Elite Pharmaceuticals Inc (ELTP)

[WeeZuhl]

Freedom of Information Act Request to FDA

It is impossible to make this long story into a short explanation, nor is that my tendency. I was trying to answer a series of questions, and in the process I found an interesting document with redacted information that may be relevant to the SequestOx Tmax issue. I have filed a Freedom of Information Act Request for the redacted information via the FDA’s web portal. I’ll update here whether or not I get any new information from the FDA, and I’ll share anything I learn with the company.

I was first trying to define the goal-posts for immediate-release oxycodone fed Tmax (high calorie). The official label for Roxicodone tablets and all generic tablets (ANDA’s referencing the original Roxicodone NDA) use the exact same biopharmaceutical data in their official label. It looks like this:


http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202662Orig1s000lbl.pdf




Hmmm, I say. Why do oxycodone tablets show the Tmax for the oral solution? When you trace the data back to the original NDA, it very clearly states: “The food effect for the to-be marketed tablets can be extrapolated from the food effect on IR solution.” The tablets and solution were bioequivalent in the fasting state, but the tablets were not tested in the fed state. If the original Roxicodone tablets were never tested for fed bioequivalence, were any of the currently-marketed generic tablets tested for BE after a high-calorie meal? Does the FDA even know the fed Tmax data for the array of available tablets?

Does it make a difference? Is the fed Tmax different for the tablet vs. solution? After all, the brand name for the solution is OxyFast- maybe it really is faster. Isn’t that why abusers chew (or also “parachute”) their oxyIR/Percs/Norco- for faster absorption and quicker high. Maybe the fed Tmax of “Roxicodone tablets” isn’t as tidy as the FDA thinks, and maybe SequestOx is being unfairly judged against oral solution. Since Nasrat has never released the data, the controls used in ELI-200 studies are unknown. We know it was a three-way crossover (that sounds hot!) but not if any control formulations were tested in the fed state. “Three-way crossover” sounds to me like #1 Roxicodone fasting, #2 SequestOx fasting, and #3 SequestOx fed. This means that SequestOx failed to be bioequivalent to FDA data and not to an oxycodone “fed control” group run in crossover with ELI-200. In other words, SequestOx did not fail head-to-head, instead it failed against what the FDA deems to be the proper fed Tmax. This is very important, especially if the FDA data on fed Tmax is as sketchy as it seems.

Next I started trying to track down the fed Tmax for oxycodone tablets, and it turns out that it is not public information, as far as I can find. But! I did find the fed Tmax for oxycodone capsules! I don’t understand the full history of how this happened, but somehow along the way a bunch of generic manufacturers started making oxycodone 5mg in capsule form and oxycodone solution with a different manufacturing technique. They were doing this without proper approvals and the FDA swept them all off the shelf at once, similar to what they did to us with Lodrane. Lehigh Valley (with Glenmark Pharmaceuticals) subsequently received approval for their two products via 505b2 NDA’s for a 5mg capsule- and a second NDA for oral solution. Both NDA’s use Roxicodone as a reference product. The approval documents for these NDA’s contain the fed Tmax data for the capsules, and the official label for the capsule (and every generic oxy 5mg capsule ANDA based on Lehigh Valley’s capsule NDA) refers to the data from this NDA application, and it looks like this:


http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/200534s000lbl.pdf




This is massively important in multiple ways. First off, this proves that there is a significant difference between the fed Tmax of oral solution compared with capsules. After a high-fat meal, oral solution Tmax increases from 1.25 to 2.5 hours (200%), while the capsule Tmax increases from 1 hour to 3 hours (300%). There is no question that after a high-calorie meal, the excipients in the solid capsule affect the Tmax more than the excipients in the liquid solution. Which Tmax is SequestOx supposed to meet for bioequivalence? Liquid or solid? 200% or 300%? Does it meet neither? Nasrat knows.

Second, based on the capsule’s 3 hour fed Tmax, there is almost definitely a path forward for SequestOx. As long as SequestOx fed Tmax is within 3 hours 45 minutes (125% of 3 hours), then it is bioequivalent to the Lehigh Valley capsule NDA. All that should be required is to change the reference drug to Lehigh Valley’s oxycodone capsule NDA. (Important note: the Lehigh Valley NDA is only for 5mg capsules, so ELTP would likely have to ditch everything except 5mg. But 5mg represents a large majority of the scripts.) Fun thought: **IF** the fed Tmax for SequestOx is less than 3 hours 45 minutes, then SequestOx 5mg should be immediately approved as bioequivalent to Lehigh Valley oxycodone capsules.

