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Case number 18-1112 at L. Breckenridge Pharmaceutical Inc.

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at L. Petitioners vs. Food and Drug Administration at L. Ms.

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Reines for the petitioners and Ms.

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Carroll for the respondents.

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Thank you.

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May it please the court.

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At stake on this appeal is a prescription system for the laxative PEG that encourages roughly a million patients a month, a million patients a month to be treated

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for longer use of a laxative with the benefit of doctor supervision.

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And everyone's agreed that this has been a safe and efficacious system as it is.

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The legal problem with the FDA decision making here is its categorical refusal to even consider whether differences in duration of use

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can be a meaningful, safety-based distinction.

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Can you take it week by week?

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Sure.

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For the second week, at least two minutes, leaders follow the directions.

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A doctor's description is necessary.

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Consultant consultation is necessary, right?

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Yes.

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OK.

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So then we have the first group.

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Right.

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And your argument has to be that it's completely contradicting the FDA's original approval of an OTC version.

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that the risks of tubes are materially great, so great in that first week that allowing people to use it without a prescription has a serious safety procedure, right?

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That has to be your argument.

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I don't believe that's the argument.

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I'm not sure it's the argument you make, but it seems to me it has to be your argument.

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The argument that we make, which I think is very straightforward and is undisputed, is that there is a serious risk during a second week of use that there would be safety problems.

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That's the definition of a prescription drug.

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by going to your doctor.

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Now, the prescription would get the first week, too, by going to your doctor.

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But the fallacy of that, at least from our perspective, respectfully, is that all patients, no matter how infirm or addicted, are going to adhere to notices on a small bottle.

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If that were true, we wouldn't need prescriptions at all.

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Because your hypothetical assumes that everyone after a week is going to terminate use and see a doctor.

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I mean, the role of the prescription is to make sure that someone is actually qualified to deal with matters.

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But the assumption of dual system, OTC and prescription, is that users are capable of adhering to instructions.

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If that premise is completely false, the whole system falls apart, everything should be prescription.

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No, I don't agree with that.

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I think we... Except for drugs that you can just take without limit.

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One distinction here is that there's a unique circumstance, idiosyncratic to this particular situation, of masking where what's happening... I understand the masking completely, but no one is suggesting we're good.

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could obviously be masking in those first few days.

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But back in 2008, 2009, the FDA determined that the risk of that masking in the first seven days was insufficient to require a description.

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as long as it was limited to over the counter for seven days, right?

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So everybody agrees that any use for 14 days is something that requires doctor supervision.

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And I think the premise is that everybody, no matter how infirm under this fact pattern, can be presumed conclusively to be adhering to what the label states.

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And I just don't understand.

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You have to assume that they're adhering to the OTC label.

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Otherwise, what's the point of your argument?

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The OTC label says use no more than seven days.

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If they're actually using it as long as they want,

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then they wouldn't have any need for the prescription drug.

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Except that we know that's counterfactual because we have a million patients roughly a month.

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So are you telling me that they are reading the OTC wave?

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I'm saying that doctors are advising people that want to use for more than a week

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that they should get a prescription and be under doctor's supervision.

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That seems perfectly... Do you believe that they are reading the late... If you pick up the Muralax OTC, which says use no more than seven days, do you think they stop at the end of seven days?

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That's what I'm asking.

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I think in some situations they will.

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In some situations they won't.

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It's been unstudied.

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I think there's so many questions here that are worthy of study, because I don't believe that's as rigid as saying, let's assume everybody adheres to the notice.

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What we have here is the FDA has stated time and again, five different times, that there's a safety-based need to have a seven-day limit on over-the-counter.

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Okay?

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Okay.

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Right?

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And so that has been stated that 14 days is not a safe period.

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That's the definition of a prescription drug.

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There are risks associated with the extra week sufficient to justify in the judgment of the FDA requirement of Dr. Seuss.

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Everybody agrees that.

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But what's overlooked here is the rule that's being applied.

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The meaningful difference test

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state that the prescription products safe only under the supervision of a licensed practitioner.

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And so, I mean, to assume that... You're not challenging the previous decision to go from Rx to OTC on Miralax, are you?

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Not at all.

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Okay.

