[00:01:20] Speaker 01:
Good morning, and may it please the court, Elizabeth Pappes for Petitioner PMRS.

[00:01:34] Speaker 01:
Five for a rebuttal, please.

[00:01:37] Speaker 01:
My client is a businessman who represented himself and his company in the FDA proceedings in this case, which concern drug labeling at the heart of the opioid crisis and should have been a straightforward administrative proceeding.

[00:01:50] Speaker 01:
Five years, 10,000 plus pages, millions of dollars later, FDA has denied his application for what would have been the only opioid on the market that includes label limitations the CDC recommended after seeing science linking duration and dosage to death.

[00:02:14] Speaker 01:
Review of this order

[00:02:16] Speaker 01:
presents heartland ethical core and state farm issues for the court, because the order on its face reads reasonably.

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What I would like to do today is cover two fundamental APA violations that are inherent in the order.

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And with the court's guidance, I hope we can work together to unpack, to understand what really went on in this proceeding.

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The first violation reflects the FDA's unwillingness

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to engage a chronic labeling issue that's at the heart of the crisis under the CDC studies, but the agency does not want to engage because it has approved these labels for 14 years.

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It's the first and primary state farm issue, APA issue in this case, and it arises out of the FDA's application of Section 505D of the FD&C Act

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under the very standard in their order and brief.

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And that standard is at the order appendix 22 to 23 and in their brief at 22.

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They say the issue here, the only one they've presented to the court under Chenery, is whether our label, our draft label, falsely suggests that our product is safer than conventional formulations with respect to the risk of abuse.

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That's the standard they give.

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What our client did in this record, starting in April 2017, in the very label they cite, Appendix 6667, is said, our product, we believe, is safer for two reasons.

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We have some physical and chemical properties that can deter abuse and

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We are the only product that would include that CDC-endorsed label indication.

[00:04:02] Speaker 03:
Ms.

[00:04:02] Speaker 03:
Pappas, I thought the FDA's position was that there was no evidence that the dye in the solution would actually deter abuse.

[00:04:10] Speaker 01:
You're exactly right, Your Honor, and I'm glad you raised it.

[00:04:14] Speaker 01:
If I may unpack that, we briefed it.

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I think we can dispose of the entire order if we look hard at the record on that issue.

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What I want to say about that first, just for the record, is the FDA does say

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This whole case stands or falls on the fact that we put in no evidence whatsoever that the dye would deter an actual drug abuser out there in the world from injecting our formulation or snorting it.

[00:04:38] Speaker 01:
Two top line things and then I'll move on to the real evidence that I think will move the court, I hope, the way it moved me.

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The first point is, that's not the question.

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The statutory question is the one at 22 to 23 and 22 in their brief.

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It's the product offering as a whole safe for now.

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They say that all goes down to this die question.

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They say in their brief, all we rely on is the die.

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That's not true.

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They're rewriting the question, and what they're really doing is an APA violation there, but just on the evidence, what I want to say, and this was really compelling to me when I went through the record, but it took some unpacking, is let's spot them that.

[00:05:12] Speaker 01:
Let's spot them, their construction.

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That this case is really, that all we did was the die.

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and that we didn't connect it to user reaction.

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Statute doesn't require connections to user reactions.

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That's from their guidance, because we can't predict how a user is going to react.

[00:05:28] Speaker 01:
But let's spot them that that was even the issue.

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Their point that there was no evidence is flatly belied by the record.

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And if the court has a moment, I think it's worth looking.

[00:05:38] Speaker 01:
This is Joint Appendix 66 to 67 is the label that they say fails this test.

[00:05:44] Speaker 00:
But in the first sentence of that label,

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or the first sentence that I'm focusing on says essentially that the drug is formulated with inactive ingredients that make the capsule more difficult to manipulate for misuse and abuse.

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And I guess the EPA's point is that that's false and misleading

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because there is no clinical evidence to support the fact, as Judge Rowell has mentioned, that this is going to deter abuse.

