[00:00:05] Speaker 00: I am Jim Aink, Appellant versus Alex Michael Azar, the second, and his official capacity as Secretary of the United States Department of Health and Human Services at EL. [00:00:15] Speaker 00: Mr. Stenson for the Appellant, Mr. Biro for the Appellate. [00:00:40] Speaker 02: Good morning, Your Honors, and may it please the Court. [00:00:42] Speaker 02: My name is Kate Stetson. [00:00:43] Speaker 02: I represent the appellant Amgen. [00:00:46] Speaker 02: It is difficult to study drugs in children. [00:00:48] Speaker 02: Success is not guaranteed. [00:00:51] Speaker 02: So when Congress created an incentive in the form of six months of exclusivity to encourage drug sponsors to do those studies, it didn't require success. [00:01:02] Speaker 02: It required three things before a secretary had to accept the studies. [00:01:06] Speaker 02: that the studies were performed in accordance with basic science principles, that the studies were filed in accordance with the FDA's filing requirements, and that the studies fairly respond to the written request. [00:01:18] Speaker 02: Now, successful studies get the grand prize. [00:01:22] Speaker 02: They get a new pediatric indication. [00:01:24] Speaker 04: Ms. [00:01:24] Speaker 04: Stetson, is there a mootness issue lingering here? [00:01:27] Speaker 04: Hasn't Amgen's key patent [00:01:29] Speaker 04: expired and generics have been approved? [00:01:33] Speaker 04: Am I wrong about that? [00:01:34] Speaker 02: The key patent has expired, or one of them has expired. [00:01:38] Speaker 02: There have been a few generics that have been approved, but none of them is on the market yet. [00:01:44] Speaker 02: And our exclusivity period, if this court agrees with our arguments, would run through September of 2018. [00:01:51] Speaker 02: So there's no mootness issue. [00:01:53] Speaker 02: The difference between successful studies, though, and simply fairly responding, I think, is worth reiterating again. [00:01:59] Speaker 02: Successful studies get a pediatric indication, and that, among other things, enables a drug manufacturer to market a drug for children. [00:02:08] Speaker 02: They also get the pediatric... Successful. [00:02:11] Speaker 05: When you say successful, you mean successful in the sense that the study tends to show that the drug is safe and effective for children? [00:02:23] Speaker 02: I do mean that, yes. [00:02:25] Speaker 05: Okay, so you're clearly right. [00:02:26] Speaker 05: The study doesn't have to be successful in that sense, but why doesn't the study have to be successful in the weaker sense of just yielding meaningful data one way or the other? [00:02:42] Speaker 05: It could be successful in the sense it proves that the drug shouldn't be used for children, or it could be successful in the sense that [00:02:52] Speaker 05: you get a good valid study and the data is inconclusive. [00:02:57] Speaker 05: And all of that, it would be helpful to the FDA, but none of it happened here. [00:03:03] Speaker 02: And all of that is not what the FDA described as the fairly response standard. [00:03:08] Speaker 02: So the fairly response standard that FDA articulated [00:03:13] Speaker 02: in all three of its administrative decisions is that you either have to meet every single term of the written request, or you have to produce what the FDA called meaningful labeling across all age groups and uses. [00:03:25] Speaker 02: And to your question, Judge Katzis, inconclusiveness was not enough. [00:03:29] Speaker 02: If you look at Joint Appendix 709, which is the third letter of denial, the last phase of review, the culminating statement about what meaningful labeling means [00:03:40] Speaker 02: is IE, not EG, but IE, studies led to a conclusive finding, either positive or negative, for each age group requested in the written request. [00:03:53] Speaker 02: That is the FDA standard that they are holding us to, and it cannot get comfortably packaged within Fairly Respond. [00:03:59] Speaker 05: Do you have a quarrel with the two-pronged standard that they've articulated on appeal? [00:04:11] Speaker 02: Well, yes, the first quarrel being that they... Meet the objectives. [00:04:15] Speaker 05: Meet the terms of the study or meet the objectives by providing clinically meaningful information. [00:04:22] Speaker 05: I understand your argument. [00:04:23] Speaker 02: That's not what they did below, but... So that's my first quarrel is, of course, that's not what the agency articulated the standard to be. [00:04:31] Speaker 05: But even if... But I'm asking, suppose they had. [00:04:33] Speaker 05: Would you still be arguing [00:04:35] Speaker 05: That that's outside the bounds of reasonable interpretation. [00:04:40] Speaker 02: Why? [00:04:40] Speaker 02: I would because of what FDA described clinically meaningful labeling to be. [00:04:44] Speaker 02: If you look at Joint Appendix 703, clinically meaningful, i.e. [00:04:50] Speaker 02: useful to practitioners, public health information related to the use of the drug in pediatric populations as expressed in the drug's labeling. [00:05:00] Speaker 02: So the fact that FDA is receding from its standard actually suggests that it's not really receding from its standard. [00:05:08] Speaker 02: And in all events, the standard that brought us on appeal is the standard the agency articulated, not the government. [00:05:14] Speaker 05: Sorry, I think you just restated your argument that they've changed standards. [00:05:20] Speaker 05: Which we'll get into, but I'm trying to focus on whether... Right. [00:05:26] Speaker 02: You asked me, yes, you asked me whether I had a quarrel with the current standard. [00:05:31] Speaker 02: My first quarrel is procedural, but