[00:00:00] Speaker 05: Case number 24-1049, Vanda Pharmaceuticals, Inc. [00:00:04] Speaker 05: Petitioner versus United States Food and Drug Administration, EDEL. [00:00:08] Speaker 05: Mr. Hughes for the petitioner, Mr. Yelling for the respondents. [00:00:12] Speaker 05: Good morning, Mr. Hughes. [00:00:14] Speaker 00: Good morning, Your Honor, and may it please the court, Paul Hughes for Vanda Pharmaceuticals. [00:00:20] Speaker 00: I'd like to start with why we're here. [00:00:21] Speaker 00: FDA has sought to arrogate to itself control over drug development. [00:00:28] Speaker 00: FDA has decided that it itself will determine which new drug indications are appropriate. [00:00:32] Speaker 00: And FDA has escalated the standard of evidence for drug approval far beyond what Congress intended, in part by refusing to consider objectively, to objectively evaluate the scientific evidence that applicants submit. [00:00:47] Speaker 00: Now, Vanda is a pharmaceutical innovator, and it has suffered immensely. [00:00:53] Speaker 00: It has spent tens of millions of dollars to develop a novel treatment for jet lag. [00:00:58] Speaker 00: The evidence in our view is overwhelming that Hetlios works to treat this condition. [00:01:03] Speaker 00: People fall asleep far faster and stay asleep far longer than FDA requires for all other sleep medications. [00:01:11] Speaker 05: But that's just a sleep disorder, isn't it? [00:01:13] Speaker 05: There's a difference between a sleep disorder and jet lag disorder, isn't there? [00:01:17] Speaker 00: Well, yes, Your Honor. [00:01:18] Speaker 00: There are, you know, 18 approved medications for a variety of sleep disorders. [00:01:22] Speaker 00: Jet lag is one kind of sleep disorder. [00:01:24] Speaker 00: And our evidence is that this works, you know, essentially better than any product that's been approved for all the other forms of sleep disorders. [00:01:32] Speaker 00: But ultimately, we think this case doesn't require the court to make a determination as to this drug is necessarily approvable. [00:01:40] Speaker 00: We think where FDA absolutely went wrong was denying Vanda a hearing. [00:01:45] Speaker 00: The evidence to us is quite clear that there are a multitude of disputes of facts. [00:01:50] Speaker 00: So everything that's in part two of our brief, both our opening brief and our reply brief, illustrate the broad variety of true disputes that exist in this case. [00:02:01] Speaker 00: And because of those disputes, [00:02:02] Speaker 00: Our principal submission to the court was that essentially the grant of summary judgment, the denial of a hearing was improper. [00:02:09] Speaker 00: So we don't think the court needs to wade into the various disputes because those actually deserve a hearing where there will be a testimony by our experts, testimony by FDA's experts, and there can be a contested proceeding [00:02:23] Speaker 00: in order for FDA to fairly evaluate all of that evidence in the process that Congress created. [00:02:29] Speaker 05: Well, doesn't that just boil down to your subjective sleep measures, which were not pre-specified? [00:02:37] Speaker 05: That's kind of like, once I kind of dug down through it all, it seemed that that's kind of the main issue there. [00:02:44] Speaker 00: So, Your Honor, FDA's principal contention is that because [00:02:48] Speaker 00: Their submission is that we don't have evidence of efficacy as to next day functioning, what they call a criterion B, that they can grant summary judgment. [00:02:56] Speaker 00: There are three independent problems with that. [00:02:58] Speaker 00: First is the sleep experts show that you don't actually have to treat criterion B symptoms in order to get approval. [00:03:05] Speaker 00: The 18 drugs that I mentioned, as Dr. Roth explained, none of them, except for one only for half of its indication, actually has a criterion B indication. [00:03:14] Speaker 00: And Dr. Roth explains, [00:03:16] Speaker 00: why you don't need criterion B indications. [00:03:18] Speaker 05: So if we could just dig down on that for a minute, because my understanding of your argument is that the FDA says we treat essential features. [00:03:29] Speaker 05: We don't look at the criterion. [00:03:30] Speaker 05: We're looking at essential features. [00:03:31] Speaker 05: For jet lag disorder, essential features happens to include a criterion B, criterion, if I can finish, which is [00:03:40] Speaker 05: impairing next day function. [00:03:42] Speaker 05: You're saying there are all these other drugs or other disorders that have essential features that include criterion B, and drug companies haven't been required to address the criterion B symptoms. [00:03:58] Speaker 05: But when I actually look what's in the record of the disorders of insomnia that you point to, [00:04:05] Speaker 05: They don't include criterion B features. [00:04:08] Speaker 05: So chronic insomnia disorder has a single essential feature. [00:04:12] Speaker 05: It's frequent and persistent difficulty initiating or maintaining sleep that results in general sleep dissatisfaction. [00:04:19] Speaker 05: That's the essential feature. [00:04:21] Speaker 05: There's no Criterion B in that. [00:04:23] Speaker 05: It goes on to say the sleep complaint is accompanied by distress, poor sleep. [00:04:28] Speaker 05: Those are Criterion B things. [00:04:30] Speaker 05: But that's not an essential feature. [00:04:32] Speaker 05: That's just something that accompanies the essential feature. [00:04:35] Speaker 05: So if I can finish, likewise, short-term insomnia disorder, same thing. [00:04:41] Speaker 05: There's a singular essential feature, and it's accompanied by criterion B feature. [00:04:46] Speaker 05: So I don't think this record supports your argument that the FDA is being inconsistent when it talks about essential features. [00:04:53] Speaker 05: Because essential features can include A, it can include B, it can include D. For jet lag disorder, it happens to include B. And there are plenty of other ones where they don't include B. I just don't think this record supports your argument. [00:05:06] Speaker 00: So let me address this in a multitude of ways. [00:05:09] Speaker 00: So first, I have two independent arguments, even if the court rejects me on that, that show why we've actually proven next day functioning. [00:05:17] Speaker 00: So even if we have to, we have a dispute of fact as to whether we've proven next day functioning. [00:05:21] Speaker 00: We also have a dispute as to whether or not a narrowing of the indication would solve that. [00:05:26] Speaker 00: That's my point one. [00:05:26] Speaker 00: I want to come around to that. [00:05:27] Speaker 00: So I'll get to the court's question. [00:05:29] Speaker 00: The point two, before I get directly to the court's question, is [00:05:32] Speaker 00: Our principal contention is that what actually qualifies as jet lag disorder is a scientific issue. [00:05:39] Speaker 00: It's not an FDA regulatory issue. [00:05:41] Speaker 00: This is decided by sleep medicine experts, some of which may reside at FDA, but not all of which. [00:05:50] Speaker 05: Are you disputing that the ICSD is an appropriate source? [00:05:54] Speaker 00: Yeah, and let's talk about the ICSD. [00:05:55] Speaker 00: So if the court looks to Joint Appendix page 2088, this is the ICSD listing. [00:06:03] Speaker 00: This is the description of chronic insomnia disorder. [00:06:05] Speaker 00: And as the court noted, diagnostic criteria B includes, for example, fatigue and malaise. [00:06:12] Speaker 00: And there are nine of them. [00:06:14] Speaker 00: And that's at Joint Appendix page 2085 to 2086. [00:06:16] Speaker 00: Then at page 2087 is where the ICSD begins discussing its description of essential features. [00:06:27] Speaker 00: And if we turn the page to 2088, [00:06:30] Speaker 00: This is all in the description of essential features. [00:06:33] Speaker 00: It describes everything that is contained under criterion B. No, I don't think so. [00:06:38] Speaker 05: I mean, I think just because there's a section of the, of the document that says essential features, you have to read the doc. [00:06:46] Speaker 05: The documents more specifically says, as I said, for chronic insomnia disorder, the essential feature, one feature is, and it's one sentence. [00:06:57] Speaker 00: But there's a whole description. [00:06:59] Speaker 00: This is under the heading. [00:07:00] Speaker 00: So at 2087, there's the heading essential features. [00:07:04] Speaker 00: And then at 2008. [00:07:05] Speaker 05: I understand the heading says essential features, but you have to read that section. [00:07:08] Speaker 05: And within it, there's a sentence that identifies what the real essential feature is. [00:07:12] Speaker 00: But then if you turn to page 2089, it describes associated features. [00:07:18] Speaker 00: What we think, and this is what Dr. Roth, I believe, describes, is that what is contained under the heading essential features are the essential features of the disorder. [00:07:26] Speaker 00: It's not just