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

Nos. 23-235 and 23-236

IN THE

Supreme Court of the United States

————

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

Petitioners,

v.

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

Respondents.

————

DANCO LABORATORIES, L.L.C.,

Petitioner,

v.

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

Respondents.

————

On Writs of Certiorari to the

United States Court of Appeals

for the Fifth Circuit

————

MOTION FOR LEAVE TO FILE BRIEF AND

BRIEF AS AMICI CURIAE OF FORMER

COMMISSIONERS OF THE U.S. FOOD

AND DRUG ADMINISTRATION

IN SUPPORT OF PETITIONERS

————

WILLIAM B. SCHULTZ

Counsel of Record

MARGARET M. DOTZEL

ALYSSA M. HOWARD

ZUCKERMAN SPAEDER LLP

1800 M St. NW

Ste. 1000

Washington, DC 20036

(202) 778-1800

wschultz@zuckerman.com

Counsel for Amici Curiae

WILSON-EPES PRINTING CO., INC. – (202) 789-0096 – WASHINGTON, D.C. 20002

Supreme Court of the United States

___________

No. 23-235

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

PETITIONERS

v.

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

___________

No. 23-236

DANCO LABORATORIES, L.L.C., ET AL., PETITIONER

v.

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

___________

MOTION FOR LEAVE TO FILE

BRIEF OF FORMER FDA COMMISSIONERS

AS AMICI CURIAE

IN SUPPORT OF PETITIONERS

___________

Former commissioners and acting commissioners of

the U.S. Food and Drug Administration (Former FDA

Commissioners)1 respectfully request leave to submit a

brief as amici curiae in support of Petitioners.

Although Former FDA Commissioners recognize

that such motions are not favored, proposed Amici

respectfully submit that the unusual circumstances

here merit the Court’s consideration. Pursuant to

1 Former FDA Commissioners are: David A. Kessler, M.D.; Jane

E. Henney, M.D.; Margaret Hamburg, M.D.; Michael A. Friedman,

M.D.; Joshua M. Sharfstein, M.D.; Stephen Ostroff, M.D.; and

Norman E. “Ned” Sharpless, M.D.

2

Supreme Court Rule 25.1, Petitioners’ merits briefs

were due on January 29, 2024, meaning that amicus

briefs supporting Petitioners would have been due on

February 5 if Petitioners had filed on the deadline. See

S. Ct. R. 37.3. However, Petitioners filed their briefs six

days early, on January 23, and counsel for Amici did

not become aware of this until January 31, 2024. While

counsel for other amici who filed briefs during the

Court’s consideration of the petitions for writs of

certiorari received electronic notice of the filing of

Petitioners’ briefs, Former FDA Commissioners did not

file a brief as amici curiae before the merits stage, and

accordingly, counsel did not receive such electronic

notice. The Court’s acceptance of Former FDA

Commissioners’ amicus brief also will not prejudice any

party, as this proposed brief is filed just two days after

it was due under the Court’s Rules, giving Respondents

ample time to respond to any point raised in the amicus

brief.

Further, Former FDA Commissioners’ proposed

brief draws on their expertise and provides important

information about FDA’s role in monitoring the safety

and efficacy of drugs to help inform the Court’s

consideration

of

the

merits.

Former

FDA

Commissioners are uniquely positioned to explain the

onerous requirements imposed on manufacturers

seeking to market new drugs as well as FDA’s nuanced

approach to considering New Drug Applications and

subsequent modifications to conditions of use. As

physicians, Former FDA Commissioners are also

qualified to explain why FDA’s rigorous scientific

review of mifepristone’s initial approval and

subsequent modifications to its conditions of use merit

deference. Additionally, the amicus brief of Former

FDA Commissioners sets forth the potential

3

catastrophic consequences to public health that would

ensue if the Fifth Circuit’s decision were upheld.

Accordingly,

Former

FDA

Commissioners

respectfully ask the Court to grant them leave to file

this brief as amici curiae.

