Reply Brief — Alliance for Hippocratic Medicine, et al., Petitioners v. Food and Drug Administration, et al.

NO. 23-395

IN THE

Supreme Court of the United States

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

Cross-Petitioners,

v.

U.S. FOOD AND DRUG ADMINISTRATION, ET AL.,

Cross-Respondents.

and

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

Cross-Petitioners,

v.

DANCO LABORATORIES, L.L.C.,

Cross-Respondent.

On Petition for Writ of Certiorari to the

United States Court of Appeals for the Fifth Circuit

REPLY BRIEF FOR CROSS-PETITIONERS

JAMES A. CAMPBELL

CODY S. BARNETT

ALLIANCE DEFENDING

FREEDOM

44180 Riverside Pkwy

Lansdowne, VA 20176

(571) 707-4655

ERIN M. HAWLEY

Counsel of Record

JOHN J. BURSCH

MATTHEW S. BOWMAN

ERIK C. BAPTIST

ALLIANCE DEFENDING FREEDOM

440 First Street NW, Suite 600

Washington, DC 20001

(202) 393-8690

ehawley@ADFlegal.org

Counsel for Cross-Petitioners

i

CORPORATE DISCLOSURE STATEMENT

The Corporate Disclosure Statement in the

Conditional Cross-Petition for Writ of Certiorari

remains unchanged.

ii

TABLE OF CONTENTS

CORPORATE DISCLOSURE STATEMENT ............ i

TABLE OF AUTHORITIES ..................................... iii

INTRODUCTION ...................................................... 1

REPLY ARGUMENT ................................................. 2

I. FDA reopened its 2000 Approval when it

overhauled the mifepristone regimen in 2016

and authorized mail-order abortion in 2021........ 2

A. Express Reopening .......................................... 3

B. Constructive Reopening .................................. 5

II. FDA violated the APA and the FDCA when

approving mifepristone under Subpart H. .......... 7

A. Subpart H applies only to drugs that treat

illnesses, but pregnancy is not an illness. ...... 7

B. Chemical abortion does not provide a

meaningful therapeutic benefit over

surgical abortion. ............................................. 8

C. The 2000 Approval violated the FDCA and

the APA. ........................................................... 9

D. The FDAAA provides no refuge for FDA’s

unlawful 2000 Approval. ............................... 11

III.Cross-Petitioners have standing to challenge

the unlawful 2019 Generic Approval. ................ 12

CONCLUSION ......................................................... 13

iii

TABLE OF AUTHORITIES

Cases

Cuomo v. Clearing House Association,

557 U.S. 519 (2009).............................................. 8

Department of Homeland Security v. Regents of

University of California,

140 S. Ct. 1891 (2020).......................................... 9

District of Columbia v. Heller,

554 U.S. 570 (2008).............................................. 8

Motor Vehicle Manufacturers Association of

United States, Inc. v. State Farm Mutual

Automobile Insurance Company,

463 U.S. 29 (1983)........................................ 10, 11

National Association of Reversionary Property

Owners v. Surface Transportation Board,

158 F.3d 135 (D.C. Cir. 1998) .............................. 3

National Biodiesel Board v. EPA,

843 F.3d 1010 (D.C. Cir. 2016) ............................ 6

National Mining Association v. United States

Department of Interior,

70 F.3d 1345 (D.C. Cir. 1995) .............................. 3

North Dakota Retail Association v. Board of

Governors of the Federal Reserve System,

55 F.4th 634 (8th Cir. 2022) ................................ 2

Outdoor Amusement Business Association v.