my second quarrel is that even though they have recast the standard, this formulation doesn't appear anywhere below. [00:05:42] Speaker 02: If they are talking now simply about clinically meaningful information, the place that we would look to discover what that means is back into the record. [00:05:52] Speaker 02: What has FDA said they mean when they say clinically meaningful information? [00:05:57] Speaker 02: And it's that quote that I just read to you, which ends with, as expressed in the drugs labeling. [00:06:02] Speaker 02: So the fact that they've taken out labeling from their current formulation doesn't mean it's not still in there, it's just hidden. [00:06:08] Speaker 05: All right, so sorry, where is that? [00:06:10] Speaker 05: You really want to talk about whether they've changed the standards. [00:06:13] Speaker 05: So sorry, you're on 703. [00:06:15] Speaker 02: I'm on 703. [00:06:17] Speaker 05: Yes, I thought that was which paragraph. [00:06:35] Speaker 01: Is the paragraph. [00:06:37] Speaker 01: beginning in the middle of Joint Appendix 703. [00:06:41] Speaker 05: With when or occasionally? [00:06:43] Speaker 01: I'm sorry? [00:06:44] Speaker 05: With the paragraph that begins with when or the paragraph that begins with occasionally? [00:06:49] Speaker 01: the paragraph that begins when? [00:06:52] Speaker 05: Right. [00:06:53] Speaker 05: So there they say, the key sentence to me is towards the middle of the paragraph where they say, in addition, where the specific terms of the study are not met, but the information produced is clinically meaningful across all age groups, i.e. [00:07:12] Speaker 05: where the FDA can apply its scientific expertise to determine that the objectives of the study have been met, [00:07:19] Speaker 02: Yes. [00:07:20] Speaker 05: The agency will consider the sponsor studies to have fairly responded. [00:07:24] Speaker 02: Yes. [00:07:25] Speaker 05: That sounds to me a lot like the standard they're defending in the red brief. [00:07:31] Speaker 02: I'm going to go back up to the very top. [00:07:33] Speaker 02: Okay. [00:07:34] Speaker 02: This is the definition that I just read to you. [00:07:35] Speaker 02: So this is clinically meaningful and what that means in turn to FDA. [00:07:40] Speaker 02: Clinically meaningful, i.e., useful to practitioners. [00:07:42] Speaker 05: Okay, sorry, go back up to where? [00:07:44] Speaker 02: Back up to the very top of that page. [00:07:46] Speaker 05: Oh, in implementing? [00:07:48] Speaker 02: in implementing Congress's goal of obtaining clinically meaningful, i.e. [00:07:53] Speaker 02: useful to practitioners, public health information related to the use of the drug in pediatric populations as expressed in the drug's labeling. [00:08:05] Speaker 02: So all of this, of course, is setting aside the elusiveness of the standard compared to how it was articulated below. [00:08:16] Speaker 02: And I want to make clear exactly what the board, the pediatric exclusivity board, based its decision on below, because it wasn't this. [00:08:25] Speaker 02: If you look at Joint Appendix 643, which is the first of the three administrative rulings, [00:08:32] Speaker 02: What you'll find on Joint Appendix 643 is if the totality of safety information Amgen submitted had provided an appropriate safety assessment in younger children and supported a label description, it would have been found to have fairly responded. [00:08:47] Speaker 02: That's the first decision. [00:08:48] Speaker 02: Second decision. [00:08:49] Speaker 02: Joint Appendix 675, based upon the lack of meaningful labeling information, the board determined that Amgen did not fairly respond to the written request. [00:09:00] Speaker 02: Third decision, Joint Appendix 709, that's the chart that I mentioned before, where the agency describes meaningful labeling, i.e., [00:09:08] Speaker 02: studies led to a conclusive finding, either positive or negative, for each age group requested in the written request. [00:09:17] Speaker 02: Those are the three agency articulated bases for finding that Amgen, falling short in one respect, did not fairly respond to the written request. [00:09:29] Speaker 06: But isn't the bottom line here that for the age group of up to six years old, [00:09:37] Speaker 06: there wasn't sufficient data under the explicit terms of the WR to basically reach any conclusions for in-human studies for that age group. [00:09:59] Speaker 06: Isn't that the bottom line? [00:10:01] Speaker 02: That is the bottom line, but it does draw upon one of Judge Katz's earlier questions as well, that the statute that contemplates pediatric studies and labeling actually contemplates inconclusive results just like this. [00:10:14] Speaker 02: It requires that even inconclusive results go on the labeling, but that's not what FDA. [00:10:23] Speaker 06: being able to complete the study. [00:10:25] Speaker 06: You can have a complete study that yields inconclusive results or you can have a study that just doesn't get concluded and therefore it's inconclusive. [00:10:36] Speaker 02: Right. [00:10:37] Speaker 02: The statute, though, doesn't distinguish between substantive inconclusiveness and procedural inconclusiveness. [00:10:44] Speaker 02: It says if you reach the end of the study and your data are inconclusive, even that goes on the label. [00:10:49] Speaker 02: But what FDA required of us is a conclusive finding of either safety or not safety before it would award exclusivity. [00:10:58] Speaker 05: Now, we are not... Why is that? [00:11:04] Speaker 05: You make a reasonable point that there's some muddiness here to the extent they are mixing and matching the exclusivity part of the statute with the labeling part of the