Respectfully submitted,

WILLIAM B. SCHULTZ

Counsel of Record

MARGARET M. DOTZEL

ALYSSA M. HOWARD

ZUCKERMAN SPAEDER LLP

1800 M St. NW, Ste. 1000

Washington, DC 20036

(202) 778-1800

wschultz@zuckerman.com

mdotzel@zuckerman.com

ahoward@zuckerman.com

February 1, 2024

Counsel for Amici Curiae

i

TABLE OF CONTENTS

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

INTERESTS OF THE AMICI CURIAE ...................... 1

SUMMARY OF THE ARGUMENT ............................. 3

ARGUMENT ................................................................ 5

I.

Congress granted FDA broad authority to

approve drugs and to modify the applicable

postmarketing restrictions. ................................... 5

A. The Agency’s drug approval process

requires rigorous review of available

scientific evidence. ........................................... 6

B. After a drug’s approval, FDA continues

to monitor safety data and retains the

authority to restrict its distribution

through REMS. ................................................ 9

II. After careful review confirming the safety

and efficacy of mifepristone, FDA approved

the drug in 2000. ................................................. 10

III. Consistent with the FDCA and FDA

regulations and mifepristone’s improved

safety profile, FDA amended the drug’s

postmarketing restrictions in 2016 and 2021. ....13

IV. Under the proper standard of review,

which requires significant deference

to FDA’s scientific experts, the challenges

to FDA’s decisions must be rejected. .................. 15

ii

V. FDA’s 2016 changes to mifepristone’s

REMS were not arbitrary and capricious. .......... 18

VI. FDA’s decision not to enforce the

in-person dispensing requirement in 2021

was not arbitrary and capricious. ....................... 21

VII. Allowing the Fifth Circuit’s decision

to stand would upend FDA’s drug approval

system and harm patients. ................................. 22

CONCLUSION ........................................................... 24

iii

TABLE OF AUTHORITIES

CASES

Balt. Gas & Elec. Co. v. NRDC,

462 U.S. 87 (1983) .................................................. 16

FCC v. Prometheus Radio Project,

592 U.S. 414 (2021) ...........................................15, 22

FDA v. Am. Coll. of Obstetricians & Gynecologists,

141 S. Ct. 578 (2021) ................................. 3-4, 17, 20

Michigan v. EPA,

576 U.S. 743 (2015) ...........................................19, 20

Mutual Pharm. Co. v. Bartlett,

570 U.S. 472 (2013) .................................................. 5

NRDC v. U.S. Nuclear Regul. Comm’n,

823 F.3d 641 (D.C. Cir. 2016)................................. 16

Nuclear Energy Inst., Inc. v. EPA,

373 F.3d 1251 (D.C. Cir. 2004)............................... 16

Pharm. Mfg. Rsch. Servs., Inc. v. FDA,

957 F.3d 254 (D.C. Cir. 2020)................................. 17

Schering Corp. v. FDA,

51 F.3d 390 (3d Cir. 1995) ...................................... 17

Serono Labs., Inc. v. Shalala,

158 F.3d 1313 (D.C. Cir. 1998)..........................16, 17

iv

Shrimpers & Fishermen of the RGV v. U.S. Army

Corps of Eng’rs,

56 F.4th 992 (5th Cir. 2023) ................................... 16

Troy Corp. v. Browner,

120 F.3d 277 (D.C. Cir. 1997)................................. 16

ViroPharma, Inc. v. Hamburg,

898 F. Supp. 2d 1 (D.D.C. 2012)............................. 17

Wyeth v. Levine,

555 U.S. 555 (2009) ................................................... 8

Zero Zone, Inc. v. U.S. Dep’t of Energy,

832 F.3d 654 (7th Cir. 2016) .................................. 16

STATUTES

21 U.S.C. § 355(d)..................................................... 5, 6

21 U.S.C. § 355(d)(7) .................................................... 5

21 U.S.C. § 355-1 .......................................................... 9

21 U.S.C. § 355-1(g)........................................................9

21 U.S.C. § 355-1(h)...................................................... 9

Food and Drug Administration Amendments Act of

2007, Pub. L. No. 110-85, Tit. IX, 121 Stat. 922:

