one example that a drug with marginal efficacy and statistically not meeting primary end point can and was approved by the FDA. Thus, if the biggest concern MNKD has is in the worst case secondary sensitive analysis, we would not meet the end point by .08%, then I'll take that bet any day of the week for a positive ruling outcome. I know us longs are passionate about our "Afrezza baby", but if you step back and see the role of the reviewer as someone unbiased who was tasked with identifying areas of concerns for the entire FDA voting staff to mull over, than he/she is doing his job (except for some stupid commentary remarks as pointed out in earlier posts) of pointing out some "relatively minor compare to other drugs FDA have approved". I was not expecting a glorious review or rubber stamp of approval neither. I was bracing for really "bad" news that we had discover a worsen safety profile or something new that could really derail approval. If the smoking gun was just this secondary statistical worst case analysis, than I am relieved and confident we will have a positive outcome. I am holding all my position... Amazing insights. You are answering my number one subconscious fear! Thank you, JPG |
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Post by StevieRay on Mar 30, 2014 14:15:23 GMT -5
StevieRay, I believe that you cannot do a superiority study in the T1s (correct me if I'm wrong, any of you who are more up on study design). Since the T1s have an absolute requirement for insulin, you can only compare 2 treatments and not compare to a placebo. Thus the non-inferiority study. You can do a superiority study with standard medication like whatever insulin a type 1 is on and comparing it to Afrezza. An interesting study that will or could be done using continuos glucose monitoring would look at variability (highs and lows) of glucose, HbA1c and orher clinical outcomes (hypoglycemia or more complex longer term outcomes) using basal (daily or BID or by pump) and Afrezza in one arm and basal (daily or BID or by pump) and prandial sc. in the other arm. The possibilities for doing outcome studies with Afrezza with hard meaningful outcomes are huge. I am not even talking of how useful these studies would be for marketing purposes. Yet... JPG First of all I know nothing about study design and couldn’t tell the difference between a double blind study and a single blind study. I’m sure there are a 1000 different ways you can design a study. One way might be to take T1 baseline HbA1c for some period of time for their current regiment (aspart). And have them change over to Afrezza for another period of time. Then compare their results. Is this too simple? |
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Post by liane on Mar 30, 2014 14:18:11 GMT -5
Thanks jpg!
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Post by alcc on Mar 30, 2014 14:42:24 GMT -5
mnkdfan,
Thanks for the perspective. However, I am not sure this is a good comp. Droxidopa treats a rare (small population) condition for which there is no present standard treatment.
Re 171, seems to me this was designed as a low bar test and, as such, is incapable of showing off Afrezza's pivotal advantages (favorable PK). The problem with a low bar is that you had better clear well over the bar, which did not happen. It's like a champion marathoner being asked to run the sprint to prove his prowess. D'oh!
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Post by jpg on Mar 30, 2014 15:03:22 GMT -5
You can do a superiority study with standard medication like whatever insulin a type 1 is on and comparing it to Afrezza. An interesting study that will or could be done using continuos glucose monitoring would look at variability (highs and lows) of glucose, HbA1c and orher clinical outcomes (hypoglycemia or more complex longer term outcomes) using basal (daily or BID or by pump) and Afrezza in one arm and basal (daily or BID or by pump) and prandial sc. in the other arm. The possibilities for doing outcome studies with Afrezza with hard meaningful outcomes are huge. I am not even talking of how useful these studies would be for marketing purposes. Yet... JPG First of all I know nothing about study design and couldn’t tell the difference between a double blind study and a single blind study. I’m sure there are a 1000 different ways you can design a study. One way might be to take T1 baseline HbA1c for some period of time for their current regiment (aspart). And have them change over to Afrezza for another period of time. Then compare their results. Is this too simple? For some very limited things you could do that. Rating ease of use or 'which is better' type of studies maybe? For most 'hard' outcome data you need randomization and the more randomized time the better.that is why HbA1c became such a big deal. It was and still is (sadly...) used as a surrogate marker for outcome. Get a good HbA1c and you patient will do well... The MD who's CV I posted is one of the guys trying to change this surrogate (good for us). What Afrezza needs to do is show that big swings or variability is glucose levels (like volatility in stock price) is bad for your........ Fill in the blank with whatever outcome you want. That can only be done with randomization and time (and continuous or very frequent glucose monitoring I think but that is only a personal opinion). JPG |
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Post by mnkdfan on Mar 30, 2014 19:20:37 GMT -5
Alcc, perhaps a closer look at Novo Victoza Adcom vote and BD will be a better comparison. Below is a link to the BD, adcom vote, and FDA approval letter. www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-fda.pdfwww.fda.gov/newsevents/newsroom/pressannouncements/ucm198638.htmwww.firstwordpharma.com/node/358352?tsid=17#axzz2xUYCtdJPThe Adcom vote outcome was unimpressive to say the least (8:5 for cardiovascular risk) and (6:6; one abstain for cancer risk). Although the big red flag with Victoza is around the cancer and numerous safety profile, it also had minor issue in the statistical analysis of the efficacy result for one of the dosage (pg 59/60 statistical review). This is what one of the reviewer had to say: "FDA staff reviewers noted that cancerous thyroid tumours were observed in animal models administered Victoza over a two-year period, and they indicated there was not enough evidence to rule out a risk to humans. Panel member Peter Savage commented Thursday that "the animal data is worrisome, and I didn’t see sufficient human data to feel reassured...I’m also not convinced that the benefit of adding this drug with the risk at this time outweighs the tradeoffs." Needless to say the FDA proceeded to approve Victoza a short time later in 1/2010 and sales for Victoza is approaching $2B for 2014. Regardless of increasing evidence of patients using this drug coming down with Pancreatic cancer and call for it to be removed from market along with the nasty label warning, Novo will continue to be successful because type II will do anything to avoid or cut down on having to take three shots per day. I had my finger pricked twice to measure my glucose before/after meal and cringed like a little girl. I think MNKD will be a major success in type II patients because it will provide the "SAFE", effective, and convenient (painless)alternative for type II patients. www.webmd.com/diabetes/news/20120420/consumer-group-to-fda-take-victoza-off-marketBesides, we can't have Spiro go on a witness protection program to hide from his wife if MNKD fail for the 3rd time  . Looking forward to the vote response on Tuesday!!!! MNKDFAN |
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Post by jpg on Mar 30, 2014 21:23:05 GMT -5
The Barron article (quoted in another tread) also seems to go along the same Iine of thought as the BD for other approved medications Mannkindfan pulled up.
Thanks again,
JPG
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. Looking forward to the vote response on Tuesday!!!!