statute. [00:11:22] Speaker 05: But when you go to the labeling part of the statute, it seems awfully broad what goes on the label. [00:11:29] Speaker 05: If the study shows safety and efficacy, that goes on the label. [00:11:35] Speaker 05: If the study shows the opposite, that goes on the label. [00:11:39] Speaker 05: And if the study is inconclusive, that goes on the label. [00:11:42] Speaker 05: So even if they did sort of this odd cross-reference, what's the harm to you where the labeling provision seems to say that any [00:11:51] Speaker 05: scientifically meaningful information, including a valid study that's inconclusive, goes on the label. [00:12:01] Speaker 02: Well, to be clear, the information from our study went on the label. [00:12:06] Speaker 02: If you look in the joint appendix starting, I think, at 587, it's the post-studies label. [00:12:12] Speaker 02: And the information about our study, how many subjects were studied, for how long, what happened, [00:12:17] Speaker 02: that the results were inconclusive. [00:12:19] Speaker 02: All of that is on the label. [00:12:20] Speaker 05: But the point here... The specific study they didn't like, the one which had only four respondents instead of 15? [00:12:26] Speaker 02: Each of the studies, each of the three studies that were requested and required to go into the label were mentioned on the label, yes. [00:12:35] Speaker 02: But with respect to the statute talking about inconclusiveness, the reason I think that's important is because you can't [00:12:43] Speaker 02: set aside inconclusiveness for purposes of labeling and require conclusiveness for purposes of pediatric exclusivity. [00:12:51] Speaker 02: There's simply no one. [00:12:52] Speaker 04: We're talking about study three. [00:12:54] Speaker 04: The word inconclusive may not be, may not capture it. [00:12:58] Speaker 04: It wasn't done. [00:12:59] Speaker 04: It wasn't as if the study was done and they weren't certain of the results. [00:13:06] Speaker 04: The criticism is that there just weren't enough young children in the study to know [00:13:13] Speaker 04: the information they need to know to decide whether to go forward or not. [00:13:17] Speaker 02: That was indeed the criticism. [00:13:18] Speaker 02: It was exactly the criticism that the FDA leveled at Merck in the Merck case. [00:13:23] Speaker 02: There, Merck was supposed to study about approximately 35, was the written request, 35 women. [00:13:30] Speaker 02: It studied five. [00:13:32] Speaker 02: The FDA denied it exclusivity. [00:13:34] Speaker 02: Merck took them to court. [00:13:36] Speaker 02: The FDA said close enough isn't good enough for Fairly Respond, and Judge Robertson said Fairly Respond plainly does not contemplate that every term of a written request must be satisfied. [00:13:48] Speaker 02: Fairly Respond means if the studies as a whole answered the request, that's a fair response. [00:13:54] Speaker 02: So the fact that the studies weren't completed, to both of your questions, doesn't mean that they didn't fairly respond to the written request. [00:14:02] Speaker 02: When you take these studies as a whole, there were hundreds and hundreds of pages of studies that were submitted to FDA. [00:14:09] Speaker 02: We did fall short in one request, in one respect. [00:14:13] Speaker 02: We satisfied FDA in every single other respect. [00:14:16] Speaker 02: And Merck made exactly this point in saying that that is a fair response. [00:14:22] Speaker 02: Now, FDA claims deference, and I want to make an important point on this. [00:14:29] Speaker 02: This does not warrant any Chevron deference. [00:14:32] Speaker 02: This is an unpublished, unpublic, informal adjudication. [00:14:38] Speaker 02: It doesn't have any of the indicia that this court has looked at before when it comes to awarding Chevron deference. [00:14:45] Speaker 02: It's very similar to the Fogo de Chao case in that respect. [00:14:49] Speaker 02: The FDA cases that the government cites all are backed by some kind of public process, either regulation. [00:14:57] Speaker 05: What about Mylan? [00:14:58] Speaker 05: Isn't Mylan regulatory letters of the kind at issue here? [00:15:04] Speaker 02: It was a letter, but Mylan specifically says it relied on the regulations. [00:15:09] Speaker 02: and two published decisions. [00:15:11] Speaker 02: So that was my point of saying that even the letter rulings that they point to are backed by something else. [00:15:17] Speaker 02: They are either backed by a long-standing interpretation, a regulation, or in some of the cases Novartis and Teva publicly docketed, publicly commented upon [00:15:30] Speaker 02: So this is, I think, an unusual case when it comes to FDA, because normally when you get an FDA challenge, there is something behind it. [00:15:38] Speaker 02: There's a regulation, or there's a citizen petition, or there's a public process. [00:15:42] Speaker 02: Here, there is none of that. [00:15:44] Speaker 05: The unpublished nature cuts in your favor. [00:15:48] Speaker 05: I'll give you that. [00:15:49] Speaker 05: But, I mean, need is sort of open-ended. [00:15:53] Speaker 05: what counts or doesn't count, and cutting in the agency's favor is sense. [00:16:01] Speaker 05: You look at this entire thing and the decisions are extensive. [00:16:09] Speaker 05: There's this back and forth process. [00:16:11] Speaker 05: There's a rulemaking record. [00:16:13] Speaker 05: It doesn't have the feel of some minion in a field office dashes off a two page dear colleague letter. [00:16:22] Speaker 05: It feels very different from that. [00:16:23] Speaker 02: Judge Katzis, there is no rulemaking record. [00:16:26] Speaker 02: There is a record good for this