one single sentence. [00:07:28] Speaker 05: I don't think we can not read that. [00:07:31] Speaker 05: that particular provision. [00:07:33] Speaker 05: We are the sentences say they which don't support you are the headings as essential features and it has multiple paragraphs that describe essential features and as a second description of what's interesting you have to read the section because the heading says essential features doesn't mean everything that's in that is an essential feature. [00:07:48] Speaker 05: I think this is an interesting dispute which is exactly the kind of thing that goes to a hearing because you can have sleep experts because I think it shows that you haven't met your burden to establish that there's any problem with the way the FDA handled this. [00:08:00] Speaker 00: But again, as I said, this argument is sort of one of multiple independent arguments that we present. [00:08:07] Speaker 00: So even if the court, I can't convince the court that everything that's under essential features is actually essential features as distinct from associated features, which is separately spelled out by the ICSD, which is how Dr. Roth, our sleep expert, says one trained in sleep medicine would understand this, which shows that there's a distinction between insomnia. [00:08:24] Speaker 00: I think that's pretty powerful. [00:08:25] Speaker 00: And I think that on its face deserves a hearing. [00:08:27] Speaker 00: But even if the court disagrees with that submission, I appreciate not to convince your honor, we have lots of evidence that even show we do show next day functioning. [00:08:35] Speaker 00: This is with the KSS and the VA scales. [00:08:37] Speaker 00: Sure. [00:08:41] Speaker 00: So on the KSS and the VAS and the other associated evidence of next day functioning, we think there is a tremendous wealth of evidence that exists in the record demonstrating how individuals report that they have substantially improved next day functioning as a result of taking this drug. [00:09:00] Speaker 05: I think what FDA's... What about the pre-specification? [00:09:03] Speaker 00: Yeah, so Your Honor, there are two problems with the FDA's pre-specification analysis. [00:09:07] Speaker 00: The most important that I'll point the court to that FDA has essentially no response to is we provided an expert declaration from Dr. Platt, which did an analysis showing in this context what you're trying to control for with pre-specification is what's called type one error. [00:09:21] Speaker 00: That's the result of a potential false positive. [00:09:24] Speaker 00: So as FDA's analysis points out, they're not wrong in an abstract matter that you do pre-specification so as to avoid doing a post hoc analysis [00:09:32] Speaker 00: and finding data that points to a conclusion but has a false positive risk associated with it. [00:09:37] Speaker 00: That's the general theory. [00:09:39] Speaker 00: So I don't disagree. [00:09:40] Speaker 00: In the general abstract, that is one thing that one considers. [00:09:44] Speaker 00: What Dr. Platt did, though, is he said, let's look at the actual risk of type 1 error in the facts of this case using all the evidence before us. [00:09:52] Speaker 00: This is at page 2,299 of the record where Dr. Platt has his conclusions. [00:09:57] Speaker 00: And he says, there are 22 separate endpoints [00:10:00] Speaker 00: That would that have been shown in this throughout all of the studies, he did a meta analysis and he said all 22 endpoints show directional improvement. [00:10:09] Speaker 00: And so, in that context where everything shows that this product works, the risk of there being type one error is negligible and he said it's there's no material risk. [00:10:19] Speaker 00: One of the things. [00:10:20] Speaker 02: that the FDA said about Platt's declaration was that essentially what you did was take your answer to each individual study suffers the same flaw was to do a meta-analysis of all the studies with the same flaw. [00:10:35] Speaker 02: And that can't fix the flaw. [00:10:36] Speaker 02: It's just now intrinsic embedded into your meta-analysis. [00:10:40] Speaker 00: That's what they said. [00:10:42] Speaker 00: And frankly, that's an absurd position, because the whole point of Dr. Platt, who's an expert in statistics, is to say, I know what you're trying to control for as a general matter is type 1 error and the reasons that you have pre-specification. [00:10:54] Speaker 00: But I can look in the context of this particular case, use scientific methods, and explain why what it is you're trying to control for in type 1 error does not exist in the context of the evidence that we have before us. [00:11:07] Speaker 00: So sure, if you look at an abstract theoretic matter, [00:11:10] Speaker 00: is that pre-specification have some value? [00:11:13] Speaker 00: Yes. [00:11:13] Speaker 00: But the question is, what does it do in the context of this evidence before us? [00:11:18] Speaker 00: And Dr. Platt says essentially nothing. [00:11:20] Speaker 00: And FDA has no response to that other than to say, well, it is also post hoc. [00:11:25] Speaker 00: But the absurdity point of that is he's describing from an expert perspective why the post hoc feature of this is not actually a problem. [00:11:33] Speaker 00: And FDA doesn't respond to that with any substantive analysis. [00:11:37] Speaker 00: They just essentially say no. [00:11:38] Speaker 05: I'll give you a hypothetical. [00:11:39] Speaker 05: Like, I'm not an expert in, I guess, statistics or what's the best way to do a study. [00:11:45] Speaker 05: But it seems to me that what is at stake here, what's in play, is just sort of a methodological accepted practice, which you should pre-specify to avoid a certain type of error. [00:11:57] Speaker 05: So if we had, for example, [00:12:00] Speaker 05: A sample, usually I think you need to have 30 or more for a sample. [00:12:03] Speaker 05: And Vanna came up, well, we have a sample of five. [00:12:07] Speaker 05: And the criticism was, well, that's not a big enough sample. [00:12:10] Speaker 05: And Vanna got an expert that said, well, usually you need a sample of 30. [00:12:14] Speaker 05: But in this case, it was just so convincing that you should accept our sample of five. [00:12:19] Speaker 05: Would the FDA not be able to be like, we don't accept your methodology? [00:12:23] Speaker 05: Because on its face, that's not. [00:12:25] Speaker 00: So what American Sign Amid this court's case, I think, addresses that, which says, if you have a dispute of fact that is, quote unquote, palpably shallow, then a palpably shallow dispute of fact is not something that entitles one to a hearing. [00:12:37] Speaker 00: We don't think these disputes of fact are remotely to the range of being palpably shallow. [00:12:42] Speaker 00: And to get to the particulars of this. [00:12:44] Speaker 05: But what about my? [00:12:46] Speaker 05: hypothetical because it seems to be similar to what you're saying here there's a methodology that's accepted we didn't follow it we've been expert that says it doesn't matter and what about my sampling. [00:12:56] Speaker 05: FDA would you have to have a hearing on that if you only had a sample of five. [00:13:00] Speaker 00: I think the question is, is there a finding that that analysis is essentially palpably shallow and there's no meaningful dispute around it. [00:13:08] Speaker 00: And if, if one can draw that conclusion to the summary judgment standards, not distinct, I don't think from how the court looks at summary judgment saying there's no actual essential factual dispute here, then the hearing would not be required. [00:13:20] Speaker 00: But in circumstances where there is a dispute in here, [00:13:23] Speaker 00: We have a pretty expert statistician who's explaining why there isn't a risk of type one error in this context. [00:13:30] Speaker 00: And FDA has no actual technical or meaningful argument. [00:13:35] Speaker 00: They just have an attorney argument saying it's post hoc. [00:13:39] Speaker 00: But the whole point of the analysis is to explain why not all post hoc analysis is bad. [00:13:44] Speaker 00: And this kind of goes to the broader problem here, is FDA can always say, run another test with another kind of pre-specification. [00:13:51] Speaker 00: You can always do more and more to try to eliminate what's called type one error. [00:13:55] Speaker 00: But the problem that you have is you lead to a graveyard of unapproved drugs because you lead to type two error, which is you have false negatives. [00:14:02] Speaker 00: If you make the standard too demanding, you have products that actually work, which is this product that don't get to approval. [00:14:08] Speaker 00: there has to be a balance between trying to control for type one and type two error and again i'm not saying this court strikes that balance i'm saying you have a hearing to strike that balance can just go back to the one of your other other arguments is that your evidence does show the type of improvement in next day functioning that fda is asking for yes