Department of Homeland Security,

983 F.3d 671 (4th Cir. 2020) ............................... 2

iv

Sendra Corp. v. Magaw,

111 F.3d 162 (D.C. Cir. 1997) .............................. 7

Sierra Club v. EPA,

551 F.3d 1019 (D.C. Cir. 2008) .................... 5, 6, 7

Utah ex rel. Utah Department of Environmental

Quality, Division of Air Quality v. EPA,

750 F.3d 1182 (10th Cir. 2014)............................ 2

Statutes

21 U.S.C. 355 ........................................................ 9, 10

21 U.S.C. 355-1....................................................... 3, 6

Other Authorities

FDA Risk Evaluation and Mitigation Strategy

(REMS) Public Dashboard .................................. 7

Hyland Hunt, Notice & Comment D.C. Circuit

Review – Reviewed: A Quiet Week, Yale J. on

Regul. (Oct. 8, 2023) ............................................ 2

Regulations

21 C.F.R. 10.45 ........................................................... 4

21 C.F.R. 314.500 ....................................................... 8

1

INTRODUCTION

Cross-Petitioners agree there is no compelling

reason for this Court to grant interlocutory review of

the modest decision below. Yet Cross-Respondents

ask this Court to intervene mid-litigation to review

fact-bound and splitless issues. Then, seeking to have

their cake and eat it too, Cross-Respondents ask the

Court to limit its review to half a case. The Court

should deny all three petitions and allow the parties

to develop a full record in the district court. But if the

Court is inclined to review any issue, it should review

them all.

FDA and Danco ask this Court to examine the

FDA’s 2016 and 2021 actions while denying the crosspetition. But the cross-petition provides the regulatory framework for—and presents questions intertwined with—the very issues FDA and Danco insist

are cert-worthy. For example, FDA and Danco say in

their petitions that the Fifth Circuit’s decision will

wreak regulatory havoc. Yet in their brief opposing

the cross-petition, they say that the 2016 and 2021

changes did not alter the basic regulatory scheme.

Both arguments cannot be true. If reinstating safeguards for women’s health upends the regulatory

regime, so does removing them.

Cross-Petitioners’ challenge to the 2000 Approval

is timely under the reopening doctrine, and FDA’s

approval of mifepristone under Subpart H was fatally

flawed under both the FDCA and the APA. If the

Court agrees that interlocutory review is warranted,

it should grant this cross-petition and review the

Fifth Circuit’s entire decision now.

2

REPLY ARGUMENT

I.

FDA reopened its 2000 Approval when it

overhauled the mifepristone regimen in

2016 and authorized mail-order abortion in

2021.

Danco and FDA spill much ink disparaging the

reopening doctrine. But the doctrine is wellestablished in the D.C. Circuit—whose docket

consists of 33% administrative law cases. 1

Far from undermining the cross-petition, CrossRespondents’ arguments highlight the need for this

Court’s guidance. On Danco’s telling, the Eighth

Circuit in North Dakota Retail Association v. Board of

Governors of the Federal Reserve System, 55 F.4th 634

(8th Cir. 2022), cast shade on the reopening doctrine,

potentially limiting it in conflict with D.C. Circuit

precedent. Danco.BIO.13–14. So too have other courts

of appeal that Danco references. Danco.BIO.12 n.2

(citing Outdoor Amusement Bus. Ass’n v. Dep’t of

Homeland Sec., 983 F.3d 671, 682 n.5 (4th Cir. 2020);

Utah ex rel. Utah Dep’t of Env’t Quality, Div. of Air

Quality v. EPA, 750 F.3d 1182, 1185-86 (10th Cir.

2014)). That means there is more of a circuit split on

the first issue in the cross-petition than those in FDA

and Danco’s petitions. If those petitions warrant this

Court’s review, so does the cross-petition.

Moreover, the reopening doctrine applies here

because FDA (1) expressly reopened the 2000 Approval by reexamining it and (2) constructively reopened

Hyland Hunt, Notice & Comment D.C. Circuit

Review – Reviewed: A Quiet Week, Yale J. on Regul.

(Oct. 8, 2023), https://perma.cc/TG4K-543K.

1

3

it by removing safeguards it previously found

indispensable to mifepristone’s safe use.

A. Express Reopening

FDA admits that a new limitations period begins

to run upon an agency’s reconsideration of a decision.

FDA.BIO.13. Here, because FDA removed the prerequisites on which mifepristone’s approval was

based, the limitations period “beg[an] anew.” Nat’l

Ass’n of Reversionary Prop. Owners v. Surface Transp.

Bd., 158 F.3d 135, 141 (D.C. Cir. 1998). Whether

viewed “as a timely challenge to the new decision,”

FDA.BIO.13 (emphasis omitted), or an express

reopening of the initial approval, Cross-Petitioners’

challenge can proceed.