participant only that wouldn't even have been public were it not for this litigation. [00:16:34] Speaker 02: There was an iterative process, as the FDA calls it in its brief, back and forth between this party and the FDA. [00:16:40] Speaker 02: It was exactly the same iterative process in Fogo de Chao. [00:16:43] Speaker 02: That didn't warrant any extra treatment or any extra deference due to the agency there. [00:16:49] Speaker 02: The question in need is, did the agency intend by this pronouncement for it to carry the force of law? [00:16:57] Speaker 02: And when you have a pronouncement that is backed by something like a regulation or like that public process, then the answer is almost always yes. [00:17:04] Speaker 02: But when you have a pronouncement that is non-published, non-public, informal, non-precedential, that doesn't satisfy Chevron. [00:17:12] Speaker 05: And how do you answer their response to that, that a lot of these kinds of rulings are not published because they tend to contain proprietary information to benefit the drug companies? [00:17:29] Speaker 02: I think there's two responses. [00:17:30] Speaker 02: One of them is that proprietary information could be redacted, but the second is if they're not published and informal and non-precedential, [00:17:37] Speaker 02: then they just don't get Chevron deference. [00:17:40] Speaker 02: It's not a reason to give them deference. [00:17:42] Speaker 02: It doesn't count for anything in the Chevron inquiry. [00:17:45] Speaker 02: And if we are at Chevron step zero, then I think the answer is very clear. [00:17:50] Speaker 02: And if I may finish with a couple of points. [00:17:52] Speaker 02: The first is there is nothing in that statute that talks about [00:17:57] Speaker 02: filing protocols, scientific protocols, and Fairly Respond that warrants importing an entire labeling inquiry into the question of what Fairly Responds. [00:18:08] Speaker 02: There's an entirely different statute, section 21 USC 355D, that in detail gives what has to go into a secretary or the FDA's finding of labeling. [00:18:19] Speaker 02: There's no support for the idea that that comes into the Fairly Respond standard. [00:18:24] Speaker 02: The last point I would make is even if [00:18:27] Speaker 02: this interpretation survives the whole Chevron gauntlet, you are left then with a significant fair notice question. [00:18:35] Speaker 02: And I would point you to General Electric, and I would point you to the Gates and Fox case that's cited therein. [00:18:41] Speaker 02: Because in both of those cases, what the court ultimately found was [00:18:46] Speaker 02: Yes, this interpretation is tolerable. [00:18:49] Speaker 02: It's reasonable. [00:18:50] Speaker 02: But it was not available to the regulated party with ascertainable certainty. [00:18:56] Speaker 02: FDA doesn't even contest that this was publicly available. [00:19:00] Speaker 02: It says that we should have been aware of the framework. [00:19:03] Speaker 02: The only thing we were aware of, of course, was Merck. [00:19:06] Speaker 02: which said what I read to you earlier, and the public statement on the FDA's website that said pediatric exclusivity is not tied to labeling, which is exactly what they determined here. [00:19:18] Speaker 02: Do we have any further questions? [00:19:39] Speaker 03: May it please the court? [00:19:41] Speaker 03: Charles Gero, on behalf of the appellee. [00:19:45] Speaker 03: Now the specific issue here relates to FDA's interpretation application of the phrase fairly respond. [00:19:51] Speaker 03: There are a number of key important facts that are not at issue here that inform much of the case. [00:19:57] Speaker 03: First, Amgen is not challenging FDA's conclusions that its studies produce data that was insufficient [00:20:04] Speaker 03: to draw any conclusions. [00:20:06] Speaker 03: And that's the language that appears on the label. [00:20:08] Speaker 03: Again, there's a difference between having studies that are inconclusive, as Judge Wilkins pointed out, and having studies that just don't furnish enough data to make any conclusions. [00:20:20] Speaker 03: That labeling decision about not having sufficient data is not something that's at issue here. [00:20:26] Speaker 03: It's a subtle fact. [00:20:27] Speaker 04: How do you distinguish this from Merck? [00:20:29] Speaker 04: I recognize that was just a district court case. [00:20:32] Speaker 03: What FDA has done is taken the lessons of Merck, which had a specific ruling that FDA couldn't require that the only criteria used be meet all of the terms of the written request. [00:20:47] Speaker 03: That opinion goes on to say that the FDA should look at the entire study as a whole and see if that is a fair response to the written request. [00:20:56] Speaker 03: And that's exactly what FDA has done here, is they've taken a look [00:20:59] Speaker 03: at the entire study, study three here being the critical study, and applied a test to see if there were any meaningful results. [00:21:10] Speaker 04: The deficiency here is in study three, right? [00:21:13] Speaker 04: That's the problem. [00:21:14] Speaker 04: And what was it about study three that was deficient, that wasn't also deficient in the murder case? [00:21:21] Speaker 03: Well, with regards to, it was the number of finishers, but what FDA now does after Merck is take a look further at the study as a whole to understand what has been learned from the study and look to see if that produces clinical meaningful information. [00:21:41] Speaker 03: So it's not asking specifically for meeting all the terms of the written request. [00:21:46] Speaker 03: That's where it starts because when the FDA puts out a written request, [00:21:50] Speaker 