and [00:14:29] Speaker 02: Am I right that the main evidence you're referring to is the KSS and the VAS metrics? [00:14:35] Speaker 00: Yeah, there are other pieces of evidence, but those are the two principles. [00:14:37] Speaker 02: But aside the questionnaires and all that. [00:14:39] Speaker 02: Those are the two principles. [00:14:40] Speaker 02: Right. [00:14:40] Speaker 02: And so my understanding of what FDA said is you may have evidence that those are measures of sleepiness versus alertness. [00:14:50] Speaker 02: And it might be true that if you say you're sleepy, that will correlate with next-date functioning. [00:14:58] Speaker 02: But those don't capture the situation where somebody feels alert but is still impaired in their functioning on the next day, which FDA says their definition is that that's the key sort of independent feature of jet lag disorder. [00:15:14] Speaker 02: You could separate from sleep disturbance. [00:15:16] Speaker 02: Because of the circadian rhythm change, you're going to have next day functioning problems. [00:15:22] Speaker 02: Do you have evidence that goes to that kind of thing? [00:15:24] Speaker 00: Well, that's what Dr. Roth tells us, is that KSS in the sleep medicine world [00:15:28] Speaker 00: is sort of the gold standard for figuring out how somebody is performing on the next day is looking at the KSS standard. [00:15:34] Speaker 00: It is, do you feel? [00:15:36] Speaker 02: In the sleep medicine world, not in a circadian rhythm, you've traveled to the other side of the world. [00:15:42] Speaker 02: And I don't fully understand this, but the FDA says, and ICSD says, even if you're sleeping, totally fine. [00:15:50] Speaker 02: The fact that your circadian clock is so off is going to impair your functioning. [00:15:55] Speaker 02: That's an essential feature of jet lag. [00:15:58] Speaker 02: I don't think Roth speaks to that. [00:16:00] Speaker 00: What Ross says is the way that you get at that question about next day functioning is you do these surveys of people and you ask them, how are you functioning? [00:16:11] Speaker 00: What is your alertness versus your sleepiness level? [00:16:13] Speaker 00: Because that is what is directly tied to your functioning in a particular day is how somebody is doing compared against their baseline. [00:16:19] Speaker 00: So it's not the evidence that goes to criterion A is you fall asleep faster and you sleep longer. [00:16:25] Speaker 00: Those are objective scientific facts. [00:16:27] Speaker 00: The next question about [00:16:28] Speaker 00: if we get to criterion B, if that's even required, and again, we have a disagreement about that, but if it's required, then the question is, well, what's a way that you show your next day functioning? [00:16:37] Speaker 00: You learn from people how they experience their performance, what their alertness versus sleepiness is that next day. [00:16:47] Speaker 02: And I think- So you're equating performance to alertness versus sleepiness. [00:16:50] Speaker 02: And here's just one way of many that FDA made this point. [00:16:54] Speaker 02: I just want to know what your response is. [00:16:55] Speaker 02: So they say, quote, [00:16:57] Speaker 02: This scale would not capture the impairment of someone who felt subjectively alert, but performed poorly behind the wheel of the car. [00:17:05] Speaker 00: So this kind of goes to the key problem, is FDA can always come up with some other test of, oh, put somebody behind a wheel of a car. [00:17:11] Speaker 00: But nothing in criterion B says, put somebody behind the wheel of a car. [00:17:15] Speaker 00: It's just an example, right? [00:17:16] Speaker 02: The fundamental point is, you could have somebody who does not feel sleepy, feels very alert, but is functionally impaired, and that you didn't measure for any study that goes to that. [00:17:28] Speaker 02: At least, that's my understanding. [00:17:29] Speaker 00: that's wrong your honor because the alertness study is actually is the person functioning that is that is directly tied that's what the evidence shows is is if the person is alert they are have that that degree of functioning but again these are not questions that I think this court needs to be deciding these are questions that are scientific [00:17:48] Speaker 00: expert questions about people who actually spend their life doing sleep medicine. [00:17:51] Speaker 00: And now maybe FDA disagrees with Dr. Ross' explanation of what KSS and VAS show and how they demonstrate next day functioning. [00:18:00] Speaker 00: And that's a fine dispute for us to have on a full factual record. [00:18:04] Speaker 00: where FDA produces what it is that they believe is the evidence that contradicts our evidence. [00:18:08] Speaker 00: But right now, we don't have any evidence from the FDA. [00:18:10] Speaker 00: We just have FDA rejecting our evidence. [00:18:13] Speaker 00: And again, the statutory standard to bring it back to is substantial evidence. [00:18:17] Speaker 00: As FDA said, this is often a low standard. [00:18:20] Speaker 00: We don't have to have overwhelming evidence of efficacy. [00:18:22] Speaker 00: We don't have to have every conceivable piece of evidence that FDA might wish we have. [00:18:27] Speaker 00: The question is, do we have substantial evidence of efficacy? [00:18:31] Speaker 00: And again, going back to the statutory standard, [00:18:33] Speaker 00: What's critical is, is there a qualified expert who fairly and responsibly concludes that we have demonstrated the effectiveness of our drug? [00:18:42] Speaker 05: We've provided two experts, Dr.- It seems to me that the implication of your argument is that any time a drug company has an expert that says, there's a question of fact here, the FDA has to hold a hearing. [00:18:55] Speaker 05: Because the standard says, you know, you have to have substantial evidence, but [00:19:00] Speaker 05: The practice is if there's no way you can meet that standard, the FDA shouldn't have to waste its time holding a hearing. [00:19:07] Speaker 05: But what you're saying is any time a drug company can get an expert to come in and say, actually, our opinion is there is a question of fact here. [00:19:15] Speaker 05: The FDA has to hold a hearing. [00:19:17] Speaker 00: So I have a few responses to that. [00:19:19] Speaker 00: First, there is a relief valve in the palpably shallow, as American Sinomed, this court held. [00:19:24] Speaker 00: So it is not in every case. [00:19:25] Speaker 00: But second, as a factual matter, we describe in our brief [00:19:28] Speaker 00: There have been only five since 2018. [00:19:30] Speaker 00: And I think this stretches back at least a decade. [00:19:32] Speaker 00: There've only been five requests for a hearing in all of FDA. [00:19:36] Speaker 00: And FDA has denied a hearing in all five cases. [00:19:39] Speaker 00: So we're not in a situation where FDA has a glut of hearing request or a glut of hearings. [00:19:43] Speaker 00: They deny all of them. [00:19:45] Speaker 05: Do you say that they never have hearings? [00:19:47] Speaker 00: So far as I know, no. [00:19:48] Speaker 05: So drugs get approved? [00:19:52] Speaker 00: The approval happens without a hearing. [00:19:54] Speaker 00: Right that the approval happens with a lower level official issuing an approval letter without a here. [00:20:02] Speaker 00: So there are no hearings on drug approvals essentially there are advisory committee proceedings that's the closest FDA comes but in my knowledge and we are we go back at least a 2018 there's not been. [00:20:13] Speaker 00: any hearings before the commissioners on drug approval. [00:20:15] Speaker 05: So my impression is, and correct me if I'm wrong, it seems like it's a sort of interactive, almost collaborative process because just from reading this record it seemed like [00:20:25] Speaker 05: there was a lot of communication between Vanda and the FDA. [00:20:29] Speaker 05: We want to do this. [00:20:30] Speaker 05: FDA says, well, our concerns are this. [00:20:31] Speaker 05: Can you address this? [00:20:32] Speaker 05: You go back and have studies. [00:20:34] Speaker 05: You try to address the concerns. [00:20:35] Speaker 05: You come back. [00:20:36] Speaker 05: So is that why that there usually aren't hearings? [00:20:40] Speaker 05: Because usually, it's more of a collaborative and less of an adversarial process. [00:20:45] Speaker 00: I'm not sure if we've studied it in this brief or in else, but a former general counsel of GSK was quoted as saying, when FDA says, John, [00:20:52] Speaker 00: if you're in the pharmaceutical industry, you ask how high. [00:20:55] Speaker 00: That is how usually drug approval works. [00:20:57] Speaker 00: So I will agree with that general approach. [00:21:00] Speaker 00: But the point is, Congress put into the statute a hearing mechanism for when there are actual disputes between the agency and the parties, the applicants. [00:21:10] Speaker 00: And I think American Sinemid, which is sort of shocking to me, a case that the government doesn't even cite in their brief. [00:21:17] Speaker 