FDA disputes this straightforward application of

reopening by arguing that the only question in 2016

“was whether mifepristone would remain safe and

effective without [the post-marketing] conditions.”

FDA.BIO.15 (emphasis omitted). That ignores the

statutory framework. In 2000, FDA deemed the drug

to be unsafe without post-marketing limitations (later

known as Elements to Assure Safe Use or ETASUs).

Those FDA-imposed limitations were necessary antecedents to FDA’s approval. 21 U.S.C. 355-1(f)(1)(A)

(certain dangerous drugs “approved only if, or would

be withdrawn unless, such elements are required”).

When FDA removed those antecedents, the question

became whether the drug nevertheless was safe for

approval. This literal reopening was “a serious,

substantive reconsideration” of the 2000 Approval.

Nat’l Mining Ass’n v. U.S. Dep’t of Interior, 70 F.3d

1345, 1352 (D.C. Cir. 1995).

4

Danco contends that, even if the 2016 Major

Changes reopened the 2000 Approval, CrossPetitioners’ challenge would still be untimely because

it was filed more than six years after their issuance.

Danco.BIO.16. Not so. Under 21 C.F.R. 10.45(b),

those changes became final only in December 2021

when FDA denied the 2019 Citizen Petition.

FDA also suggests that it could not have reopened

its 2000 Approval because some of the CrossPetitioners filed a citizen petition. FDA.BIO.16. But

the relevant inquiry is what action the agency—not

Cross-Petitioners—took. FDA’s removal of crucial

safeguards in 2016 and 2021 was not “merely” a

response to a citizen petition, ibid., but transformative agency action that removed crucial safeguards.

FDA is likewise wrong that its 2021 actions did

not expressly reopen the 2000 Approval because

judicial review is limited to the “narrow issues”

defined in a citizen petition. FDA.BIO.16. Again, the

appropriate inquiry is the scope of the agency’s

action—not the citizens’. Because FDA necessarily

reconsidered its original decision, reopening applies.

Regardless, the 2019 Citizen Petition expressly urged

FDA to “not further erode patient protections” and

thus keep the in-person dispensing requirement—

precisely what FDA eliminated in 2021. ROA.765.

None of Cross-Respondents’ cases suggest that

the filing of a citizen petition defeats reopening when

an agency dramatically changes course. FDA.BIO.16

(citing cases). Indeed, Danco admits that an agency’s

response to a petition “could conceivably reopen an

administrative proceeding,” but without a hint of

irony, says such an intent must be “clear from the

5

administrative record.” Danco.BIO.17 n.5. Here, that

record remains in cold storage. Oral Arg. at 24:49 (5th

Cir. May 17, 2023). Danco thus appears to support

Cross-Petitioners’ point that FDA should produce,

and the district court should rule based on, a full

record before this Court’s review.

B. Constructive Reopening

The 2016 and 2021 actions also constructively reopened the 2000 Approval. A constructive reopening

occurs when the revision of regulations “significantly

alters the stakes of judicial review as the result of a

change that could have not been reasonably

anticipated.” Sierra Club v. EPA, 551 F.3d 1019, 1025

(D.C. Cir. 2008) (quotation omitted). This standard is

met here.

As every panel member below concluded, erasing

crucial safeguards in 2016 and 2021 “meaningfully

altered” the drug regimen. FDA.Pet.App.47a. Danco

suggests that these changes did not “significantly

alter[] the stakes of judicial review,” Sierra Club, 551

F.3d at 1025, because eliminating “a more stringent

requirement in favor of an alternative does not work

such a sea change.” Danco.BIO.20 (cleaned up). That

cannot be correct. Such a theory would immunize

agencies anytime they swap out a stringent requirement for a more lenient one. Indeed, the D.C. Circuit

found the elimination of a crucial safeguard to work

just a sea change in Sierra Club.

Hard put to deny the sea-change occasioned by

the 2016 and 2021 actions, Cross-Respondents pull a

stray line from Sierra Club to suggest that reopening

applies only where the initial action “may not have

been worth challenging” on its own. Danco.BIO.21.