03: It works with the study sponsor to come up with this protocol, which it believes will get it the information it is looking for. [00:21:57] Speaker 04: So you're saying that in the Merck case, the studies were otherwise adequate and gave the FDA the information [00:22:05] Speaker 03: I can't comment on how good the studies were underlying Merck. [00:22:09] Speaker 03: What happened was it was rejected first for not meeting the specific terms of the written request. [00:22:16] Speaker 03: Later the FDA looked further at additional information relating to Merck. [00:22:20] Speaker 03: found that the written request had basically been met and was later awarded exclusivity on that. [00:22:29] Speaker 04: I don't know that- Am I right here that the problem here is with study three? [00:22:33] Speaker 04: Correct. [00:22:33] Speaker 04: Okay. [00:22:34] Speaker 04: Yes. [00:22:34] Speaker 04: That's where the- but your argument I take it is that it was so deficient that it infected [00:22:41] Speaker 04: the entire written response. [00:22:43] Speaker 03: Correct. [00:22:44] Speaker 03: The other three studies had met the written request, and so there weren't any questions about whether those studies would have qualified for pediatric exclusivity. [00:22:51] Speaker 03: Study three, with only four or 15 finishers, was just not enough data to provide any sort of conclusions about safety. [00:23:01] Speaker 03: And that's what went into the label. [00:23:04] Speaker 03: And the idea here is under the statute is FDA is looking for information that goes to the use of the drug and may produce health benefits. [00:23:14] Speaker 03: And that's the language of the statute of when the FDA issues a written request. [00:23:19] Speaker 03: So it uses that language to look for actual information [00:23:23] Speaker 03: that provides a health benefit, that provides physicians with information about how they can use this drug. [00:23:29] Speaker 03: And that's what that's back in there. [00:23:32] Speaker 06: So, suppose the study was terminated because there were a number of, let's just say, you know, very adverse events, maybe a death or some other very significant adverse event. [00:23:49] Speaker 06: So the study is terminated early. [00:23:52] Speaker 03: Would the result be the same? [00:23:57] Speaker 03: Well, if in something sort of catastrophic like that or for potentially if [00:24:03] Speaker 03: You know, they're looking at the study protocols and it's just unworkable. [00:24:09] Speaker 03: There can be amendments. [00:24:10] Speaker 03: We have five amendments here such that the written request can be changed to accommodate something. [00:24:16] Speaker 06: I think that should... So that's the way that should be resolved is by amending the written request rather than saying, well, what happened fairly responded to the written request that had been approved. [00:24:30] Speaker 03: I'm not sure I get your question. [00:24:31] Speaker 03: I think the idea is that if there is a indication that the study, you know, because of adverse events here in study two, there was a death and it was ended, that it would be proper to say, you know, we'll amend the written request, but to the extent the study is, it's possible that it's going to still result in meaningful data. [00:24:52] Speaker 03: There wouldn't necessarily be a reason to alter the written request if that answers your question. [00:24:59] Speaker 05: Back to Merck for a second. [00:25:01] Speaker 05: So the primary holding that you can't comply with all terms standard doesn't really hurt you here. [00:25:10] Speaker 05: But there's this further piece from Merck which is the court's statement that disappointment with the data [00:25:19] Speaker 05: is not a sufficient ground for denying pediatric exclusivity. [00:25:25] Speaker 05: And that's potentially pretty broad. [00:25:29] Speaker 05: So how do you understand that statement? [00:25:32] Speaker 05: And why doesn't, you know, here they're disappointed with the data from study three or whatever, but they can't use that as a basis for denial? [00:25:40] Speaker 05: Why would that be an overreading of [00:25:42] Speaker 03: I read the disappointment of the data relating to not finding a positive correlation that leads to specific pediatric use that can go in the labeling. [00:25:54] Speaker 03: Sort of the idea of, you know, not looking just specifically for positive data. [00:26:00] Speaker 05: Disappointed because a valid study shows that this drug just won't work for kids. [00:26:06] Speaker 03: That's how I read it. [00:26:07] Speaker 03: In that sense, okay. [00:26:10] Speaker 03: Yeah. [00:26:12] Speaker 03: I also wanted to stress that to the extent of, and this goes to the fair notice point, is that Amgen had been working with the FDA for over 10 years on this study. [00:26:24] Speaker 03: So there was plenty of time to discuss what the standards and the objectives were. [00:26:31] Speaker 05: But Merck was decided in 2001, 17 years ago, [00:26:36] Speaker 05: And so far as one can tell, there's no public statement of the two-part test or whatever else the commission's position might be in light of Merck. [00:26:52] Speaker 05: That seems a little troubling. [00:26:54] Speaker 03: Well, there's no specific guidance that's been given out. [00:26:57] Speaker 03: It goes back to what I was starting to talk about, sort of the process which makes this case unique from much of these other administrative law cases, which is the parties are working together on this. [00:27:09] Speaker 03: There should be clear expectations. [00:27:11] Speaker 03: There can be expectations shared between the two that these are the objectives of the study. [00:27:16] Speaker 