The savvy Tmax aficionados among you probably noticed that if the Lehigh Valley capsules fed Tmax increased by 300% then it is NOT bioequivalent with Roxicodone reference drug (200%). Despite this, the capsules are listed as bioequivalent to Roxicodone in the FDA’s Orange Book (code “AB”= “Meets necessary bioequivalence requirements”). Likewise, the capsule’s T max delay is not considered a safety issue, and the capsules do not have any food-effect warnings or instructions to take on an empty stomach. There are multiple reasons why FDA may choose to approve a drug which is outside of bioequivalence range. For instance, these capsules had previously been sold on the market before being removed, and the dose size is diminutive- an extra 5mg capsule is much less dangerous than an extra 15mg or 30mg capsule. The reasons for approval, which are highly relevant to SequestOx, are generally discussed in the Summary Review. Clearly there were “multiple formulation changes” in the process, but multiple areas of discussion in the Summary Review are redacted. The Summary Review for Lehigh Valley NDA is signed by Dr. Sharon Hertz:













Avridi used oxycodone tablets as a control, but all of their Tmax data is reported as median and not mean, so it is apples to oranges. I went back and calculated the means based on some of their graphs. This is kind of like putting a T-bone through a meat grinder and then trying to put it back together as a steak. It certainly was not pretty, but it fed a hungry man. The data is very, very rough, but basically shows the oxycodone tablet mean Tmax going from 1 hour fasted to 1.8 hours fed (median was 1.5 hours) and Avridi mean Tmax going from 1 hour to 5.1 hours (median was 4.5 hours). I believe reporting the median instead of mean artificially diminished the Tmax delay for both oxycodone tablets and Avridi. Avridi’s Tmax delay is probably even worse than it appears, but this sketchy data does not indicate a major difference in fed Tmax between the oxycodone tablets and the published data for oxycodone oral solution. Remember, Avridi has detergent-based ADF, so the major high-fat food effect makes sense. SequestOx is a standard capsule and should act more similar to Lehigh Valley generic capsules and less like Avridi, but for now, only Nasrat & Eugene know for sure.

It is possible ELTP already has access to fed Tmax data for oxycodone tablets, since Elite formulated the Epic oxycodone ANDA. If fed bioequivalence was performed, Nasrat has the data. We know definitely capsules are slower than solution, and while not proven, it seems logical that fed Tmax of tablets will fall somewhere in between. What it seems to me, though, is that SequestOx capsules have been judged against oral solution, and it is doubtful that any oxycodone capsules have ever or will ever approach a similar fed Tmax to oxycodone solution.



SUMMARY

1. Original Roxicodone tablets were never tested (or at least never reported) under high-calorie fed conditions.

2. Every oxycodone tablet sold in U.S. carries a label that reports the food effect data (Tmax) of oral solution instead of tablet. It is unknown how many, if any, of the currently-marketed generic tablets were tested for bioequivalence after high-calorie meal. Many times ANDA applications are granted “in vivo waivers,” meaning their bioequivalence is assumed based on “in vitro” biochemical analysis.

3. Currently-approved oxycodone 5mg capsules have significantly slower Tmax compared with oral solution- double the Tmax effect and well-outside of the range of bioequivalence with oral solution. These capsules are not considered to have a food effect and do not carry instructions to take on an empty stomach.

4. Currently-approved oxycodone 5mg capsules have Tmax after high-cal meal of 3 hours. Bioequivalence standards require SequestOx to be within 125%, or 3 hours 45 minutes. If SequestOx fed Tmax is equal to or less than 3 hours 45 minutes, then it is already bioequivalent to Lehigh Valley NDA #200-534 and could be immediately approved in 5mg size if RLD is changed.

5. Lehigh Valley Pharmaceticals received Approval for oxycodone 5mg capsules, despite significantly delayed fed Tmax, without any food-effect labeling or safety concerns. The commentary which may explain why this was allowed has been redacted from the NDA’s Summary Review, which is signed by FDA’s Dr. Sharon Hertz. A Freedom of Information Act Request has been submitted by me for the redacted discussion.

6. While there is a significant difference in the effect of a high calorie meal on Tmax of oxycodone solution compared with capsules, there is no published data regarding the fed Tmax of tablets. In a three-way crossover pivotal BE study, it is unlikely SequestOx had any “fed control” arm with tablets. Nasrat likely has access to tablet fed Tmax data because of Elite’s work on Epic’s oxycodone tablet ANDA. This may be the kind of information he is collecting to show FDA.

7. Avridi used oxycodone tablets as a fed control, but the data is reported as “median” instead of “mean,” so it is not comparable to published data. Extrapolation suggests the mean is slower than the reported median for both Avridi and oxycodone tablets, but it was not suggestive of major Tmax difference between oxycodone tablets and solution. Based on my guesstimation, if Avridi reported fed Tmax as “mean” instead of “median”, it would look even worse, greater than 5 hours (and therefore outside the bioequivalence range of even the Lehigh Valley capsules). Avridi has detergent ADF, but SequestOx does not.