6

But the standard is whether the new agency action

“significantly altered” the prior one, including “by

stripping out virtually all of the [previous safeguards].” Sierra Club, 551 F.3d at 1025 (cleaned up).

And just because agency action was initially worth

challenging does not foreclose the reopening doctrine.

That some Cross-Petitioners might have challenged

the 2000 Approval no more defeats reopening here

than did the challengers’ submitted comments

opposing the initial rule in Sierra Club. Id. at 1026

(noting that commenters raised objections to the

initial 1994 rule). It is similarly irrelevant whether

Cross-Petitioners personally oppose abortion. Cf.

Danco.BIO.21.

Cross-Respondents also contend that since drug

applicants can ask FDA to make “revision[s]” to a

REMS, Danco.BIO.20, it was “entirely foreseeable”

that FDA would modify mifepristone’s post-marketing restrictions in a drastic way, FDA.BIO.17. Hardly.

The basic assumption of the 2000 Approval was that

mifepristone’s safety depended on the included safeguards. See Nat’l Biodiesel Bd. v. EPA, 843 F.3d 1010,

1017 (D.C. Cir. 2016). It was not “reasonably foreseeable”—much less entirely so—that FDA would strip

away nine safeguards it once determined necessary

for safety. Nor was it foreseeable that FDA would

erase the “cornerstone” safeguard of an in-person

dispensing requirement. FDA.Pet.App.229a. FDA’s

changes are not garden-variety REMS modifications

or efficacy supplementation, cf. Danco.BIO.22 & n.7,

but specific ETASUs that FDA once determined were

“necessary to assure safe use,” 21 U.S.C. 355-1(f)(1).

Only 63 drugs have active ETASUs and removing

those elements does not occur with any frequency. See

FDA Risk Evaluation and Mitigation Strategy

7

(REMS) Public Dashboard, https://perma.cc/N787MQ2F.

Danco says constructive reopening hasn’t applied

outside the rulemaking context. Danco.BIO.20. But

there’s no reason to exempt agency adjudication from

the prohibition on bait-and-switch maneuvers applied

in Sierra Club. Otherwise, an agency could fundamentally alter the “package deal that [it] devised and

sold to the public as adequate protection,” Sierra

Club, 551 F.3d at 1026—exactly what happened here.

Tellingly, the D.C. Circuit has already suggested that

the “alteration” of an original adjudication can constitute reopening. Sendra Corp. v. Magaw, 111 F.3d 162,

167 (D.C. Cir. 1997) (considering reopening where

agency “altered its original decision” even though the

order stated “only that it [was] denying reconsideration”).

II.

FDA violated the APA and the FDCA when

approving mifepristone under Subpart H.

Cross-Respondents’ procedural arguments cannot

hide the 2000 Approval’s glaring deficiencies. FDA

improperly classified pregnancy as an “illness” and

asserted without basis that chemical abortion

provides a “meaningful therapeutic benefit” over

surgical abortion. FDA also lacked evidence and

satisfactory explanations for excluding safeguards

employed in every clinical trial. The 2000 Approval

violated the APA and the FDCA.

A. Subpart H applies only to drugs that treat

illnesses, but pregnancy is not an illness.

Subpart H approvals are only for new drugs

“treating serious or life-threatening illnesses.” 21

8

C.F.R. 314.500. But pregnancy is not an illness.

Cross-Pet.25. FDA and Danco know this. Ibid. So they

argue that Subpart H also applies to drugs that treat

“conditions”—a term absent from the regulation.

Their basis for that argument is Subpart H’s preamble. FDA.BIO.22–23; Danco.BIO.26–27. But the

preamble does not extend the regulation to drugs that

treat “conditions.” FDA.Pet.App.92a–93a, 161a.

Equally important, a preamble cannot override clear

regulatory text. Dist. of Columbia v. Heller, 554 U.S.

570, 578 n.3 (2008); Cuomo v. Clearing House Ass’n,

557 U.S. 519, 533 (2009). FDA’s efforts to contort Subpart H cannot justify the 2000 Approval. CrossPet.26.

B. Chemical abortion does not provide a

meaningful therapeutic benefit over

surgical abortion.