03: And keep in mind that this is science here, and it's a clinical trial run for a reason. [00:27:21] Speaker 03: And so the reason is to find some sort of answer to a question, whether positive or negative. [00:27:27] Speaker 03: And so the idea that FDA was expecting the objectives of a study to be met such that, you know, the safety and efficacy of a drug can be described and evaluated, that there would be a requirement that there would be clinically meaningful information coming out of that as being an indication that the [00:27:45] Speaker 03: study met its objectives is pretty basic and almost goes without saying. [00:27:51] Speaker 03: There was at least in 2013, September 2013, communication between the FDA and Amgen about whether what they had done up to that point had been sufficient or not. [00:28:05] Speaker 03: And at that point, FDA did, in very particular language, get back to them and explain that they had not gathered enough information at that point. [00:28:15] Speaker 03: to support, to quote that the study's current program was, rather I should say, the FDA did not believe that the current program was sufficient to inform the public on the safe use of Cinecal Set and would not be adequate to support a written request. [00:28:36] Speaker 03: To the extent that there's specific interactions, we can point to that as well as just the general reading of the statute, which again goes to a very specific purpose, getting information that physicians can use. [00:28:52] Speaker 03: There's any number of indications that what the standard would be. [00:28:58] Speaker 05: How do you respond to the point about [00:29:02] Speaker 05: the arguably shifting nature of Prong 2 on the question whether it requires clinically meaningful information in the abstract or something that's meaningful on the label. [00:29:20] Speaker 05: Is that not a difference that matters or? [00:29:25] Speaker 03: The the three letters at issue are all very clear and I should go it even goes back after after the decision in Merck we can find letters [00:29:37] Speaker 03: going back to 2001, where the standard is set out. [00:29:40] Speaker 03: The standard hasn't changed, and the standard might be reworded in certain instances, but the material aspect of the standard hasn't changed, and it's to get clinically meaningful information from these things. [00:29:53] Speaker 05: And I had thought that the paragraph in the middle of 703 tied that down pretty well and conforms to what you say in the red brief. [00:30:04] Speaker 05: But I have to say, Ms. [00:30:06] Speaker 05: Stetson made a pretty good point that if you go up a paragraph, you see that clinically meaningful, the agency is using clinically meaningful to mean something on the label. [00:30:21] Speaker 03: Well, to be clear, these applications [00:30:27] Speaker 03: Well, let me take a step back. [00:30:30] Speaker 03: I think the district court explained it best when it said that adopted our understanding and then of the standard as has been set out and noted that. [00:30:43] Speaker 03: whether there's clinical meaningful information, or rather, let me start again, if there's labeling, meaningful labeling, that is an indicia of whether the studies had produced clinically meaningful information. [00:30:56] Speaker 03: And what you see in a lot of the language, and Amgen and the district court quote some of the same language on that, where the FDA letters are discussing [00:31:09] Speaker 03: that they consider whether labeling had been met. [00:31:13] Speaker 03: Again, consider can be used as an indicia. [00:31:18] Speaker 03: The three letters themselves, all at the start, start with very clear language and talk about if a study doesn't result in interpretable language, or I'm sorry, interpretable, if the study's not interpretable, i.e. [00:31:30] Speaker 03: if it doesn't have enough data, [00:31:32] Speaker 03: it's most likely going to be denied. [00:31:34] Speaker 03: So that's set out very clearly at the beginning of all three of these letters, that concept. [00:31:39] Speaker 03: Now, some of the languages we get in there gets a little bit muddy, but the bottom line is they are separate inquiries. [00:31:46] Speaker 03: The Orencia case. [00:31:48] Speaker 05: Is it the case, is the following legal proposition true, which is if there is a scientifically valid study [00:32:01] Speaker 05: on the useful safety efficacy of this drug for children that either points one way or the other or is inconclusive. [00:32:10] Speaker 05: Good study, just the data, don't resolve it. [00:32:13] Speaker 05: Would that as a matter of law go on the label? [00:32:20] Speaker 03: Yes. [00:32:22] Speaker 03: Well, first off, [00:32:24] Speaker 03: To clarify, there is the section 355AJ, which means anything goes on the label. [00:32:30] Speaker 05: Yeah, that's what I was reading, and I would have thought that would lead to an argument on your side that doesn't really matter whether you said clinically meaningful or clinically meaningful on the label, because everything that's clinically meaningful goes on the label. [00:32:47] Speaker 05: But I don't think your brief makes a point quite that crisply. [00:32:52] Speaker 03: No, no, no, it does not. [00:32:54] Speaker 03: And to the extent that it gets mentioned, we're parrying this idea that [00:32:59] Speaker 03: Just because something is mentioned on the label, it automatically means it should have got pediatric exclusivity, which we would say is not the case because there is basically no bar to getting on the label under 355AJ. [00:33:13] Speaker 03: It becomes a question of whether that's actual meaningful labeling. [00:33:18] Speaker 03: And again, we're referring back to the