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By the time the Food and Drug Administration gets a marketing application, a drug developer has probably had a dozen or more interactions with the FDA about its drug. From reviewing phase 2 data to establishing doses and endpoints for clinical trials, there's a lot to be worked out. And by "worked out," I mean that the FDA says, "Jump!" and the company says, "How high?"
The last thing the FDA wants to see when it dives into a marketing application is surprises.
But that's exactly what MannKind (NASDAQ: MNKD ) appears to have given the FDA.
Let's go back three years
The FDA briefing documents for the advisory committee meeting on Tuesday are a treasure trove of regulatory history of MannKind's inhaled insulin product. The drug has already been up for approval between twice, but until now we've only gotten MannKind's version of the events.
Between its first and second application, MannKind decided to change the inhaler it was using to a smaller inhaler called Dreamboat. While that was probably a good move from a marketing standpoint, the FDA likes consistency between what's used in clinical trials and what's approved for use. If a company is going to make a change, the FDA needs data to confirm what will be sold is equivalent to what was used in the clinical trials.
In MannKind's case, the biotech had data showing the two devices were equivalent in laboratory tests outside of humans, called in vitro, and a study comparing single doses of the two devices.
I'll let the FDA reviewer tell you what happened next:
The FDA had no experience with which to judge the acceptability of this approach and asked the applicant to share full results of the in-vitro comparative performance data for review prior to resubmission of the application. The applicant did not and proceeded with submitting their Complete Response which included in vitro performance data for the new device, a PK study comparing single dose PK profiles of the new and old device and the result of a post-hoc analysis performed on an early terminated trial in subjects with T1 DM using the MedTone Device.
Needless to say, the FDA rejected the new device and asked for full clinical trials to show the new inhaled insulin device, Afrezza, was safe and effective.
Fast forward a couple of years
MannKind successfully completed the requested clinical trials. Barring some unforeseen safety issue, an approval seemed more likely than not.
Instead MannKind made another change.
Type 1 diabetics switching from Eli Lilly's (NYSE: LLY ) Humalog and Novo Nordisk's (NYSE: NVO ) Novolog to Afrezza need to know how much of the new inhaled insulin to take. In the clinical trial of type 1 diabetics, MannKind told patients that one cartridge was equivalent to four units of injected insulin. If patients needed more, there was a double-strength cartridge that was the equivalent of eight units. You can mix and match the cartridges to increase the dose from there.
In its application though, MannKind switched to one cartridge being equivalent to three units of insulin instead of four. And the double-strength cartridge was the equivalent of six units instead of eight. MannKind justified the change because it believes an equivalency study comparing injected to inhaled insulin established the ratio.
The FDA wasn't impressed with the study, which measured pharmacokinetic, the relative availability of the insulin. The agency would much rather see pharmacodynamics, the effect of the dose and the duration of the insulin where it acts. The duration seems to be especially important because Afrezza comes off quicker, closer mimicking how insulin works in the body.
The FDA reviewers were unequivocal about the change:
Considering this, we find that the clinical pharmacology data in this submission does not adequately support the new proposed dosing regimen and the respective dosing conversion factors in the dosage chart.
It's not clear to me why MannKind made the change. Perhaps we'll know more when the company presents its side of the story on Tuesday. It seems possible that the company could just switch back to the one cartridge equals four units conversion that was used during the clinical trial in type 1 diabetics. It doesn't appear there were any issues in the trial, which ultimately showed that Afrezza was equivalent to Novolog (although just barely).
MannKind also tested Afrezza in type 2 diabetics, which hadn't started insulin yet, so there isn't an issue with conversion in that class of patients. It's possible that Afrezza could get approved for type 2 diabetics, but not type 1 diabetics until MannKind can satisfy the FDA's need for pharmacodynamics data.
In both types of diabetics, the drug seems to have modest effects on blood glucose levels. Fortunately the safety doesn't seem to be a major issue, so MannKind may be able to squeak by with a positive recommendation from the panel.
Assuming nothing else changes between now and then.
This company doesn't need a positive FDA decision to have a good 2014
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