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Post by vdhingra on Feb 3, 2014 14:32:55 GMT -5
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Post by vdhingra on Feb 3, 2014 17:32:59 GMT -5
Here's are my take aways (critiques are welcomed):
a) procedurally, seems FDA was focused on the clinical results and Adcom (building on clinical results) dwells more into practical implementation (dosage linearity; patient training; device malfunction etc.) issues
b) FDA opening statements to committee acknowledge that what is being discussed is Human Insulin (which in itself has no surprises on mechanism of action) delivered through a new novel route
c) FDA EFFICACY assessment was principally based off HBA1c and SAFETY on Hypo's
d) Pulmonary safety obviously was BIG and a stand alone topic
d) Exubera mechanism (onset and half life) was more close to that of RAA's (Lispro in particular)
e) Exubera pulmonary data (FEV and DLco) indicate deteriorating lung function - seems everybody acknowledged that, and still approved
f) Conflict of Interest is taken seriously at committee
g) The potential of inhaled insulin was seeming acknowledged by all
h) The Committee members are very easy asking for additional data and studies
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Post by alcc on Feb 4, 2014 2:12:34 GMT -5
vdhingra,
Thank you for digging up the documents. Really interesting. I have gone through the Exubera Adcom session transcript. Further to your observations, which I generally agree with, I will add:
1) I encourage everyone to read FDA's Dr. Mahoney's and Dr. Seymour's comments (p. 119 and 174, respectively). Mahoney's remarks deal with efficacy, specifically re T1. Seymour's deal with pulmonary safety. I suspect both issues will arise in Afrezza's adcom.
2) Mahoney was skeptical re Exubera's efficacy for T1 (he was ok with the T2 data). His reasoning is worth noting. He felt that even though for A1c reduction Exubera was statistically non-inferior v. subcutaneous RAA (-.3% v. -.2%) the fact that it failed to bring more than 28% of the test subjects' A1c below DCCT's recommended 7% gave him pause. Note: for Afrezza this assertion of non-inferiority v. RAA was -.21% v. -.40%. I know these numbers from two different tests are not directly comparable. However, the fact remains that Exubera was numerically superior to RAA whereas Afrezza was numerically inferior! Mannkind afaik did not release data on percent of subjects whose A1c came in below 7% at end of 24 weeks. Given the .21% reduction, I would not expect that number to be better than Exubera's. I note that other than A1c and fasting plasma glucose Afrezza is clearly the superior product. It has lower post prandial excursion and lower severe hypo events. However, and that's a big however, note comment by FDA's Dr, Orloff (p.262-263): "the [FDA]does not label drugs with regard to specific claims of efficacy related to effects on post prandial glucose. The valid surrogate for diabetes control and efficacy of hypoglycemic agents that we accept is A1c." In other words, the FDA seems to put a lot more weight on A1c than on excursion and hypo events. Ugh.
3) Re efficacy, the adcom actually came to Exubera's rescue and effectively countered Mahoney's skepticism by bringing perspective to the whole question of tight A1c control. In the end they voted 7-2 in favor re T1 (and 9-0 re T2). Let's hope our adcom is as helpful.
4) Re pulmonary safety, neoplasm/tumor was really a non-issue. Seymour raised dramatically increased incidence events of insulin antibodies versus subcutaneous RAA. I have not heard MNKD mention antibodies or seroconversion. Does Afrezza cause a similar immune response? The adcom came to Pfizer's rescue once again, noting no historical data tying this to adverse metabolic or clinical effects. Again, let's hope our adcom is as helpful.
5) Net, net, in the case of Exubera, it appears adcom helped the company. The questions it raised were reasonable, e.g. asking for more data re patients who have a cold, flu or other respiratory impairment.
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Post by brentie on Feb 4, 2014 10:34:50 GMT -5
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Post by vdhingra on Feb 4, 2014 12:29:56 GMT -5
alcc, I kinda noted that as well (FDA mention of population < 7% HBA1c being low for Exubera), but was a little heartened by: a) it being one of the stated (secondary) end-point for Exubera trail (vs. AF); and b) Committee acknowledging that HBA1C goals are exactly what they are: goals, and typically not met in practical setting (in fact one of the members noted that had the trial met the strict HBA1c goals, he would have questioned the generalization ability of the results; he also noted that 7% was the median value in the DCCT trails). But your point on Committee coming to the rescue is well taken, and I hope we get the same treatment. Another thing that encouraged me was that all the discussion centered on 1 or 2 pivotal trials (for example, study 107 for Exuebra). To that, I called up Matt P. asking which trials I should think off as the pivotal. And he basically said 171, 175 and 030 for T1, T2 efficacy and Safety respectively (study 030 was 2 year safety study that was undertaken with Medtone C device). Assuming Mgmt. has not held back any material negative info (171 and 175), think we should be in good standing. p.s. if anybody is interested in detailed briefing docs that FDA prepared for the committee (vs. presentation slides linked above; and vs. the Sponsor prepared briefing docs), please ping me; happy to share.
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Post by alcc on Feb 4, 2014 13:51:32 GMT -5
The antibodies data (only 2-3x sc) is reassuring. After reading the transcript I have to say I would be shocked -- shocked -- if Afrezza does not sail through adcom.
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