§ 901, 121 Stat. 922 .............................................. 9

§ 909(b), 121 Stat. 950-951 (21 U.S.C. note) ........ 9

v

REGULATIONS

21 C.F.R. § 201.56 ........................................................ 5

21 U.S.C. § 201.57 ........................................................ 5

21 C.F.R. § 314.50 ........................................................ 5

21 C.F.R. § 314.70(c)(6)(iii)(A) ...................................... 8

21 C.F.R. § 314.80......................................................... 7

21 C.F.R. § 314.80(b) .................................................... 7

21 C.F.R. § 314.80(c)..................................................... 8

21 C.F.R. § 314.105(c) .................................................. 5

21 C.F.R. § 314.126 ...................................................... 5

21 C.F.R. § 314.500 .................................................. 8, 9

21 C.F.R. § 314.520 ...................................................... 9

Final Rule: New Drug, Antibiotic, and Biological

Drug Product Regulations; Accelerated Approval,

57 Fed. Reg. 58,942 (Dec. 11, 1992) ......................... 9

OTHER AUTHORITIES

Claudia Diaz Olavarrieta et al., Nurse versus

physician-provision of early medical abortion

in Mexico: a randomized controlled

non-inferiority trial, 93 Bull World Health

Organ 249 (2015) .................................................... 20

vi

Cong. Budget Off., Research and Development

in the Pharmaceutical Industry (Apr. 2021).......... 24

Daniel Grossman et al., Effectiveness and

Acceptability of Medical Abortion Provided through

Telemedicine, 118 Obstetrics & Gynecology 296

(2011)........................................................................18

Rachel K. Jones et al.,

The Public Health Implications of the FDA

Update to the Medication Abortion Label,

Guttmacher Inst. (June 30, 2016) ............................ 8

Elizabeth G. Raymond et al.,

The Comparative Safety of Legal Induced

Abortion and Childbirth in the United States,

119 Obstetrics & Gynecology 215 (2012) ............... 18

Rachel Roubein et al.,

Abortion Pill Fight May Have

Broader Implications for FDA Drug Approval,

Wash. Post (Mar. 15, 2023) ...................................... 7

Gilda Sedgh et al.,

Mifepristone for Abortion in a Global Context:

Safe, Effective and Approved in Nearly 100

Countries, Guttmacher Inst. .................................. 12

Katie Thomas,

The Unseen Survivors of

Thalidomide Want to Be Heard,

New York Times (Mar. 23, 2020) ............................. 3

U.S. Food & Drug. Admin.,

Risk Evaluation and Mitigation Strategy (REMS)

vii

Single Shared System for Mifepristone

200 mg (Jan. 2023)...................................................15

U.S. Gov’t Accountability Off., Food and Drug

Administration: Approval and

Oversight of the Drug Mifeprex,

GAO-08-751 (Aug. 2008).............................. 10, 11, 12

U.S. Gov’t Accountability Off., Food and Drug

Administration: Information on Mifeprex

Labeling Changes and Ongoing Monitoring Efforts,

GAO-18-292 (Mar. 2018) .............................18, 19, 21

U.S. Gov’t Pub’g Off., RU-486: Demonstrating a Low

Standard for Women’s Health?: Hearing Before the

Subcomm. on Crim. Just., Drug Pol’y, & Hum. Res.

of the H. Comm. on Gov’t Reform, 109th Cong.

(2006) ...................................................................... 11

Paul M. Wax,

Elixirs, Diluents, and the Passage of the 1938

Federal Food, Drug and Cosmetic Act,

122 Annals Internal Med. 456 (1995) ...................... 2

Supreme Court of the United States

___________

No. 23-235

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

PETITIONERS

v.

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

___________

No. 23-236

DANCO LABORATORIES, L.L.C., ET AL., PETITIONER

v.

ALLIANCE FOR HIPPOCRATIC MEDICINE, ET AL.,

___________

BRIEF OF FORMER FDA COMMISSIONERS

AS AMICI CURIAE

IN SUPPORT OF PETITIONERS

___________

INTERESTS OF THE AMICI CURIAE1

Amici served as commissioners and acting

commissioners of the U.S. Food and Drug

Administration (FDA or the Agency) and place a high

Pursuant to Supreme Court Rule 37.3, counsel for Amici

certify that: No party’s counsel authored this amicus brief in whole

or in part; no party or party’s counsel contributed money that was

intended to fund preparing or submitting this amicus brief; and

no person or entity, other than Amici or their counsel, contributed

money intended to fund the preparation or submission of this

amicus brief. This brief represents the views of the individual

Amici and not necessarily of their organizations.