[00:06:33] Speaker 01:
I'm with you 100%.

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So let's start right there.

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That's exactly what it says.

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Now note, right below that in that label, it says we're not claiming any clinical abuse.

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So now they have to go to there's no evidence at all of the statement you just read.

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And that's what I take their position to be, that we have no evidence at all

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that there's anything physical or chemical that would deter the abuse.

[00:06:53] Speaker 01:
Here's where I'll give you the record sites so we can walk through them, because this is really, I think, incredibly important.

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Joint appendix 459 to 60 is where this starts.

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The applicant put in evidence of these extraction studies that is different than the die, first form.

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So you'll see that at appendix 459 to 60.

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In page 459, he talks about the die selection study that FDA has in its sites.

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You turn the page to 460, and you see at the bottom of the page this 3-2-P-2-2-1-4-1 extraction study on page 460 of the appendix.

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My point on these pages is extraction, he did a study that's different than the die, they are not the same.

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Now, if we turn to page 473 in the appendix,

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What you'll see here, and this I found very significant because FDA says nothing whatsoever about this.

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On 473 of the appendix, this study, which is contemplated by the statute because it is a controlled in vitro study, found, and I'm quoting from page 473, the difference in purity results are statistically significant between our client's product

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and the reference product.

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And if you turn to page 475, he explains this point and relates it to abuse deterrence.

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He says, the percent purity results for our product show that in our capsule, the active pharmaceutical, the thing that you want to get high, cannot

[00:08:32] Speaker 01:
be effectively extracted from the formulation matrix, and in Roxycodone it can.

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And on 475 he says this is a chemical abuse to deterrent.

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Why?

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Because it's a solubility issue.

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If you have a needle and you put five mils of solution in that, but

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In our product, the active pharmaceutical that gives you the high is the same solubility as the other excipients that don't give you a high.

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That five mils is filled with less pure API than the competitor product.

[00:09:03] Speaker 01:
He put this in the record.

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And more importantly, if you look at JA590, this is a page on which he said, this is a factual issue.

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FDA is not understanding our study or our argument

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And we want a hearing on it.

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And JA 590 note 18 cites exactly the record study I just walked through.

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Now, they say nothing about this.

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We are not asking the court to look at the study and agree with the chemistry.

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We're not asking the court to approve the label of the product.

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I point this out because there is indeed evidence in this record.

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We cited page 590 in our opening brief on page 16.

[00:09:46] Speaker 01:
You know what?

[00:09:47] Speaker 01:
In the FDA's brief?

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They cited all the pages around that one on pages 16 and 17 of their brief.

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They cited page 591 of the appendix.

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They didn't cite page 590.

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So this is out there.

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It's a real issue.

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I raised it because there is evidence.

[00:10:03] Speaker 00:
Isn't it addressed in footnote one of the denial?

[00:10:06] Speaker 01:
It's not addressed there, Your Honor, at all.

[00:10:08] Speaker 01:
What they say there is they kind of brush it off as some sort of definitional issue.

[00:10:12] Speaker 01:
But we have record evidence.

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If you look at 590 and then 897 of the appendix where our client said, this is a factual issue under cases like Edison, Cyanamid.

[00:10:23] Speaker 01:
If the FDA doesn't think this is good enough evidence to give us the label, fair enough.

[00:10:28] Speaker 01:
But we have a factual dispute on what we've shown beyond the dye.

[00:10:32] Speaker 01:
More importantly, the client went on to point out to them, we have another what medicine, this court's precedent, called a threshold dispute about whether it's necessary for an applicant to do more than a chemical study to get this kind of label.

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And our client's position has always been, you need more.

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You don't need more, because what they want in that guidance is to go and test how a user might react to it.

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We don't do pre-market tests by actually injecting people.

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It's unethical and dangerous.

[00:11:00] Speaker 01:
So the only kind of study that we could have done beyond this one was to get a bunch of recreational drug users in a room, and you do basically what they call a liking survey, or it's like a survey poll, and you say,

[00:11:11] Speaker 01:
Would you rather inject a clear solution or a dark one?