00: It's a feature of our opening brief from this court. [00:21:19] Speaker 00: The government doesn't even cite it. [00:21:21] Speaker 00: If you look at the concluding paragraph of what this court held in American Sinamide, it is this case. [00:21:26] Speaker 00: And so here's what this court said. [00:21:29] Speaker 00: Sinamide presented FDA with scientific studies, which, in the opinion of some experts, proved that proban may be safely used by dog owners without professional supervision. [00:21:38] Speaker 00: This was about an animal product. [00:21:39] Speaker 00: So that's our case. [00:21:40] Speaker 00: We have scientific studies, the opinion of experts. [00:21:43] Speaker 00: Sineman's experts disputed FDA's interpretation and critiques of the study's results in methods. [00:21:49] Speaker 00: So we dispute FDA's interpretation and critiques of our studies. [00:21:52] Speaker 00: That's exactly what our experts do. [00:21:54] Speaker 00: They raised, too, a number of material questions about the appropriateness of the methodological standards the director attempted to graft onto the statute. [00:22:01] Speaker 00: That's exactly what we're doing. [00:22:02] Speaker 00: We're saying the FDA is putting additional standards onto the statute. [00:22:07] Speaker 00: And last sentence, in short, the papers on file in this matter [00:22:11] Speaker 00: generate several material issues of fact and science that FDA attempted to resolve without a hearing in contravention of the Food Drug and Cosmetic Act. [00:22:19] Speaker 00: That is our case. [00:22:21] Speaker 02: Just in terms of what the standard is, do you think it is it essentially the same standard we apply in summary judgment cases? [00:22:27] Speaker 02: Is there material dispute of fact or is there some other more demanding? [00:22:31] Speaker 00: I think it's a practical matter. [00:22:33] Speaker 00: It's probably similar, Your Honor, to summary judgment standard. [00:22:35] Speaker 00: What the American Sinemid case said is, if a dispute, and I've said this a few times, is palpably shallow, then there would be no need for a hearing in those circumstances. [00:22:44] Speaker 00: So it can't be a trivial dispute of fact, or it can't be something that a court could say. [00:22:49] Speaker 00: It could be a material dispute. [00:22:52] Speaker 00: That's right, Your Honor. [00:22:53] Speaker 00: It's certainly a material dispute. [00:22:57] Speaker 00: So, Your Honor, I think probably shallow material dispute is probably synonymous. [00:23:01] Speaker 00: But yes, so there is, in fact, to Your Honor's question, we're not suggesting that every dispute automatically gets there. [00:23:09] Speaker 00: There has to be a material dispute. [00:23:10] Speaker 00: And we think our expert. [00:23:12] Speaker 01: Any doubting is the government. [00:23:14] Speaker 01: I didn't see it anywhere. [00:23:15] Speaker 01: I just want to confirm. [00:23:16] Speaker 01: They're not doubting that your experts are indeed experts in the field. [00:23:22] Speaker 01: Is that right? [00:23:22] Speaker 00: No. [00:23:23] Speaker 01: That's not the least bit contested. [00:23:25] Speaker 00: Yes, Your Honor. [00:23:26] Speaker 01: So there's a jouse between so-called experts on the government side and so-called experts on your side. [00:23:33] Speaker 01: And material disagreement to the matter and issue, right? [00:23:37] Speaker 01: Yes, Your Honor. [00:23:39] Speaker 00: We don't know who the government's experts are. [00:23:41] Speaker 00: At a hearing, we'd like to cross-examine them. [00:23:44] Speaker 00: And the government can cross-examine our experts. [00:23:46] Speaker 00: We can test those disputes. [00:23:48] Speaker 00: And we get a better process, a fair process, when those experts get subject to a hearing. [00:23:55] Speaker 00: And then FDA adjudicates what it views the correct result to be. [00:24:02] Speaker 00: Again, what we ask the court for is simply an application of American Sign Amid. [00:24:09] Speaker 00: I was preparing and read this course concluding paragraph, it feels to me like that paragraph could be written for this case, because we are in exactly the same circumstance. [00:24:18] Speaker 00: I don't deny these are important disputes of fact. [00:24:21] Speaker 00: And we are not asking the court. [00:24:24] Speaker 00: Let me say, the court does not need to resolve any of these. [00:24:26] Speaker 00: It just needs to recognize that these are pretty weighty disputes that warrant scientific treatment. [00:24:37] Speaker 05: Thank you. [00:24:38] Speaker 05: We'll give you two minutes for a bottle. [00:24:39] Speaker 04: Thank you. [00:24:51] Speaker 03: Good morning, your honors. [00:24:52] Speaker 03: May it please the court. [00:24:53] Speaker 03: I'm Louis Yellen from the Department of Justice. [00:24:55] Speaker 03: I'm here today on behalf of the FDA. [00:24:58] Speaker 03: I'd like to start with Judge Pan's observation about the collaborative nature of new drug and supplemental new drug applications and describe how the process usually works and what happened in this case. [00:25:10] Speaker 01: Let me go to the point that they're raising, which is what's before us. [00:25:15] Speaker 01: The statute says very clearly they're entitled to a hearing. [00:25:19] Speaker 01: It doesn't say maybe. [00:25:21] Speaker 01: It says they're entitled to a hearing. [00:25:23] Speaker 01: American cyanide is a law of the circuit. [00:25:26] Speaker 01: It is controlling [00:25:28] Speaker 01: precedent. [00:25:29] Speaker 01: And as I read it and as I read other cases like it, it seems very clear to me that disputes among experts on a scientific question involving expert scientific judgment are material factual disputes. [00:25:47] Speaker 01: I cannot comprehend in reading your brief and reading the other side's arguments how you can possibly say they're not entitled to a hearing. [00:25:56] Speaker 01: I don't know when [00:25:58] Speaker 01: But experts, and you don't contest that they're experts, experts disagree with the scientific judgments that have been offered by the agency. [00:26:10] Speaker 01: These are factual disputes. [00:26:12] Speaker 01: They are in lots of context of the law. [00:26:15] Speaker 01: I really was kind of amazed at your arguments, kind of like we exist. [00:26:20] Speaker 01: And if we look at the record and we think we're going to end up ruling against you, we don't have to have a hearing. [00:26:25] Speaker 01: That's not the law. [00:26:27] Speaker 01: That is absolutely not the law. [00:26:28] Speaker 01: And American Cyanamate is the law of the circuit. [00:26:32] Speaker 03: Respectfully, Your Honor. [00:26:33] Speaker 03: So the law of the circuit is also PMRS and Campanos. [00:26:39] Speaker 03: And Campanos and response specifically to American Cyanamate, but to set that up, [00:26:46] Speaker 03: Campano says if the FDA has given adequate notice of the necessary evidence, it can determine without hearing that there is not evidence in the record that could support. [00:26:58] Speaker 01: Their experts disagree with you about whether or not. [00:27:01] Speaker 01: If I might finish your honor. [00:27:03] Speaker 01: Let me put it in context. [00:27:04] Speaker 01: Their experts disagree with you about whether or not what's being proffered by them is adequate to support the conclusion they reach. [00:27:13] Speaker 01: You can't just say, well, no, we're not going to accept it. [00:27:16] Speaker 01: Your Honor. [00:27:17] Speaker 01: I don't have any regulation that forecloses them from offering the evidence that they're relying on. [00:27:23] Speaker 01: And it's certainly not implausible. [00:27:25] Speaker 01: I don't know who's right, but there's certainly nothing implausible about it. [00:27:29] Speaker 03: Your Honor, as Judge Pan observed a little bit earlier, [00:27:32] Speaker 03: If it just because an expert says something doesn't mean that there's a genuine and substantial disagreement of fact. [00:27:39] Speaker 03: An expert can make conclusory statements that are not supported either by reasoning or by studies. [00:27:45] Speaker 03: I read these experts. [00:27:46] Speaker 01: They're not conclusory. [00:27:48] Speaker 01: They're going through what's before you and they're saying [00:27:52] Speaker 01: Here's the way we analyze it. [00:27:55] Speaker 01: And that's a dispute between experts. [00:27:57] Speaker 01: This goes on all the time. [00:27:58] Speaker 01: And the forensic science war goes on all the time. [00:28:00] Speaker 01: Respectfully, Your Honor. [00:28:01] Speaker 01: Competing experts disagree on how you assess the record and what's a viable conclusion in light of your assessments. [00:28:09] Speaker 01: That's a factual dispute. [00:28:11] Speaker 01: Respectfully, Your Honor. [00:28:12] Speaker 01: Is that a factual dispute? [00:28:13] Speaker 01: No, Your Honor. [00:28:13] Speaker 03: It's not a factual dispute because the agency says no? [00:28:18] Speaker 03: If I might respond, Your Honor. [00:28:19] Speaker 03: The dispute here is about