statute. [00:33:20] Speaker 03: the statute specifically asking for information that provides a health benefit. [00:33:25] Speaker 03: You can tell the physician what to do. [00:33:28] Speaker 03: So going back to the labeling point, Orencia is a study where FDA granted pediatric exclusivity. [00:33:39] Speaker 03: It didn't meet the terms of the written request. [00:33:42] Speaker 03: It did provide clinically meaningful information, but it did not lead to any new label change. [00:33:49] Speaker 03: There are instances where that happens. [00:33:54] Speaker 06: Can I just make sure I understand your position? [00:33:59] Speaker 06: If in this case, they had actually completed with 15 subjects, study three, which was the number required by the written request. [00:34:12] Speaker 06: And basically, the results of the study were inconclusive as to safety and efficacy. [00:34:24] Speaker 06: It's your position that they would or would not have met the fairly respond standard? [00:34:30] Speaker 03: They absolutely would have if they've had all of their finishers for that written request. [00:34:36] Speaker 06: OK. [00:34:37] Speaker 06: So let's say they had 14 complete. [00:34:44] Speaker 06: and instead of 15 and still inconclusive results with 14, what would be the result? [00:34:53] Speaker 03: Well it becomes a question I think of the specific analysis and then the data that comes in to the extent you're talking about studies that garner enough data that can be analyzed and you can look is there a connection [00:35:07] Speaker 03: between safety and efficacy here and can actually inform a physician on how to treat a patient, then yeah, it would be clinical meaningful information that would provide a health benefit for physicians and maybe not, and would still get exclusivity. [00:35:25] Speaker 06: How does the study with 14 [00:35:33] Speaker 06: versus the study with 15 subjects, how do they differ with respect to whether it's clinically meaningful results? [00:35:44] Speaker 03: There is, I mean it would I think take a specific dive into the evidence and the data. [00:35:51] Speaker 03: I mean there is also [00:35:53] Speaker 03: Well, there is this idea that the dosage on these children was very slowly going up, so you needed to look at that. [00:36:03] Speaker 03: So to the extent you need to make sure you understood how the drug was reacting. [00:36:09] Speaker 03: 15 data points isn't very much, and so if you have one less finisher, it could dramatically change what the results were, particularly if [00:36:20] Speaker 03: We are talking about children who are titrated at a sort of a different rate. [00:36:25] Speaker 03: I mean, if there is some potential flexibility to amend the request, if there is some reason to change it to 14 in this instance, but I think it becomes a very stack-specific sort of inquiry that's difficult to answer in the abstract. [00:36:42] Speaker 04: How is an entity to know at the beginning of the process, they get the written request, how are they to know what they need to produce in order to gain the pediatric exclusivity? [00:36:54] Speaker 04: The regime that you're describing seems to leave an awful lot of [00:36:58] Speaker 03: discretion to the FDA and you're using, you've said repeatedly it's case specific and that's... The written request set out specific objectives here was to evaluate and then once you're on that idea of well are we, you know, once we're going to take a look and say did you evaluate this, can you describe the sort of safety profile, [00:37:20] Speaker 03: Then it becomes a scientific discussion about how tight the statistics are and what sort of trends we can actually discuss and how robust the data is. [00:37:33] Speaker 03: As you set out on one of these experiments, again, it's science and the FDA is working with the study sponsor to come up with a protocol that's doable, that a sponsor can actually get enough enrolled patients in. [00:37:50] Speaker 03: You know, the study sponsors at this point, as I was saying earlier, are often also still looking for an indication and meaningful labeling. [00:37:59] Speaker 03: And so they're going to be interested in trying to get as robust a data as possible. [00:38:03] Speaker 03: So the companies are working with the FDA. [00:38:06] Speaker 04: So if I'm the general counsel to the company, what's the advice I give them? [00:38:12] Speaker 04: They've gotten the written responses, what's the advice I give to them about what they need to do to make certain they gain the pediatric exclusivity? [00:38:22] Speaker 03: Well, I would be... Besides do everything the FDA tells you to do, right? [00:38:26] Speaker 03: Right. [00:38:27] Speaker 03: That was point number one, in that regard. [00:38:30] Speaker 03: meet all the terms of the written request and to the extent that there are starting to be difficulties with that, bring it to the FDA's attention to amend the written request if needed and to explain potential problems with the study and talk with the FDA about what they believe the sufficient amount of data is to be interpretable. [00:38:56] Speaker 03: And that's what typically happens in these cases. [00:38:58] Speaker 03: There's 40-some [00:39:00] Speaker 03: interactions that are just listed in the documents here. [00:39:03] Speaker 06: On this record, at some point when it was discovered that there was going to be a problem completing study three, Amgen brought that to the FDA's attention and the FDA, as I recall, refused a request for a meeting and just said kind of proceed at your discretion. [00:39:25] Speaker 06: Something to that effect. [00:39:27] Speaker 06: Am I right about that? [00:39:29] Speaker 03: Yes, that was in the very late