[00:11:14] Speaker 01:
Would you rather inject pure API or less pure API?

[00:11:18] Speaker 01:
And you can get a response.

[00:11:19] Speaker 01:
Your client has done that kind of study.

[00:11:20] Speaker 01:
I'm sorry?

[00:11:21] Speaker 03:
There's that kind of study in the record.

[00:11:23] Speaker 01:
No, our client said there's no point to doing that kind of study.

[00:11:26] Speaker 01:
It's not scientific or controlled under 505.

[00:11:29] Speaker 01:
Now, FDA disagrees.

[00:11:31] Speaker 01:
But that comes from their guidance.

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We said you can't apply that as law.

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And we have a threshold issue under Edison.

[00:11:37] Speaker 01:
We should go have a hearing on that.

[00:11:38] Speaker 01:
And they said no.

[00:11:40] Speaker 01:
That all happened, Your Honor, and the one thing I want to leave the court with and reserve my time is just all of this, the reason this is really important is it gets us over this order, but the real game here is in that CDC indication.

[00:11:53] Speaker 01:
I could not emphasize more how important that is.

[00:11:56] Speaker 01:
FDA does not want to talk about it because they have this history of approving the chronic label.

[00:12:01] Speaker 01:
They approved that label based on a 14-day study back in 1995.

[00:12:05] Speaker 01:
The CDC said that is not scientific support for the safety or efficacy of that label that is on every single opioid out in the market today.

[00:12:14] Speaker 03:
Isn't that a policy argument more than a legal argument?

[00:12:17] Speaker 01:
You know, it's not because we made it as a factual argument and the core of our application here.

[00:12:23] Speaker 01:
They've denied us this issue in every forum.

[00:12:25] Speaker 01:
You know, the citizen petitions, the other docket, they said you don't have standing.

[00:12:29] Speaker 01:
Here we have standing.

[00:12:30] Speaker 01:
We made it a core part of our application.

[00:12:32] Speaker 01:
We hammered it from that April 2017, J66 to 67, right above the sentences you read, is that acute use indication.

[00:12:39] Speaker 01:
They don't want to talk about it because it leads to a very difficult place for the agency.

[00:12:44] Speaker 01:
But we need to do more at this point and better than playing administrative gotcha with a pro se applicant to avoid confronting this tough issue.

[00:12:51] Speaker 01:
It is a tough one, but we just want a hearing and all we'd ask

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is that if this case does get remanded, that it's not just to dicker over the purity study, because that doesn't advance the ball or move the market.

[00:13:02] Speaker 01:
It's to have a hearing fair and square on this use indication, because that's the issue that we raise.

[00:13:08] Speaker 01:
I'll reserve my time.

[00:13:11] Speaker 01:
All right, there's Carol.

[00:13:27] Speaker 02:
May it please the court, Sarah Carroll, on behalf of the government.

[00:13:30] Speaker 02:
PMRS proposed the labeling stating that its product, as Judge Wilkins noted, quote, is formulated with inactive ingredients that make the capsule more difficult to manipulate for misuse and abuse.

[00:13:40] Speaker 02:
And shortly after that, PMRS proposed to state that in vitro physical and chemical manipulation studies had shown that PMRS has capsules in comparison to Roxycodone tablets.

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That's the non-abuse deterrent product on which PMRS relied for safety and effectiveness.

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had increased resistance to physical and chemical extraction.

[00:13:59] Speaker 02:
There was no evidence to support these statements, and in fact, PMRS's study showed that more oxycodone could be extracted from its product 98% than from oxycodone.

[00:14:09] Speaker 02:
That's in footnote one of FDA's order.

[00:14:12] Speaker 02:
On appeal, PMRS focuses primarily on this chronic versus acute indication issue, but that issue has no bearing on

[00:14:22] Speaker 02:
whether PMRS's statements about the formulation of its product were false or misleading.