standards, not about facts. [00:28:23] Speaker 03: For example, the dispute about whether the so-called subjective endpoints, the KSS and so forth, produce statistically supportable studies is about whether or not you can have a study that does not pre-specify its analytic methods. [00:28:42] Speaker 03: and whether that can support robust findings from the study. [00:28:46] Speaker 01: And they've answered your contentions on that. [00:28:50] Speaker 01: They've answered it in a way that is entitled to be listened to, respected, and then heard. [00:28:58] Speaker 01: And then you make findings after you listen to both sides. [00:29:01] Speaker 01: Your Honor. [00:29:02] Speaker 01: I must say, I didn't want to have to go through this. [00:29:05] Speaker 01: But I did go through it. [00:29:06] Speaker 01: And what they've said is not stupid or implausible. [00:29:10] Speaker 01: These are really smart people in the field in which you're claiming to have expertise as well. [00:29:15] Speaker 01: And they completely disagree with you on how you assess what's before us. [00:29:19] Speaker 01: The statute seems absolutely clear they're entitled to a hearing. [00:29:24] Speaker 01: You may win, but they're entitled to a hearing. [00:29:27] Speaker 03: Respectfully your honor if an expert says one plus one equals three you're not entitled to a hearing and the the argument about Statistical one plus one equals three is discernibly wrong [00:29:39] Speaker 01: And your honor, you're saying is not discernibly right. [00:29:43] Speaker 01: You're saying we don't assess sleep disorder in that way. [00:29:47] Speaker 01: Another expert says, no, you can assess sleep disorder in this way as distinguished from your way. [00:29:54] Speaker 01: You were not discernibly right. [00:29:56] Speaker 01: I don't know whether they're right. [00:29:58] Speaker 01: There's a dispute between experts and what we do in the law and in the forensic science fields goes on all the time. [00:30:04] Speaker 01: the challenges under Daubert this is what happens experts come together they disagree on how you assess the approaches the methodology the results and what they mean that's why you have hearings but you're only have the judge say in those kinds of cases I'm just deciding that I don't care what the experts your honor that's not entirely correct even in the Daubert entirely correct even in the Daubert setting there are circumstances where you don't get to a hearing [00:30:32] Speaker 03: Because the experts have not. [00:30:33] Speaker 03: Yeah, the one plus one equals three. [00:30:35] Speaker 03: Right, Your Honor. [00:30:36] Speaker 03: And pre-specification is a basic method of statistical analysis. [00:30:40] Speaker 03: It is so basic. [00:30:42] Speaker 03: It is so fundamental that the FDA has guidance going back decades about the need for pre-specification in statistical research. [00:30:52] Speaker 01: Why are you afraid of a hearing to make that point? [00:30:55] Speaker 01: You're afraid that you might come up with something that will disprove your point? [00:30:59] Speaker 01: I don't get it. [00:31:00] Speaker 01: This statute's so clear on their right to a hearing. [00:31:02] Speaker 03: Your Honor, and this court in Campanos, in PMRS, in multiple opinions has recognized that unless there is a substantial and genuine issue of fact, a hearing is not required. [00:31:15] Speaker 03: If so long as the FDA puts on notice the applicant of the sort of evidence that needs to be submitted, if that evidence is not submitted, and here there was not valid evidence submitted about [00:31:28] Speaker 03: treatment of impairment of next day functioning. [00:31:31] Speaker 02: No hearing is required. [00:31:32] Speaker 02: Can we just go another level down on the pre-specification issue? [00:31:35] Speaker 02: Yes, Your Honor. [00:31:36] Speaker 02: My understanding is the problem with not pre-specifying is that there is a risk of false positives. [00:31:40] Speaker 03: Yes, Your Honor, that's exactly right. [00:31:42] Speaker 02: They enlisted an expert, a statistical expert, to specifically address that issue, and he concluded, based on [00:31:49] Speaker 02: Some kind of analysis contained in an expert declaration that here, there was no risk or a very negligible risk of false positives. [00:32:00] Speaker 02: And the response seems to be, but you have to pre-specify to avoid false positives. [00:32:06] Speaker 02: The actual specific response to his declaration in the CDER reply gets very technical. [00:32:15] Speaker 02: It doesn't seem to say, you didn't pre-specify. [00:32:19] Speaker 02: Regardless, if they've shown they have someone saying there's no risk of false positives here. [00:32:25] Speaker 02: Why doesn't that create a fact dispute. [00:32:28] Speaker 03: So the I'm sorry. [00:32:30] Speaker 03: Yeah, the FDA order incorporates the cedar. [00:32:35] Speaker 03: explanation, rebuttal. [00:32:37] Speaker 03: And one of the things was the failure to pre-specify. [00:32:40] Speaker 03: Perhaps we used too shorthand an explanation, but the idea was the following. [00:32:46] Speaker 03: If you do a meta-analysis of a bunch of- Wait, wait, wait. [00:32:49] Speaker 01: Is this in the record? [00:32:50] Speaker 01: Yes, Your Honor. [00:32:51] Speaker 01: I thought you said you used the shorthand and didn't explain this. [00:32:55] Speaker 03: I was talking about our brief, which I believe Judge Garcia was referring to. [00:33:00] Speaker 03: So, Your Honor, at 239 to 41 is FDA's discussion of the meta-analysis and the express adoption of the center's analysis, which is at 2449 to 53. [00:33:14] Speaker 03: The problem is, if you do a meta-analysis of a bunch of studies that have inherent flaws within them, those inherent flaws, as Judge Pan, I believe, observed in the colloquy with Mr. Hughes, [00:33:29] Speaker 03: those inherent flaws are going to carry over to the meta analysis. [00:33:33] Speaker 03: FDA has explained that meta analyses are useful when you have studies that pre-specify and themselves are analytically sound. [00:33:44] Speaker 03: Doing a meta analysis that just carries over inherent statistical flaws is not going to be an answer to the inherent problem of the lack of statistical rigor in the underlying [00:33:54] Speaker 02: I guess the point is the standard is not just does that seem reasonable to us. [00:34:00] Speaker 02: It seems the standard is, is there a dispute of fact in their entire expert declaration? [00:34:06] Speaker 02: It's essentially saying that what Platt did was totally useless, because you just can't overcome the risk of false positives by doing this kind of meta-analysis. [00:34:17] Speaker 02: And his view, obviously, is you can. [00:34:20] Speaker 02: That's why he did it. [00:34:21] Speaker 02: And you're disagreeing with it. [00:34:23] Speaker 02: It's hard for us to say there's not a dispute, isn't it? [00:34:27] Speaker 03: There's a dispute. [00:34:29] Speaker 03: It's not a dispute of fact. [00:34:30] Speaker 03: It's a dispute about statistical methodology. [00:34:33] Speaker 03: And in Simpson, this court said, and I'm quoting, explication of the proper method for evaluating statistical significance, and that's the end of the quote, is something to which this court defers to the FDA. [00:34:47] Speaker 03: The sort of methodologies that are used is not the sort of question of fact that summary judgment proceedings [00:34:55] Speaker 03: excuse me, that hearings are meant to suss out. [00:34:59] Speaker 01: Conceivably... You can't be serious in that assertion. [00:35:02] Speaker 01: If I might finish my... No, no, no, no. [00:35:05] Speaker 01: I want to stop in the middle of that assertion. [00:35:08] Speaker 00: I was going to explain that assertion. [00:35:09] Speaker 01: The argument is between equally strong scientific people arguing over the methodology. [00:35:16] Speaker 01: And you're saying if there's a dispute over whether A and B are viable, [00:35:25] Speaker 01: that that is not something that raises the kind of factual dispute? [00:35:31] Speaker 01: Yes, Your Honor. [00:35:32] Speaker 03: It might raise a potential argument about arbitrary and capriciousness. [00:35:36] Speaker 03: No, no, no. [00:35:37] Speaker 03: I'm putting it right to the summary judgment. [00:35:40] Speaker 03: I know you are, Your Honor. [00:35:41] Speaker 03: I'm trying to give you my response, the FDA's response, which is, if an applicant believes that the FDA has inappropriately adopted a statistical methodology, [00:35:53] Speaker 03: they can bring an arbitrary and capricious claim about the agency's adoption of that methodology. [00:35:59] Speaker 01: If the FDA has a methodology that says one plus one equals three, the only claim I can make in challenging that is that it's arbitrary and capricious. [00:36:10] Speaker 01: It may be arbitrary and capricious, but in part because it's factually wrong. [00:36:14] Speaker 03: Your Honor, the analogy in this context is not the statement one plus one equals three. [00:36:18] Speaker 03: It's what does the plus sign