1

2

value on the regulatory framework that provides

patients access to critical drugs and vaccines. By

second-guessing FDA’s evaluation of scientific data,

the Fifth Circuit’s decision threatens to undermine the

complex, evidence-based drug approval process that

Amici oversaw during their time leading the Agency

and that exists today. As experts in the drug approval

process, Amici are qualified to explain how the Fifth

Circuit fundamentally misunderstood the science of

FDA’s approval and subsequent actions with respect to

mifepristone. Amici will also describe how the Fifth

Circuit’s decision, if allowed to stand, would harm

patients that rely on FDA-approved drugs to treat

serious diseases by allowing courts to second-guess

FDA’s evaluation of scientific evidence supporting the

approval of new drug applications or modifications of

those approvals.

Amici are:



David A. Kessler, M.D., Commissioner

(1990–1997)



Jane E. Henney, M.D., Commissioner

(1999–2001)



Margaret Hamburg, M.D., Commissioner

(2009–2015)



Michael A. Friedman, M.D., Acting

Commissioner (1997–1999)



Joshua M. Sharfstein, M.D., Acting

Commissioner (2009)

3



Stephen Ostroff, M.D., Acting

Commissioner (2015–2016, 2017)



Norman E. “Ned” Sharpless, M.D.,

Acting Commissioner (2019)

SUMMARY OF THE ARGUMENT

For more than 60 years, Congress has trusted FDA

to ensure that companies demonstrate the safety and

efficacy of new drugs before they reach the market. And

for good reason. Congress first passed the Federal

Food, Drug, and Cosmetic Act of 1938 after more than

100 people died due to toxic ingredients in elixir

sulfanilamide. This tragedy illustrated the dangers of

an unregulated drug market and led Congress to

empower FDA to serve as a gatekeeper requiring that

new drugs be proven safe before they can be marketed.2

Nearly 25 years later (in 1962) after the drug

thalidomide caused serious birth defects, Congress

expanded FDA’s authority by requiring drug

companies to prove to FDA that their drugs are

effective.3

Today, every FDA decision to approve a drug is

supported by hundreds of scientific judgments made by

a team of experts, which includes physicians, chemists,

Paul M. Wax, Elixirs, Diluents, and the Passage of the 1938

Federal Food, Drug and Cosmetic Act, 122 Annals Internal Med.

456 (1995).

2

Katie Thomas, The Unseen Survivors of Thalidomide Want to

Be

Heard,

New

York

Times

(Mar.

23,

2020),

https://www.nytimes.com/2020/03/20/health/thlidomide-survirosusa.html.

3

4

biologists, pharmacologists, and statisticians. To

determine whether a drug meets the standard

established by Congress, these experts typically must

review a massive quantity of data submitted by the

sponsor of the New Drug Application (NDA), including

complex clinical studies. The Agency’s final decision

regarding whether to approve any drug results from

this careful process—often occurring over several years

and always involving numerous scientific judgments by

experts. Once a drug is approved, its sponsor and FDA

both continue to monitor safety and efficacy data to

determine if any changes in the conditions of approval

are warranted.

This case does not involve FDA’s interpretation of

applicable law, and there is no dispute about the legal

standard that FDA applied in approving the drug at

issue here. Instead, the dispute involves FDA’s

evaluation of the scientific data submitted to support

the approval of a new drug application. As this Court

has recognized, judicial review of an administrative

agency’s action based on the agency’s evaluation of

technical evidence is extremely deferential, and a court

may not second-guess an agency’s judgment unless the

agency’s decision is arbitrary and capricious. In

applying this standard, the court’s role is to determine

whether the agency’s decision was “reasonable and

reasonably explained.” See FCC v. Prometheus Radio

Project, 592 U.S. 414, 423 (2021); see also FDA v. Am.

Coll. of Obstetricians & Gynecologists, 141 S. Ct. 578,

579 (2021) (Roberts, C.J., concurring).

In this case, instead of reviewing FDA’s 2016 and

2021 modifications to mifepristone’s postmarketing

restrictions under this firmly established standard, the

5

Fifth Circuit substituted its own opinions about the

scientific data for the expert judgments of FDA

clinicians and scientists, and on that basis overturned

FDA’s reasoned, evidence-based decisions.