[00:14:28] Speaker 02:
If a product was labeled for acute use only, and even if the product, if the labeling made some statements about the effect of long-term versus short-term use on the risk that people would become addicted, something like that, that says nothing about the formulation of the product and whether the product can be manipulated physically or chemically to permit

[00:14:52] Speaker 02:
abuse through inappropriate means.

[00:14:57] Speaker 02:
Here now, PMRS's counsel is relying on parts of the Joint Appendix that they did not focus on in their brief, but they also don't alleviate the fundamental labeling deficiencies with PMRS's new drug application.

[00:15:11] Speaker 02:
For example, JA590, I think the part that PMRS is relying on must just be this paragraph that says that the proposal to refuse the new drug application states, quote, in particular, A, the oxycodone in the formulation can be readily extracted in commonly available solvents into a solution suitable for injection, end quote, this is factually incorrect.

[00:15:34] Speaker 02:
As you noted, Judge Wilkins, FDA did address that and noted that, again, 98% of the oxycodone in PMRS's drug could be readily extracted in commonly available solvents.

[00:15:48] Speaker 02:
These statements about purity that PMRS is relying on an oral argument, I think that those are just saying, again, something that's addressed in footnote one, which is that PMRS's studies at least purported to show that

[00:16:04] Speaker 02:
if you extracted the oxycodone from the capsules, you would also get the excipients, the dye and potentially other inactive ingredients.

[00:16:12] Speaker 02:
But nothing about that would preclude someone, or there at least was no evidence that that would preclude someone from injecting the solution, excipients and oxycodone and all.

[00:16:23] Speaker 02:
So prescribers and patients rely on drug labeling to make decisions.

[00:16:29] Speaker 02:
And here, PMRS wanted to label its drug

[00:16:32] Speaker 02:
with statements that simply were not supported by the evidence.

[00:16:37] Speaker 02:
And the FDA correctly found that under 21 USC 355D, which requires it to deny a new drug application if the labeling is false or misleading in any particular, it was required to deny the new drug application.

[00:16:50] Speaker 02:
I'm happy to answer questions the court might have.

[00:16:53] Speaker 02:
I certainly want to address any concerns you have.

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But otherwise, I think our brief explains our position.

[00:17:00] Speaker 02:
Thank you.

[00:17:03] Speaker 01:
We agree completely with what page 66 says.

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We disagree that there is, quote, no evidence.

[00:17:20] Speaker 01:
The JA pages I read established that there is indeed evidence.

[00:17:24] Speaker 01:
And we did brief this in several places in our opening brief, 11 to 12,

[00:17:29] Speaker 01:
I think 16 to 17, 29, 31, the reply at 10 to 13.

[00:17:34] Speaker 01:
We went through this.

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They cannot make a no evidence argument on that record.

[00:17:38] Speaker 01:
And footnote, it doesn't hold up.

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And the other thing is it doesn't cure the major state farm issue here of not looking at the use indication.

[00:17:48] Speaker 01:
I mean, I was trying to think of a good analogy on this issue.

[00:17:51] Speaker 01:
I was thinking of maybe like a roller coaster, a big one and a little one.

[00:17:54] Speaker 01:
The roller coaster is the drug product.

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And the safety restraints are these ADTs or these ADFs.

[00:18:00] Speaker 01:
You could have a huge roller coaster with really good safety restraints, and you could have a little tiny roller coaster with a lap belt.

[00:18:06] Speaker 01:
It may well be the case that the smaller one is safer on balance.

[00:18:11] Speaker 01:
That's the analogy here.

[00:18:12] Speaker 01:
And I think my colleague just said it.

[00:18:16] Speaker 01:
Prescribers are looking at these labels.

[00:18:18] Speaker 01:
We would take away the label cover for the chronic indication the CDC has said is unsupported in any 505 evidence FDA is running from.

[00:18:27] Speaker 01:
It is killing people.

[00:18:28] Speaker 01:
How you could say under the statutory standard that FDA cited in its brief at 22 and the order sites at 22 to 23 does the product potentially be safer than a conventional formulation is the issue.