do? [00:36:20] Speaker 03: It's an argument about. [00:36:22] Speaker 01: You must use the methodology whereby one plus one equals three. [00:36:26] Speaker 01: That's the way we think about it. [00:36:28] Speaker 01: No, Your Honor. [00:36:29] Speaker 01: I'm just giving you my example. [00:36:30] Speaker 01: Use our methodology, one plus one equals three. [00:36:34] Speaker 01: I can't challenge that as a factual matter? [00:36:37] Speaker 03: No, Your Honor. [00:36:37] Speaker 03: It's not a factual challenge. [00:36:39] Speaker 03: It's an arbitrary and capricious challenge. [00:36:40] Speaker 03: And in fact, in American Snot Assign, sorry, Cyanamid, the court held that the agency had acted arbitrarily. [00:36:49] Speaker 03: It didn't say that the agency made an error of fact. [00:36:53] Speaker 03: The problem in that case was that the agency adopted a methodology without giving fair notice to the applicant. [00:37:01] Speaker 03: So I think Mr. Hughes' principal case supports the idea that arguments about methodologies are properly conceived of as challenges to whether or not the agency acted arbitrarily or capriciously. [00:37:13] Speaker 03: They're not challenges about facts which are to be resolved in [00:37:18] Speaker 03: hearings. [00:37:20] Speaker 02: I think most of us agree that your burden is high. [00:37:25] Speaker 02: You have to show there's not even a dispute of material fact. [00:37:28] Speaker 02: So we've talked a lot about this type one error issue. [00:37:31] Speaker 02: The other ground on which it seems to me you could win is if there was just no dispute of fact, [00:37:37] Speaker 02: that the sleepiness metrics, the sleep versus alertness metrics speak to the type of next day function that is an aspect of jet lag disorder. [00:37:50] Speaker 02: And I had some questions for Mr. Hughes about that. [00:37:53] Speaker 02: But I guess I would just like to hear your best argument on that issue. [00:37:59] Speaker 03: Yes, Your Honor. [00:38:00] Speaker 03: Your line of questioning did mirror implicitly the FDA's understanding here, which is, [00:38:09] Speaker 03: Vanda failed to establish that metrics concerning degrees of awakeness actually correlate to degrees of functioning or treatments for impaired functioning. [00:38:21] Speaker 03: So the example your honor gave is a good one. [00:38:24] Speaker 03: Individuals who report the same level of awakeness using the KSS scale might not perform very well in a driving test, for example. [00:38:33] Speaker 03: And that's not the sort of inquiry that Vanda undertook. [00:38:37] Speaker 03: It just took the scales, the degree of alertness scale, to be a stand-in for the impaired functioning without any underlying analysis. [00:38:47] Speaker 03: They have experts who say the KSS standard is the gold metric. [00:38:53] Speaker 03: Well, they do not have any studies or any underlying literature to show that the standards that they use are themselves [00:39:03] Speaker 03: indicative of the impaired functioning that is associated with jet lag disorder. [00:39:08] Speaker 02: So they do have, so the Combs declaration, for example, has a whole section showing, saying that this measure of sleepiness is a way of assessing next day impairment. [00:39:21] Speaker 02: And I'd like to see how you'd put the response. [00:39:25] Speaker 03: Yes, Your Honor. [00:39:26] Speaker 03: The FDA specifically responded to that by saying [00:39:30] Speaker 03: Those are assertions. [00:39:31] Speaker 03: The citations that were made do not refer to any literature, any studies, or anything that shows that correlation. [00:39:40] Speaker 03: The expert gave his opinion that there was a correlation here, but without any supporting evidence. [00:39:46] Speaker 03: And that is an example of the sort of conclusory evidence that was submitted along with Vanda's application. [00:39:56] Speaker 01: See, that's precisely the kind of thing it seems to me you do in a hearing. [00:40:00] Speaker 01: They bring in, you say what you say, they bring in what my colleague has mentioned. [00:40:05] Speaker 01: And then if you think there's something that undercuts it, you have an opportunity on cross-examination or in presentation of your own case to show why what they're asserting is limited or of no use. [00:40:17] Speaker 01: I mean, I must say in reading what they offer, it certainly doesn't come across to me as implausible and unsupported. [00:40:25] Speaker 01: And that's what a hearing is for. [00:40:28] Speaker 03: If I might, I'd like to briefly return to where I was starting, which is to say the application process usually is an iterative process between the applicant and the agency. [00:40:41] Speaker 03: Disputes like the one that we have here are extraordinarily rare because the agency and the applicants agree on what has to be established. [00:40:49] Speaker 03: In this case, BANDA identified the ICSD standard as the standard for defining jet lag disorder. [00:40:58] Speaker 03: FDA accepted that understanding of jet lag disorder. [00:41:02] Speaker 03: And I should pause to say essential features of that disorder are critical here, because the FDA agreed with Vanda that that standard accurately captured what jet lag disorder is. [00:41:14] Speaker 03: But whether something is an essential feature really comes out through this iterative process, what has to be established to gain approval of a drug. [00:41:26] Speaker 03: Despite the fact that Vanda itself identified the ICSD standard as the prevailing standard, Vanda supplied no valid evidence that there was actually an effect of its drug on next day function. [00:41:40] Speaker 03: Its principal studies concerned how well the drug allowed somebody to sleep. [00:41:46] Speaker 03: The studies that addressed degrees of awakeness suffered from the two different problems that we've been discussing. [00:41:54] Speaker 03: The statistic methodology flaw, [00:41:56] Speaker 03: and the failure to correlate the degree of awakeness and other standards that they used with functioning. [00:42:03] Speaker 03: So on the standard that Vanda itself submitted to the FDA as defining what jet lag disorder is, Vanda's evidence was insufficient. [00:42:14] Speaker 03: That's the hope that evidence is insufficient. [00:42:17] Speaker 03: That's what a hearing determined. [00:42:18] Speaker 03: Categorically, Your Honor. [00:42:20] Speaker 03: They identified a standard that says you have to have [00:42:24] Speaker 03: X, Y, and Z. They supplied evidence of X. They did not supply evidence of Y. So on their own terms, they failed to provide evidence that they acknowledged was necessary. [00:42:35] Speaker 03: And just for the court's reference, JA 2013 is a citation that shows that it's Vanda that supplied this definition that the FDA later accepted as the governing standard for this application. [00:42:50] Speaker 05: So if I could sort of [00:42:53] Speaker 05: try to frame this in a way that's easier for me to understand. [00:42:56] Speaker 05: It seems like there are two levels of dispute here. [00:43:00] Speaker 05: There's the level of the actual finding that needs to be made through a hearing, which is whether or not there's evidence this drug does what it purports to do. [00:43:12] Speaker 05: And those are the types of things like factual disputes that are suitable for hearing. [00:43:17] Speaker 05: But before we even get to that level, there's another level of dispute, which is [00:43:22] Speaker 05: what kind of evidence can prove that. [00:43:26] Speaker 05: And it seems that there is no dispute as to what the evidence of the methodology was. [00:43:36] Speaker 05: We're talking about the [00:43:38] Speaker 05: methodology dispute, not the actual factual disputes about the drug. [00:43:42] Speaker 05: The methodology was, we have KSS. [00:43:44] Speaker 05: We have these other ones. [00:43:45] Speaker 05: They're subjective. [00:43:47] Speaker 05: We did not pre-specify. [00:43:48] Speaker 05: Everybody agrees. [00:43:49] Speaker 05: And the dispute on that level is whether that evidence is strong enough even to get you to a hearing. [00:43:56] Speaker 05: Because it seems to me it's the FDA's view that if you don't pre-specify, that data is not [00:44:06] Speaker 05: Strong enough, I guess, when Mr. Hughes would say shallow level dispute is a very shallow level dispute because everybody knows through many decades of understanding of statistics and methodology that you have to pre specify because if you don't, your dad is no good. [00:44:22] Speaker 05: So we don't need to have a hearing about whether pre specification [00:44:26] Speaker 05: is necessary or not. [00:44:27] Speaker 05: That's not the type of factual dispute the hearing is for. [00:44:31] Speaker 05: The factual disputes for the hearing are does the drug work or not. [00:44:35] Speaker 05: But there's a threshold question about what [00:44:39] Speaker 05: evidence can be used to get you to a hearing. [00:44:43] Speaker 05: And if you could explain, if the FDA is relying on just decades of experience, you're saying that the FDA gets some