stages. [00:39:31] Speaker 03: There was an additional meeting request after there'd already been five amendments and there was that one was refused as being So so so did they make a formal request to amend the written? [00:39:44] Speaker 03: Request again or right there wasn't a proposed amendment six and [00:39:50] Speaker 06: And the FDA refused that, and that's not, the merits of that decision is not before us, right? [00:40:00] Speaker 03: Correct. [00:40:00] Speaker 03: It's not at appeal. [00:40:02] Speaker 03: And I think the background on that is just at some point, you know, this study needed to wrap up, and there hadn't been sufficient reason to reduce the number of completers. [00:40:14] Speaker 03: And keep in mind, I think one thing I wanted to close on just quickly is that [00:40:20] Speaker 03: This program has been immensely successful. [00:40:23] Speaker 03: It's 93% of people, 93% of studies end up finishing. [00:40:29] Speaker 03: There is a quid pro quo here that happens, and what FDA is looking for is some sort of real information. [00:40:36] Speaker 03: That's what the statute asks. [00:40:38] Speaker 05: Just one more question following up on the label point. [00:40:42] Speaker 05: If I – did I hear you correctly that sometimes, for whatever reason, there are perfectly good studies that don't end up on the label? [00:40:54] Speaker 05: Is that right? [00:40:57] Speaker 05: Right. [00:40:58] Speaker 05: Okay, if that's true, then why isn't it a problem for you to the extent your articulation of the standard sometimes in a muddy way, whatever, sometimes suggests that you need studies that will end up on the label. [00:41:15] Speaker 03: But we're looking at the studies as not necessary, but a sufficient indication. [00:41:21] Speaker 03: And so it's not a requirement to get the labeling, but it's looked at. [00:41:27] Speaker 03: And the district court said it's an indicia. [00:41:30] Speaker 03: And I think also the bottom line to keep [00:41:32] Speaker 05: Sufficient, but not necessary. [00:41:34] Speaker 03: Right, right. [00:41:35] Speaker 03: And so there's no indication that the inquiry stops at that point. [00:41:39] Speaker 03: And I think also just to keep in mind, to the extent we're talking about labeling, Amgen's submission here wasn't rejected because they didn't come up with labeling. [00:41:49] Speaker 03: It was rejected because they came up with insufficient data. [00:41:52] Speaker 04: Okay, great. [00:41:53] Speaker 04: Thank you. [00:41:53] Speaker 04: Should we have your argument? [00:41:55] Speaker 04: How much time does Ms. [00:41:56] Speaker 04: Stetson have? [00:41:59] Speaker ?: Ms. [00:41:59] Speaker 04: Stetson doesn't have any time remaining. [00:42:00] Speaker 04: We'll give you two minutes. [00:42:03] Speaker 04: for rebuttal. [00:42:07] Speaker 02: Three quick points on rebuttal, one on Merck, one on Chevron, and one on meaningfulness. [00:42:13] Speaker 02: The Merck exclusivity was granted not because the FDA concluded that somehow five finishers out of 35 was more meritorious than four out of 15. [00:42:24] Speaker 02: It was granted because, this is what the FDA says at Joint Appendix 667, the agency followed the finding of the court to recognize exclusivity based upon the determination that Merck had substantially met the written request terms, even though not meeting the exact terms. [00:42:42] Speaker 02: That's why Merck got exclusivity. [00:42:46] Speaker 02: Government Council talked a lot about the process in this case, but the process that triggers Chevron is a public process, not a lengthy, no matter how lengthy, iterative process between one regulated party and the agency. [00:43:01] Speaker 02: What gets you Chevron deference is a pronouncement that is intended to carry the force of law, and there was no such pronouncement in this case, not even this decision. [00:43:11] Speaker 02: would be public were it not for this litigation. [00:43:14] Speaker 02: Third, on clinically meaningful, I want to be very clear. [00:43:18] Speaker 02: The board based its decision, Joint Appendix 675, based upon the lack of meaningful labeling information, the board determined that Amgen did not fairly respond. [00:43:33] Speaker 02: I agree there's a lot of muddiness in those rulings. [00:43:36] Speaker 02: That is not muddy. [00:43:40] Speaker 02: The last thing I would say with respect to September 2013, Mr. Bureau mentioned that there was an exchange at that point, there was. [00:43:47] Speaker 02: What Mr. Bureau neglected to mention is that that is the meeting where Amgen put this question to FDA. [00:43:53] Speaker 02: Do you agree that we should stop these studies? [00:43:56] Speaker 02: And FDA said no, we disagree. [00:43:59] Speaker 02: we have learned a lot from the clinical data that you have collected during these studies. [00:44:05] Speaker 02: So the idea that the data that we produced, those hundreds of pages, were clinically meaningless, so meaningless that they somehow go on a label and they have no meaning whatsoever, is a little bit difficult to take. [00:44:19] Speaker 02: Even inconclusive results are clinically meaningful. [00:44:23] Speaker 02: Physicians look at that label, they make decisions based on that label, [00:44:27] Speaker 02: They can look at the public studies that resulted from our studies, and they can make clinical determinations. [00:44:34] Speaker 02: So if we are in a clinically meaningful world, not tied to conclusive labeling, which was their finding, we submitted clinically meaningful information. [00:44:44] Speaker 02: If there are no further questions. [00:44:47] Speaker 04: Thank you. [00:44:47] Speaker 04: Thank you very much. [00:44:48] Speaker 04: The case is submitted.