This unprecedented decision turns Congress’s

desired regulatory scheme on its head and opens the

door to constant legal challenges of drug approval

decisions. If permitted to stand, the Fifth Circuit’s

approach would allow courts to substitute their lay

analysis for FDA’s scientific expertise and to overturn

the Agency’s approval and conditions of use for drugs—

even after they have been on the market for decades.

The resulting uncertainty would threaten the

incentives for drug companies to undertake the timeconsuming and costly investment required to develop

new drugs and ultimately hinder patients’ access to

critical remedies that prevent suffering and save lives.

ARGUMENT

I.

Congress granted FDA broad authority to

approve drugs and to modify the applicable

postmarketing restrictions.

FDA is the expert agency that Congress has tasked

with reviewing and approving drugs according to

established scientific principles. FDA reviewers

include doctors, pharmacologists, chemists, biologists,

and statisticians—all with advanced degrees in their

respective disciplines—who review every aspect of an

NDA submitted by a sponsor. Through FDA’s

consideration of each NDA, its reviewers make

hundreds of scientific judgments that lead the Agency

to an ultimate decision whether to approve or deny the

6

application. Further, once an NDA is approved, the

Agency continues to monitor the drug’s safety and

efficacy.

A.

The Agency’s drug approval process

requires rigorous review of

available scientific evidence.

In order for a new drug to be approved, the Federal

Food, Drug, and Cosmetic Act (FDCA) directs FDA to

determine whether the sponsor’s application contains

evidence demonstrating that the drug is safe and

effective for its intended use, based on “adequate and

well-controlled investigations.” 21 U.S.C. § 355(d); see

21 C.F.R. §§ 314.50, 314.105(c). FDA has promulgated

regulations describing the requirements for clinical

investigations that meet the statutory standard and

the labeling requirements for approved drugs. See 21

C.F.R. §§ 201.56, 201.57, 314.50, 314.126. Congress

requires that FDA conduct a careful risk-benefit

analysis in considering each NDA “to facilitate the

balanced consideration of benefits and risks, a

consistent and systematic approach to the discussion

and

regulatory

decisionmaking,

and

the

communication of the benefits and risks of new drugs.”

21 U.S.C. § 355(d)(7); see also Mutual Pharm. Co. v.

Bartlett, 570 U.S. 472, 476 (2013) (“In order for the

FDA to consider a drug safe, the drug’s ‘probable

therapeutic benefits must outweigh its risk of harm.’”).

FDA imposes complex, rigorous standards in its

review of NDAs and requires drug sponsors to

demonstrate the drug’s safety and efficacy through

rigorous scientific studies, including laboratory and

pre-clinical testing as well as three separate phases of

7

clinical studies (with the later phase studies usually

including several thousand patients). Further, drug

sponsors must demonstrate that the methods used in,

and the facilities used for, the manufacturing,

processing, and packaging of the drug are adequate to

“preserve its identity, strength, quality, and purity.” 21

U.S.C. § 355(d). FDA’s scientific and medical experts

receive information from and confer with the drug

sponsor throughout the development and approval

process. Because of the high statutory standard, many

NDAs are never approved.

Under the FDCA and FDA regulations, the

conditions and indications on a drug’s approved label

are not required to be identical to the conditions under

which the drug was studied. Further, as FDA has

explained, “[m]any clinical trial designs are more

restrictive * * * than will be necessary or recommended

in post-approval clinical use; this additional level of

caution is exercised until the safety and efficacy of the

product is demonstrated.” J.A. 265. Consistent with

scientific best practices and medical ethics, conditions of

use for approved drugs frequently differ from clinical

trial protocols. For example, although biopsies were

required in clinical trials for menopause hormonal

therapy drugs to protect trial participants until safety

was established, once FDA approved those drugs as

safe and effective, such mandated biopsies were no

longer required and would have been impractical. J.A.

265.

Industry members and consumers around the world

regard FDA’s rigorous review of NDAs as the “gold

8

standard” in ensuring drug safety and efficacy.4 For

this reason, FDA’s approval of a new drug promotes its

uptake and acceptance. Drug companies look to the

consistency, clarity, and predictability of FDA’s drug

review and approval processes to inform future

investments in developing new drugs and vaccines.