deference in terms of that kind of threshold level. [00:44:53] Speaker 05: And I want to understand better, where does that deference come from? [00:44:56] Speaker 05: And what is the FDA relying on this case to say, this is a dispute that's not even worth having at a hearing? [00:45:02] Speaker 03: Yes, Your Honor. [00:45:03] Speaker 03: So in Simpson, the court [00:45:07] Speaker 03: explained that FDA is an expert scientific agency that uses statistical analysis on a regular basis. [00:45:15] Speaker 03: And as a general matter, courts defer to the agency in the agency's views about what statistical methodologies are appropriate and necessary. [00:45:26] Speaker 05: I could also say just a summary judgment context or just generally. [00:45:30] Speaker 03: I'm sorry, Your Honor. [00:45:31] Speaker 03: I don't recall the answer to that question. [00:45:33] Speaker 03: I will say this, however, Your Honor. [00:45:35] Speaker 03: Simpson also went on to say that in that case, the statistical flaw was also so basic to statistical analysis that difference wasn't even needed. [00:45:49] Speaker 03: And the same is true here. [00:45:51] Speaker 03: Prespecification is [00:45:52] Speaker 03: absolutely basic to getting robust analyses of data that are obtained. [00:45:59] Speaker 03: There are some references in our brief that identify some of the underlying FDA guidances which discuss the pre-specification. [00:46:09] Speaker 03: It is a standard that has been around for absolute, a methodology I should say, that has been around for absolute decades and decades. [00:46:18] Speaker 03: And it is so fundamental that a failure to pre-specify is [00:46:22] Speaker 03: sufficiently fundamental that there is no need to have a hearing about whether pre-specification is appropriate and or required here. [00:46:31] Speaker 05: And on your alternative ground, you said there are two reasons why it's not required. [00:46:34] Speaker 05: One is the pre-specification problem. [00:46:36] Speaker 05: The second is the one identified by Judge Garcia, which is these studies don't even address the situation where there could be impaired next day functioning. [00:46:47] Speaker 05: that a subjective person doesn't perceive, a person expressing their subjective feelings doesn't perceive. [00:46:54] Speaker 05: That's right. [00:46:55] Speaker 05: Is there any countervailing argument on that side, or countervailing evidence that's been submitted on that issue? [00:47:04] Speaker 03: Not that I am aware of. [00:47:06] Speaker 03: The record indicates Vanda's experts attesting, stating that KSS is the gold standard and provides sufficient evidence and awakeness is [00:47:18] Speaker 03: evidence of next day functioning. [00:47:20] Speaker 05: But that is just an assertion that- But that still just goes to awakeness as opposed to impaired functioning where you don't perceive that- That's right. [00:47:32] Speaker 05: There is no evidence in the record- There's no evidence in the record that there's a dispute about whether their evidence can prove that you can have impaired next day functioning that's not related to your perceptions. [00:47:46] Speaker 03: So I want to be careful here. [00:47:47] Speaker 03: I think I'm quite certain that Mr. Hughes will say there is such evidence. [00:47:51] Speaker 03: The evidence he will point to is Vanda's expert declarations stating that degree of awakeness is correlated with next day functioning. [00:48:02] Speaker 03: The FDA's determinations on that issue, however, was that there is no support for the expert's assertions that the two correlates. [00:48:12] Speaker 03: The expert didn't rely on anything? [00:48:14] Speaker 03: They cited data, which the FDA looked at and said, this has nothing to do with what you have asserted. [00:48:21] Speaker 03: Let me allow them to respond to that? [00:48:24] Speaker 03: Yes, Your Honor, throughout the entire process. [00:48:27] Speaker 03: Absolutely, Your Honor. [00:48:28] Speaker 01: And the experts ended up disagreeing, right? [00:48:31] Speaker 01: That's when you go to a hearing. [00:48:33] Speaker 01: Respectfully, Your Honor. [00:48:34] Speaker 01: They supported what they said. [00:48:36] Speaker 01: You can shake your head all you want, Counsel. [00:48:38] Speaker 01: I mean, be respectful of the process. [00:48:40] Speaker 01: I'm trying to understand what you're saying. [00:48:43] Speaker 01: And some of what you're saying sounds like gobbledygook because you say, well, they said X and they relied on Y and they offered it. [00:48:51] Speaker 01: And so I'm sitting here thinking, well, did they offer something that was showing validity and reliability? [00:48:58] Speaker 01: And you want to summarily say no. [00:49:01] Speaker 01: No meaning what? [00:49:02] Speaker 01: What does that mean? [00:49:03] Speaker 01: No. [00:49:04] Speaker 01: that no one in their right mind could have looked at what they looked at and reached the conclusion they reached? [00:49:10] Speaker 01: Is that what you're saying? [00:49:10] Speaker 03: And it was scientifically unsupported. [00:49:12] Speaker 03: Yes, that is what I'm saying. [00:49:16] Speaker 05: OK. [00:49:18] Speaker 05: I guess my only follow-up to that is, is correlation the same as evidence of the actual thing that they need to prove? [00:49:25] Speaker 03: Again, I need to be careful because these are statistical terms. [00:49:31] Speaker 03: I don't know whether correlation or some other standard would be the most appropriate here. [00:49:37] Speaker 03: All I can say is there is no connecting fiber whatsoever. [00:49:42] Speaker 03: That is, whatever the standard is, they didn't undertake tests, for example, to show that two people who report that seven on a KSS scale have successful driving ability given their report of seven or whether they instead [00:49:58] Speaker 03: in a simulated driving endeavor would get into accidents on a regular basis, despite the fact that they indicated that they thought that they were very awake. [00:50:08] Speaker 03: There is no evidence of that sort. [00:50:11] Speaker 03: There is just the assertion that this is an adequate stand-in for functioning. [00:50:17] Speaker 05: I understand. [00:50:18] Speaker 05: Thank you. [00:50:18] Speaker 05: Any other questions? [00:50:21] Speaker 03: Thank you very much. [00:50:21] Speaker 03: Thank you, Your Honors. [00:50:30] Speaker 00: Thank you, Your Honor. [00:50:31] Speaker 00: I'd just like to jump right to Judge Garcia's question, if I could, about the evidence that exists in the record showing daytime functioning. [00:50:38] Speaker 00: I'd start by pointing the court to Joint Appendix, page 249. [00:50:40] Speaker 00: This is Dr. Ross' first expert report, and if I can read from it. [00:50:46] Speaker 00: The visual analog scale, VAS, has been used to measure sleep and wake function in clinical trials. [00:50:51] Speaker 00: It is common within the sleep research community to use VAS to, and this is quoting, measure aspects of sleep and daytime functioning and the effects of therapeutic interventions on them. [00:51:01] Speaker 00: He cites to that the Zispel published article that was published in 2003, which we attach as exhibit 180. [00:51:07] Speaker 00: That in turn cites to Nicholson published in 1976, which we attach as exhibit 129, which in turn cites to Parrott published in 1978, which we attach as exhibit 132. [00:51:18] Speaker 00: Uh, then I'm sorry, right? [00:51:21] Speaker 00: This is the key issue, right? [00:51:24] Speaker 02: That everything you said could be true. [00:51:27] Speaker 02: Alertness versus sleepiness correlates with your actual functioning. [00:51:31] Speaker 02: That is sort of obvious and indisputable. [00:51:34] Speaker 02: And the common example given is if you were sleepy, you will drive worse. [00:51:38] Speaker 02: It's like, you know, having drunk alcohol. [00:51:40] Speaker 02: The key question is if someone thinks they are alert, [00:51:49] Speaker 02: do they still function well? [00:51:52] Speaker 02: Which is a different and more specific proposition. [00:51:56] Speaker 02: Am I making any sense? [00:51:58] Speaker 00: Well, perhaps, Your Honor. [00:51:59] Speaker 00: But what I just read is Dr. Ross saying, if you are an expert in sleep medicine and you want to know daytime functioning, you look at the VAS. [00:52:06] Speaker 00: And he cites the three articles saying the VAS tells you daytime functioning. [00:52:10] Speaker 02: Right. [00:52:11] Speaker 02: And do any of those have anything to do [00:52:13] Speaker 02: with the travel related circadian rhythm difference. [00:52:17] Speaker 02: That means even though you feel great, I feel great. [00:52:21] Speaker 02: But when I start writing, my hand is shaking. [00:52:24] Speaker 02: I would still report on that study. [00:52:26] Speaker 02: I feel alert. [00:52:27] Speaker 00: I guess I'm a little challenged in answering the question. [00:52:31] Speaker 00: In KSS, we have five separate articles that connect the use of KSS to jet lag particular. [00:52:37] Speaker 00: But what Dr. Roth is testifying