Subpart H also requires that a new drug have a

“meaningful therapeutic benefit,” defined as the

“ability to treat patients unresponsive to, or

intolerant of, available therapy, or improved patient

response over available therapy.” 21 C.F.R. 314.500.

But chemical abortion does not provide such a benefit

over surgical abortion, and the 2000 Approval did not

say it did. Instead, FDA said merely that mifepristone

potentially enabled women to avoid surgical abortion.

FDA.BIO.23. Crediting this justification would read

the requirement of a therapeutic benefit right out of

Subpart H.

Danco cites post-hoc studies that purportedly

show “various benefits over surgical abortion.”

Danco.BIO.28. Yet “[i]t is a foundational principle of

administrative law that judicial review of agency

action is limited to the grounds that the agency

9

invoked when it took the action.” Dep’t of Homeland

Sec. v. Regents of Univ. of Cal., 140 S. Ct. 1891, 1907

(2020) (cleaned up).

Finally, Danco references a 2008 Government

Accountability Office report that compared FDA’s

approval “processes” for mifepristone with other Subpart H approvals. Danco.BIO.27. But CrossPetitioners have never challenged FDA’s approval

processes for mifepristone. Instead, they have shown

that Subpart H was an improper vehicle for the 2000

Approval. FDA.Pet.App.90a–97a, 160a–172a.

C. The 2000 Approval violated the FDCA and

the APA.

FDA acknowledges that the 2000 Approval must

comply

with

the

FDCA

and

the

APA.

FDA.Pet.App.95a; FDA.BIO.19. But it failed to do so.

The FDCA requires FDA to reject any new drug

application if clinical studies “do not include adequate

tests … to show whether or not such drug is safe for

use under the conditions prescribed … in the proposed

labeling,” 21 U.S.C. 355(d)(1), or if “there is a lack of

substantial evidence that the drug will have the effect

it purports … to have under the conditions of use

prescribed,” id. 355(d)(5). Cf. FDA.BIO.20 (omitting

these requirements when explaining FDA’s FDCA

obligations).

FDA’s 2000 Approval relied on clinical studies that

included (1) ultrasounds to determine gestational age

and identify life-threatening ectopic pregnancies and

(2) an observation period after misoprostol administration. Cross-Pet.30. But the 2000 Approval

included neither of these safeguards. Ibid.

10

As to the first deficiency, FDA argues that the

2000 Approval “explained why an ultrasound requirement was unnecessary”: a doctor could use “other

clinical methods” to determine gestational age and

diagnose ectopic pregnancies. FDA.BIO.21. But FDA

cited no “adequate tests,” 21 U.S.C. 355(d)(1), or

“substantial evidence,” id. 355(d)(5), to support its

conclusory statement. ROA.595. That violates the

FDCA. And FDA’s failure to explain how it could

extrapolate key conclusions about safety without such

data is arbitrary and capricious under the APA. See

Motor Vehicle Mfrs. Ass’n of U.S., Inc. v. State Farm

Mut. Auto. Ins. Co., 463 U.S. 29, 43 (1983).

As to the second shortcoming, FDA excuses the

lack of an observation period after misoprostol administration by noting that its 2000 Approval listed

“[in]adequate access to emergency services” as a

contraindication. FDA.BIO.21. This falls short of a

reasonable explanation. All it does is reinforce CrossPetitioners’ standing by confirming that FDA always

envisioned that emergency room doctors—like CrossPetitioner doctors and association members—would

be a crucial component of the mifepristone regimen.

See Resp’ts.BIO.24–26 (discussing FDA’s position

that emergency room doctors are “critical for the safe”

use of mifepristone).

Danco says Cross-Petitioners did not reference the

lack of an observation period below. Danco.BIO.33.

That’s wrong. The complaint specifically highlighted

that the U.S. clinical trial required women to be

“monitored for four hours for adverse events after

taking misoprostol” and that “FDA’s 2000 Approval

did not require th[is] safeguard[].” ROA.119. The brief

in support of the motion for a preliminary injunction

made this same argument. ROA.1057. And the

11

district court noted this in finding the 2000 Approval

arbitrary and capricious. FDA.Pet.App.173a.