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So there are determination there that there was no safety need to maintain that drug with a prescription.

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You're not challenging that, right?

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That's correct.

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So now it can go to OTC and people either follow the instructions or not, but there's not a safety concern.

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There's not a safety concern assuming that people are using it for a week, which generally you hope they are, but that doesn't mean that in the context of people going to a doctor that say, I am a user that requires 14 days.

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Well, I would understand if the argument were, this is some drug that will kill you at the end of seven days, and they had

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If you had that circumstance, FDA would never have allowed it to go to OTC.

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But here they've sent it to OTC, believing that it would not cause a safety or health concern.

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And they specifically say that.

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And in this case, they have every other element of what a drug means, bioequivalence, physical chemistry, dosage level, et cetera, et cetera, population.

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And the only thing is labeling, and they explain,

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that the labeling actually is just an artifact of the way in which in the past they wanted all OTCs to be labeled the same.

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It wasn't because this particular drug had to be in a certain way, it was because for confusion purposes they wanted them to be the same.

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That's their explanation.

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Now you may not like that explanation,

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And you can certainly challenge that explanation as arbitrary and capricious, but it doesn't seem like that's a reasonable claim that it's not the same drug.

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I think it's just important for me to address that, which is it's an internally inconsistent position.

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At times, they clearly say it's safety-based, which I thought we had agreed to earlier.

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And at times, they say it's inconsistency.

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And the question of whether or not... Can I just... Oh, sure.

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I'm sorry.

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It seems to me that what the FDA was talking about

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minor aspects of the wording of the instruction were chosen in order to fit the treatment of other over-the-counter blasters.

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And so they went with that for this.

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But the basic proposition that it was safe to use for a week was

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I mean, you've said it's undisputed.

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You've said you're not disputing the decision to allow a prescription in OTC form of this.

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But the minor, if what's being assumed is that minor is this seven-day limitation, it's not minor.

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In 85, they said it's safety based.

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Oh, it's unrelated.

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Minor, major, whatever.

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But that's what the standard is, is the meaningful difference test.

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The only function in the prescription thing is that the first week is coming in as a sort

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Orphan dragged along with the second week.

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The second week is what justifies the requirement of the prescription.

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The evidence that we submitted is that hospitalizations tripled.

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Deaths doubled after it went over the counter.

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So the question isn't whether the over counter should be withdrawn.

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It's whether we want to remove a system where a million prescriptions a month are being given by doctors.

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And we have doctors who.

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All those deaths and so forth can be traced to the availability for one week.

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And most people would think it should be a withdrawal.

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None of this has been looked at.

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Before we turn this massive system on its head and throw it out the door, let's have some look at these questions.

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Presumptively assuming that there's no problem because it says seven days and stop is inconsistent with the fact that doctors are giving a million prescriptions a month out because they believe that's the right way that people should be under doctor supervision.

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And what I'm hearing is that even though it's a meaningful difference because it's safety-based, which everyone agrees the 7 versus 14 safety-based, that's why the FDA refused to give 14 days to the over-counter.

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Everyone agrees that's a safety-based distinction.

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It meets the standard.

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All I'm hearing is that we're assuming that after seven days, everyone's going to stop.

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So what's the difference?

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That's the argument.

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And I just do not think, in as complex a system like this,

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with the infirm people, addicted people that are going to doctors and being under doctor's supervision and saying, okay, maybe you need to be in an opioid detox rather than taking this week after week.

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Throwing that all out just because we assume as a matter per se that people stop after a week just seems to me to be totally improper when everyone agrees that there's a safety-based distinction which meets exactly their standard.

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And one point I want to also note on the process is that in the notice in 2008,

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duration of use is specified as something that could be a distinction, a meaningful distinction.

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I think the... That footnote is exceedingly confusing.

[00:12:19] Speaker 05:
Well, it says the manner in which a particular drug is dosed or administered, e.g.

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dose titration or duration of use, may also require clinical judgment and physician supervision and thus Rx status

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While a corresponding OTC version of the drug can be available at a different dosing regimen or duration of use does not require physician involvement.

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It's right in their own notice.

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So by the standard of everybody follows the print on the bottle, you'd never have duration of use being a problem because you can always just say and use this way and go see a doctor.