here [00:52:39] Speaker 00: is that VAS is if you're a sleep doctor and you want to know what is somebody's daytime functioning like, are they actually functioning well during that day, what you do is you administer a VAS to them and you figure out what their daytime functioning is. [00:52:54] Speaker 00: It's a methodological tool that you would use for insomnia, you'd use for jet lag, you use for a range of sleep conditions because it measures what somebody's functioning is. [00:53:03] Speaker 02: Do you think the key is whether [00:53:04] Speaker 02: You have studies that say this is validated for the specific type of functional impairment that's associated with jet lag, with the circadian rhythm. [00:53:14] Speaker 02: And so the best, so when we look for that, it's in JA 249. [00:53:18] Speaker 00: Let me give you a lot more. [00:53:19] Speaker 00: So joint appendix- To 2022. [00:53:22] Speaker 00: Yeah, so 249 is one place to start. [00:53:25] Speaker 00: But Dr. Ross, second affidavit. [00:53:27] Speaker 00: So this begins at page 2235. [00:53:31] Speaker 00: There is a heading that says VAS is an appropriate patient reported measurement tool for next day impairment associated with jet lag disorder. [00:53:39] Speaker 00: And then this continues for several pages. [00:53:41] Speaker 05: It can be appropriate, but it could be that it's not enough to check every part of the problem. [00:53:49] Speaker 00: And that's a conclusion that FDA could potentially reach in the course of a hearing. [00:53:54] Speaker 00: We'll dispute that. [00:53:55] Speaker 05: But you don't dispute that you have no evidence about [00:54:00] Speaker 05: the issue of next day functioning that you subjectively feel fine, but in fact, you are impaired. [00:54:11] Speaker 00: No, we have loads of this evidence. [00:54:11] Speaker 05: It looks to me that you have no evidence of that. [00:54:13] Speaker 00: No, we have lots of evidence of this. [00:54:15] Speaker 05: Wait, wait. [00:54:16] Speaker 05: Let's bear down, because it seems that all of your studies are these subjective, asking people, how do you feel studies? [00:54:22] Speaker 00: What the evidence says is if you're a sleep doctor and you want to know what somebody's daytime functioning is, this is what you do. [00:54:26] Speaker 05: So I hear your argument to be. [00:54:29] Speaker 05: that we shouldn't have to do that because all the experts say all we do have to do is ask people what their subjective functioning is. [00:54:37] Speaker 05: But if we accept the idea that the definition of the disease and to treat it is you have to address the circadian rhythm things. [00:54:46] Speaker 05: You know, and one of these things is you could subjectively say, I feel fine, but you could in fact be impaired. [00:54:53] Speaker 05: None of your studies address that your studies do address there. [00:54:57] Speaker 05: They are relevant. [00:54:58] Speaker 05: If how you feel is going to be correlated with how you function, but they don't address the entire. [00:55:04] Speaker 00: No, I reject that premise. [00:55:07] Speaker 00: I mean, our studies show, say, if you're a sleep doctor and you want to figure out criterion B under ICSD, this is what you do. [00:55:14] Speaker 05: We do what sleep doctors say you do to figure out criterion B. We don't think there's- But those sleep doctors, were they talking about jet lag disorder or just general next day functioning after a bad night's sleep? [00:55:26] Speaker 00: They're talking what you do. [00:55:28] Speaker 00: This is what Dr. Ross analysis. [00:55:30] Speaker 00: It starts on page 2235. [00:55:33] Speaker 00: It goes on for several pages. [00:55:34] Speaker 00: He talks about the KAS starting at Joint Appendix 2242, and it goes on for several pages. [00:55:40] Speaker 00: He says, and he cites many articles throughout it, if you're an expert in the field and your job is to figure out. [00:55:47] Speaker 05: I understand that. [00:55:48] Speaker 05: So your argument is that if experts want to look at next day functioning, they use this test. [00:55:54] Speaker 05: But the issue is, [00:55:56] Speaker 05: in this particular context, which is jet lag disorder, it says there's a circadian rhythm aspect that is not captured in some of these other sleep disorder scenarios. [00:56:07] Speaker 05: And in order to treat jet lag disorder, you have to consider the circadian rhythm effects and just merely rely on people's subjective statements of how they feel doesn't necessarily address that. [00:56:21] Speaker 05: So I'm not saying that your argument is irrelevant. [00:56:24] Speaker 05: I'm not saying that your argument, I'm just saying [00:56:26] Speaker 00: capture the entire question about efficacy for this particular disorder that has an additional no definitely not because let's start with the things that jet lag or sorry that Hetlios is currently approved for [00:56:40] Speaker 00: is non-24 and Smith-Mackenna syndrome. [00:56:43] Speaker 00: Those are circadian rhythm disorders. [00:56:45] Speaker 00: FDA agrees that I think we're really the only product that is approved to treat circadian rhythm disorders. [00:56:51] Speaker 00: That's what makes this product different than all the others. [00:56:53] Speaker 00: Most products just basically turn off your brain and knock you out, and that's why you have terrible next day functioning. [00:56:59] Speaker 00: What Hetlios does that's unique on the market is it entrains a person's circadian rhythm, so that way their brain, if there's not having an external [00:57:08] Speaker 00: Light source, in the case of non-24, people with blindness and Smith-McGinness syndrome, chromosomal disorder, in jet lag, it's jet traveled, induced phase shift. [00:57:17] Speaker 00: We know this product works. [00:57:19] Speaker 00: for the circadian rhythm aspects of phase shift, because we're the only product approved on the market to do it. [00:57:23] Speaker 00: And FDA has approved us for circadian rhythm disorders. [00:57:26] Speaker 00: The objection the FDA has is not, does it work for circadian rhythm disorder? [00:57:30] Speaker 00: They've approved us for circadian rhythm disorders. [00:57:32] Speaker 00: Their new objection is, well, what is the effect? [00:57:35] Speaker 00: How does somebody function next day? [00:57:39] Speaker 00: Because that's a criterion B. [00:57:41] Speaker 00: And so to answer that we've gone to sleep specialists who say, OK, if you want to answer that, you use VAS and KSS to get that data. [00:57:48] Speaker 00: That's the data we have. [00:57:49] Speaker 00: That's what the expert report says. [00:57:50] Speaker 00: So I don't think there's a way to disentangle this for circadian rhythm, because again, we know our product works for circadian rhythm disorders. [00:57:56] Speaker 00: FDA can't dispute that. [00:57:59] Speaker 05: The studies that you rely on here. [00:58:02] Speaker 00: Well, I mean, there are a few things. [00:58:03] Speaker 00: It's the mechanism of action. [00:58:04] Speaker 00: So how this product works, we know that the mechanism of action is one that goes to the receptors in the brain that relate to circadian rhythm disorders. [00:58:12] Speaker 00: on the label that FDA has approved with the product. [00:58:16] Speaker 00: So I mean, it's known that this is a drug that affects circadian rhythm disorders. [00:58:20] Speaker 00: So that's just sort of scientific background of how the mechanism of this product's action in fact works. [00:58:26] Speaker 00: But I know I'm getting technical with the science. [00:58:29] Speaker 00: What our request here for is for the court to apply American cyanamide. [00:58:33] Speaker 00: We don't think the court needs to address this. [00:58:35] Speaker 00: We just, I think, are entitled to a hearing. [00:58:37] Speaker 02: Can you just remind me what the best language in the second Roth declaration is that you were referring to? [00:58:42] Speaker 00: Yes, Your Honor. [00:58:44] Speaker 00: It follows under the heading VAS is an appropriate patient reported measurement tool for next day impairment. [00:58:51] Speaker 00: And he gives quite a bit of evidence that follows from there. [00:58:59] Speaker 00: Which page? [00:59:00] Speaker 00: I'm on page 2235. [00:59:01] Speaker 00: And again, [00:59:03] Speaker 00: I think what I gave you at page 249 is pretty dispositive, just to start there. [00:59:08] Speaker 00: I think that if you want one quote, I think what I gave you at 249 is clearest, where he says, the sleep research community do use VAS to, quote unquote, measure aspects of sleep and daytime functioning and the effects of therapeutic interventions on them. [00:59:22] Speaker 00: And what he's saying is, if you want to measure therapeutic intervention and daytime functioning, you use the VAS. [00:59:28] Speaker 00: And he's citing three peer-reviewed articles in order to make that argument. [00:59:32] Speaker 00: in the page range between 2235 to 2242. [00:59:36] Speaker 00: He goes through KSS and VAS in more detail. [00:59:46] Speaker 05: Thank you. [00:59:46] Speaker 05: Thank you.