After a product is approved and used by larger

numbers of people, its safety profile may change.

Accordingly, the NDA sponsor is required to monitor

the drug’s safety and report adverse events to FDA. See

21 C.F.R. § 314.80. Specifically, the drug sponsor “must

promptly review all adverse drug experience

information obtained or otherwise received by

the applicant from any source, foreign or domestic,

including information derived from commercial

marketing experience,

postmarketing

clinical

investigations, * * * reports in the scientific literature,

and unpublished scientific papers.” Id. § 314.80(b).

Further, the regulation requires that the drug sponsor

“develop written procedures for the surveillance,

receipt, evaluation, and reporting of postmarketing

adverse drug experiences to FDA.” Id. The regulation

also requires that sponsors, manufacturers, packers,

and distributors report serious, unexpected adverse

experiences to FDA within 15 days and submit

quarterly adverse drug experience reports. Id. §

314.80(c).

See Rachel Roubein, Laurie McGinley & David Ovalle,

Abortion Pill Fight May Have Broader Implications for FDA Drug

Approval,

Wash.

Post

(Mar.

15,

2023),

https://www.washingtonpost.com/health/2023/03/15/abortion-pillfda/.

4

9

Thus, the law places considerable responsibility on

manufacturers to assure the continued safety of their

drugs. For example, when new information about the

safety of a drug becomes available, FDA’s regulations

permit the manufacturer to add information to the

drug’s label without the Agency’s approval. See 21

C.F.R. § 314.70(c)(6)(iii)(A); Wyeth v. Levine, 555 U.S.

555 (2009). In addition, FDA regularly evaluates the

safety reports it receives. Sometimes after reviewing

new safety data, FDA requires that a drug be

withdrawn from the market. Sometimes (as with

mifepristone) the safety profile of the drug improves.5

B.

After a drug’s approval, FDA

continues to monitor safety data and

retains the authority to restrict its

distribution through REMS.

In 1992, FDA promulgated regulations for drugs

intended to treat “serious or life-threatening illnesses”

that “provide[d] meaningful therapeutic benefit to

patients over existing treatments.” 21 C.F.R. § 314.500,

Subpart H. The Subpart H regulations authorized FDA

See Rachel K. Jones & Heather D. Boonstra, The Public

Health Implications of the FDA Update to the Medication Abortion

Label,

Guttmacher

Inst.

(June

30,

2016),

https://www.guttmacher.org/article/2016/06/public-healthimplications-fda-update-medication-abortion-label

(explaining

that FDA’s 2016 changes to mifepristone’s conditions of use were

supported by substantial evidence gathered since the drug’s initial

approval in 2000).

5

10

to impose conditions needed “to assure safe use,”

including distribution restrictions.6

In 2007, Congress ratified and expanded on Subpart

H. Food and Drug Administration Amendments Act

(FDAAA) of 2007, 21 U.S.C. § 355-1; see FDAAA, Pub.

L. No. 110-85, Tit. IX, § 901, 121 Stat. 922. These

amendments authorized the Agency to require a “risk

evaluation and mitigation strategy” (REMS) when it

finds that restrictions on use are necessary to meet

FDA’s safety and efficacy standards, which apply to

every drug. Id.

Under the FDAAA, any conditions needed “to assure

safe use” established under Subpart H were

automatically converted to a REMS with the same

restrictions. Id. § 909(b), 121 Stat. at 950-51 (21 U.S.C.

§ 331 note). When FDA determines that new

requirements are needed to assure safe use or that

existing requirements are no longer necessary, FDA

may modify a drug’s approved REMS. Id. §§ 355-1(g),

(h).

II.

After careful review confirming the safety

and efficacy of mifepristone, FDA approved

the drug in 2000.

In 2000—after an intensive review spanning more

than four years, at least 92 submissions by the drug

sponsor, and a unanimous advisory committee vote in

favor of approval—FDA approved mifepristone (under

the brand name Mifeprex®) as safe and effective to

Final Rule: New Drug, Antibiotic, and Biological Drug Product

Regulations; Accelerated Approval, 57 Fed. Reg. 58,942, 58,958

(Dec. 11, 1992) (codified at 21 C.F.R. §§ 314.500, 314.520).