Cross-Petitioners’ argument is simple: FDA must

comply with the FDCA’s stringent requirements for

adequate testing, sufficient information, and substantial evidence of safety and effectiveness under the

labeled conditions of use. 21 U.S.C. 355(d). If FDA’s

action lacks such data, the agency must adequately

explain how it could determine that a drug was nevertheless safe under the conditions for use. State Farm,

463 U.S. at 43. FDA’s characterization of these wellestablished requirements as a “study match” mandate is misplaced. FDA.BIO.20. The problem is that a

discrepancy between the studies and the approved

label exists, yet FDA failed to justify the discrepancy

with additional data or a reasonable explanation.

State Farm, 463 U.S. at 43.

D. The FDAAA provides no refuge for FDA’s

unlawful 2000 Approval.

Abandoning Subpart H, Cross-Respondents turn

to the FDAAA. FDA.BIO.22; Danco.BIO.25. This

statutory amendment provides them no refuge.

The FDAAA “did not approve any drugs. It only

approved [REMS] for those drugs that the FDA had

already validly approved under § 314.520 of Subpart

H,” FDA.Pet.App.96a (Ho, J., concurring and dissenting in part)—and only on a temporary basis. But as

explained above, FDA failed to validly approve

mifepristone under Subpart H. Ibid. So FDAAA does

not help Cross-Respondents.

What’s more, the FDAAA only temporarily

deemed approved drugs to have REMS and required

12

Danco to submit a supplemental drug application that

FDA approved in 2011. That 2011 approval “did not

re-approve the drug apart from Subpart H.”

FDA.Pet.App.97a (Ho, J., concurring and dissenting

in part). Rather, it “made clear that the agency

continued to rely on Subpart H for its approval of

mifepristone.” Ibid. (citing FDA Suppl. Approval

Letter to Danco Labs at 1).

In sum, the FDAAA is not a “glaring vehicle

problem” for Cross-Petitioners. Contra Danco.BIO.24.

It’s a glaring merits problem for FDA and Danco.

III. Cross-Petitioners have standing to challenge the unlawful 2019 Generic Approval.

The 2019 Generic Approval relied on the previous

mifepristone submissions and approvals. CrossPet.31–32. In particular, FDA approved generic mifepristone under the 2016 Major Changes regimen.

Cross-Pet.32. Cross-Petitioners have submitted substantial evidence demonstrating that the 2000 Approval and the 2016 Major Changes have injured and

will continue injuring them. ROA.1226-1294. This

harm flows in part from the approval of generic

mifepristone, which comprises roughly two-thirds of

the chemical abortion market. Cross-Pet.33. This

establishes Cross-Petitioners’ standing to challenge

the 2019 Generic Approval.

In fact, standing to challenge that action exists

doubly so. In addition to the harm to Cross-Petitioners, three states have moved to intervene,

D.Ct.Doc.151, based on evidence showing that the

2019 Generic Approval has injured them,

D.Ct.Doc.151-1 at 2–3, 68 & Exhibits 36, 38. The

district court is poised to rule on that intervention

13

request in December. D.Ct.Doc.159. This is yet

another reason why the interlocutory nature of this

litigation supports denying the petitions and crosspetition.

Once standing is established, the merits of the

challenge to the 2019 Generic Approval rise or fall

with the rest of the case. FDA agrees that CrossPetitioners’ “challenge to the approval of generic

mifepristone is entirely derivative of their challenge

to FDA’s [2000] approval,” meaning if the latter succeeds, so does the former. FDA.BIO.24. Likewise, if the

2016 Major Changes fall, the same fate awaits the

2019 Generic Approval.

CONCLUSION

The petitions should be denied. But if they are

granted, the cross-petition should also be granted.

Respectfully submitted,

JAMES A. CAMPBELL

CODY S. BARNETT

ALLIANCE DEFENDING

FREEDOM

44180 Riverside Pkwy

Lansdowne, VA 20176

(571) 707-4655

NOVEMBER 28, 2023

ERIN M. HAWLEY

Counsel of Record

JOHN J. BURSCH

MATTHEW S. BOWMAN

ERIK C. BAPTIST

ALLIANCE DEFENDING

FREEDOM

440 First Street NW

Suite 600

Washington, DC 20001

(202) 393-8690

ehawley@adflegal.org