[00:18:42] Speaker 01:
And you can't ignore the use indication.

[00:18:44] Speaker 01:
That is a huge state farm problem.

[00:18:46] Speaker 03:
How would you respond to the government's arguments about footnote one in the order with their characterization of PMRS's own studies?

[00:18:56] Speaker 03:
with respect to solubility.

[00:18:59] Speaker 01:
Their argument is we're misunderstanding how that term is used in the context of abuse deterrent opioids.

[00:19:16] Speaker 03:
So you were suggesting that the drug is less soluble than other drugs, right?

[00:19:22] Speaker 03:
So that helps deter abuse.

[00:19:24] Speaker 03:
That was, I think, my understanding of some of the appendix sites you were saying.

[00:19:27] Speaker 03:
But they're saying that PMRS's studies show that it's actually just as soluble as other drugs.

[00:19:34] Speaker 03:
It's just a question of whether you can extract the dye or separate the dye.

[00:19:39] Speaker 01:
It's actually even more than that.

[00:19:41] Speaker 03:
I'm not a scientist.

[00:19:43] Speaker 01:
We agree completely with them.

[00:19:44] Speaker 01:
We're not disputing their study.

[00:19:45] Speaker 01:
They're only citing half of the loaf.

[00:19:48] Speaker 01:
They're cherry picking.

[00:19:50] Speaker 01:
We agree, and it's next to our purity study, these extraction studies where they say that a person can get more of our active pharmaceutical, the thing that makes you high in a solution than the other drug.

[00:20:00] Speaker 01:
True enough.

[00:20:01] Speaker 01:
We say in counterpoint, the purity point I made, which is

[00:20:05] Speaker 01:
Yes, you can get more solution.

[00:20:07] Speaker 01:
It's like 98% to 90.

[00:20:08] Speaker 01:
This is all on the appendix sites I gave.

[00:20:10] Speaker 01:
But what they ignore is what's right next to it.

[00:20:13] Speaker 01:
On the purity study, we say, but because we made these excipients with the same solubility, when you fill up your needle with five mils of that solution, you only get a much smaller percentage of the API in our solution than from theirs.

[00:20:28] Speaker 01:
So for the shooter, they're not going to get the same height.

[00:20:32] Speaker 01:
Now, we're not asking the court to evaluate the science.

[00:20:35] Speaker 01:
Undeniably, a factual dispute and perhaps a threshold Edison dispute with the agency on what you have to show to get this label.

[00:20:44] Speaker 01:
That compels a hearing under this court's precedence, Edison and Cyanamid.

[00:20:48] Speaker 01:
They don't have an answer to that.

[00:20:50] Speaker 01:
OK, so at a minimum, that's the thing that should go back.

[00:20:53] Speaker 01:
And the thing is, I want to stress, though, is that that is not really the issue.

[00:20:57] Speaker 01:
They're still going to succeed in dodging a fundamental state farm issue, a fundamental public health issue, a fundamental fairness issue to this applicant.

[00:21:05] Speaker 01:
if that hearing is also not about the use indication, because under their own interpretation of the statute and what it's supposed to do, see if this market offering makes sense as against others, could it be safer?

[00:21:17] Speaker 01:
There's no reason in the world not to consider the very thing my colleague said is important, which is how the prescriber uses these things.

[00:21:24] Speaker 01:
If you look at our briefs,

[00:21:26] Speaker 01:
This epidemic exists because these things were overprescribed under lawful mandate from the federal drug administration.

[00:21:33] Speaker 01:
That needs to change.

[00:21:35] Speaker 01:
And this court's direction is critical on this issue in an APA case, because the FDA doesn't want to deal with it for all the reasons we've briefed.

[00:21:41] Speaker 01:
So respectfully, we submit they can't stand on this order under Chenery.

[00:21:45] Speaker 01:
And the cases we cite, at a minimum, it requires a hearing under Edison and Cyanamide.

[00:21:50] Speaker 02:
Thank you.