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But let's get out of that artificial world and deal with the people that are getting doctor's help at a million a month so that people that have opioid and blockages for cancer and all this get the opportunity to doctor.

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Or at least let's have a hearing where we look at the things.

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All right.

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We're three minutes over.

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Let me just ask if any of the other judges have questions.

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OK.

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Thank you very much.

[00:13:25] Speaker 01:
May it please the court, Sarah Carroll on behalf of the government.

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FDA reasonably withdrew the approvals of petitioners' products, which, as Judge Garland noted, are identical to over-the-counter mural acts in every meaningful respect.

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They have the same approved indication.

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They have the same safety and efficacy profiles.

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They're the same in all these other ways.

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Petitioners rely solely on minor differences in the product's labeling, which again, Judge Garling correctly noted, originate from FDA's decision to promote consistency with its general long-standing.

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I just want to clarify, make sure my understanding is correct, that consistency or whatever is, is it correct that an FDA's view that if this is used for more than a week,

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It's not that the PEG 350 or whatever it is itself, the Murilax itself, becomes more dangerous to use.

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It isn't addictive.

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It doesn't build up toxicity.

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It's that after a week we don't trust the patient's self-diagnosis anymore.

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Is that the safety risk?

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That's how I understood it.

[00:14:31] Speaker 01:
I think that's basically right, Judge Millett.

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I think the public health determination FDA has made is that essentially

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if people have these symptoms for seven days and haven't gotten relief from an over-the-counter product, there might be some underlying serious condition, and the person should see a doctor to see if it is something like that.

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So there's nothing in, apart from that you should no longer self-diagnose, there's nothing harmful about taking demuralax itself for more than a week, other than you may be

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treating the wrong, you may be mistreating yourself, but the ingredient, the active ingredient itself does not become more harmful over time.

[00:15:15] Speaker 01:
I believe the record supports that, yes.

[00:15:18] Speaker 01:
I know that the over-the-counter... What if it did?

[00:15:21] Speaker 02:
I mean, because it sounded like you adopted sort of a categorical rule here, but then there's that footnote and surely there are certain drugs that have used for a short time are perfectly fine, but over a longer period of time can build up either addictive

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qualities just based on the duration of use or a buildup of toxicity in the system.

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So I was somewhat confused about what sounded like a very categorical approach to duration of use here, which seemed to be somewhat inconsistent with prior FDA statements and with scientific reality.

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What are we to do with that?

[00:15:55] Speaker 01:
Contrary to petitioners' assertion, FDA has not taken a categorical view that duration of use can never create a meaningful difference.

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FDA explained in the order that it hasn't previously found duration of use standing alone to be a meaningful difference.

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And it said at JA 673 that it was declining to find in this proceeding that duration of use standing alone was a meaningful difference.

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And that of course makes perfect sense because the asserted difference here is so small.

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But FDA has not foreclosed the possibility that there could be some different case, like Your Honor was hypothesizing,

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where perhaps duration could be more meaningful.

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And what is the difference between duration of therapy, which has been listed as a meaningful difference, and duration of use?

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I just couldn't figure that out.

[00:16:43] Speaker 01:
So I agree with Judge Williams that that footnote is not a model of clarity.

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Everywhere else in the record, FDA has made clear that it considers different factors in looking to

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what constitutes a meaningful difference, and then in that footnote in the... Is duration of therapy and duration of use, are they the same thing?

[00:17:03] Speaker 01:
I frankly do not know if duration of therapy is different from duration of use, but the reason I don't know that is because none of the examples that FDA cited in that footnote or elsewhere relied on either duration of use or duration of therapy standing alone.

[00:17:19] Speaker 01:
to find a meaningful difference.

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So I frankly don't know exactly what that reference in the footnote meant, but it doesn't matter, because even if duration of use or duration of therapy, whether they're the same or different, could hypothetically somewhere be enough standing alone to create a meaningful difference.

[00:17:36] Speaker 01:
It certainly doesn't here.

[00:17:38] Speaker 04:
Can we go to the reasons for the label on the OTC product?

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because of the previous labeling.

[00:18:03] Speaker 04:
There's no indication anywhere that that meant the FDA was sacrificing safety in allowing one week without a patient seeing a doctor, right?

[00:18:22] Speaker 04:
No, that's right.

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FDA... In terms of materiality, remember the losses of wording where the fundamental decision way back in 08 was that a week was okay.

[00:18:39] Speaker 04:
Yes, that's absolutely right, Your Honor.

[00:18:41] Speaker 04:
It's okay, but it's physically okay, so there's no need to have the impression of having to see a doctor first.

[00:18:48] Speaker 01:
Right, that's right.

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And in view, especially, of FDA's determination that Neuralax is effective within less than a week, perhaps three or four days, to treat occasional constipation, which is the only indication that either the prescription or the over-the-counter product is indicated for, it made perfect sense to adhere to FDA's long-standing policy, suggesting that people see a doctor after seven days.

[00:19:15] Speaker 01:
I'm happy to answer any other questions that the court might have.

[00:19:19] Speaker 02:
Are you claiming Chevron deference here?

[00:19:20] Speaker 02:
I didn't see it argued in your brief at all.

[00:19:23] Speaker 01:
Right.

[00:19:24] Speaker 01:
So we did not honestly take petitioners to have challenged the standard that FDA has applied.

[00:19:29] Speaker 01:
They said in their reply brief that they had, and to the extent that they are doing that, certainly Chevron would apply.

[00:19:34] Speaker 01:
This is FDA's interpretation of the statute it administers.

[00:19:38] Speaker 04:
In fact, just to challenge your use of 355 E3, that said second E3.

[00:19:48] Speaker 04:
Right.

[00:19:49] Speaker 04:
A little more puzzling.

[00:19:51] Speaker 04:
Numbering starts to seem that anyway.

[00:19:53] Speaker 03:
Except for the one in the last case.

[00:19:56] Speaker 03:
There are a lot of puzzling numbers today.

[00:19:59] Speaker 01:
That's right.

[00:20:00] Speaker 01:
That's right, Your Honor.

[00:20:04] Speaker 01:
Thank you.

[00:20:04] Speaker 03:
Thank you.

[00:20:05] Speaker 03:
Any time left?

[00:20:08] Speaker 03:
We'll give you another minute.

[00:20:11] Speaker 05:
Thank you, Your Honor.

[00:20:12] Speaker 05:
With the admission that duration of use is not an absolute bar and that you have to evaluate particular circumstances with Judge Malay handled on, hammered on the nose, there needs to be an evaluation as to whether or not people are following the label and whether there's safety and efficacy issues.

[00:20:29] Speaker 05:
If it really is case by case, as that was just established in that last questioning, then there should be an examination at a 424 and 426

[00:20:38] Speaker 05:
is the adverse events documentation that shows that the hospitalizations have doubled, tripled, and the deaths have doubled, and there's a load of information about who's following what, which populations are doing what, and there's so much to consider.

[00:20:55] Speaker 04:
The focus in your new data is overwhelming, like, for long use.

[00:21:03] Speaker 05:
No, I think that we put an adverse events database in with analysis.

[00:21:06] Speaker 05:
We put a survey in that shows which people are using it in what way.

[00:21:10] Speaker 05:
None of this has been explored.

[00:21:12] Speaker 05:
This is an important enough topic to at least look at it, since it's case by case on duration of use.

[00:21:17] Speaker 05:
Thank you.

[00:21:18] Speaker 05:
You've been very patient.

[00:21:20] Speaker 05:
Just one minor, not minor, actually important, but one thing that before I leave, first of all, we appreciate very much the court expediting the oral argument.

[00:21:28] Speaker 05:
We know you're busy in the busy day, manifestly.

[00:21:31] Speaker 05:
And then also, if there's any question about whether or not this statute's going to be upheld or not, we would ask for a stay pending the November 2nd date so that we don't turn this whole big system upside down and then have to clean it up.

[00:21:46] Speaker 05:
But it's not a one size fits all.

[00:21:49] Speaker 05:
It should be evaluated based on a hearing.

[00:21:52] Speaker 05:
Thank you very much.

[00:21:53] Speaker 03:
Thank you.

[00:21:54] Speaker 03:
Court's going to stay in session to swear in one more new member of the court.