6

11

terminate pregnancy through the first seven weeks of

gestation. J.A. 224–232. Pursuant to its authority

under Subpart H, FDA placed restrictions on the drug’s

distribution, including a requirement that mifepristone

be dispensed in person by or under the supervision of a

physician with specified qualifications. Ibid.

Mifepristone’s approval complied with the statute’s

evidentiary standard. FDA scientific and medical

experts comprehensively reviewed the totality of

scientific evidence and concluded that, with those

distribution restrictions in place, the benefits of

mifepristone outweighed its risks. In reaching this

conclusion, FDA experts performed an exhaustive

review of large volumes of clinical trial data across

three rounds of review over the course of more than

four years.7 Mifepristone’s approval was carried out

using the process Congress created and FDA has been

implementing since its enactment more than 60 years

ago. If anything, the external pressure and sensitivity

surrounding the approval of mifepristone resulted in

FDA taking particular care because the Agency knew

that the drug’s approval would face scrutiny.8 In 2008,

See generally U.S. Gov’t Accountability Off., Food and Drug

Administration: Approval and Oversight of the Drug Mifeprex,

GAO-08-751 (Aug. 2008) (“GAO-08-751”).

7

FDA was correct to assume that its approval of mifepristone

would be scrutinized. Immediately after the 2000 Approval,

several groups filed a citizen petition seeking reversal of the

decision. See J.A. 201–223. In 2006, there was a Congressional

hearing on the approval. See U.S. Gov’t Publ’g Off., RU-486:

Demonstrating a Low Standard for Women’s Health?: Hearing

Before the Subcomm. on Crim. Just., Drug Pol’y, & Hum. Res. of

the H. Comm. on Gov’t Reform, 109th Cong. (2006). In 2008, the

8

12

the U.S. Government Accountability Office (GAO)

confirmed that FDA’s review and approval of

mifepristone was consistent with the processes for

other Subpart H drugs, recognizing that the details of

FDA’s approval depended on the unique risks and

benefits of each drug.9

In its initial review, FDA compared the results of

three mifepristone clinical trials—two from France and

one from the United States—to reliable, welldocumented data on pregnancy, including rates of

miscarriage.10 These trials included more than 4,000

patients across the different studies.11

FDA also convened an advisory committee of

reproductive health drug experts to evaluate the data

on mifepristone.12 That committee voted six to zero,

with two abstentions, that the benefits of mifepristone

U.S. Government Accountability Office issued its comprehensive

review of the 2000 approval and oversight of mifepristone,

concluding that there were no irregularities. See GAO-08-751.

9

GAO-08-751 at 6.

Id. at 15–16. By the time FDA approved mifepristone in 2000,

the drug had already been approved for use in many other

countries. Mifepristone had been approved in France, China, and

the United Kingdom in the late 1980s and early 1990s, and by

1999, nearly a dozen more countries had followed suit. Today,

mifepristone is available in at least 94 other countries. See Gilda

Sedgh & Irum Taqi, Mifepristone for Abortion in a Global Context:

Safe, Effective and Approved in Nearly 100 Countries, Guttmacher

Inst., https://www.guttmacher.org/2023/07/mifepristone-abortionglobal-context-safe-effective-and-approved-nearly-100-countries.

10

11

Id.

12

Id. at 16–17.

13

outweigh its risks and seven to zero, with one

abstention, that mifepristone is safe.13

As is often the case, FDA did not approve

mifepristone after the sponsor’s initial submission.

Instead, FDA denied approval twice to require and

evaluate additional data and information from the

drug sponsor. After completing those evaluations, FDA

concluded, based on its own comprehensive review of

the

data

and

the

advisory

committee’s

recommendations, that mifepristone was safe and

effective for use in terminating early-stage pregnancies

subject to certain distribution restrictions.

III.

Consistent with the FDCA and FDA

regulations and mifepristone’s improved

safety profile, FDA amended the drug’s

postmarketing restrictions in 2016 and 2021.

The subsequent modifications to mifepristone’s

approved conditions of use were also driven by a

straightforward and thorough application of the expert

scientific review process that Congress entrusted to

FDA. In May 2015, Danco Laboratories, L.L.C.

(“Danco”), the drug’s sponsor, submitted a

supplemental new drug application proposing changes

to mifepristone’s conditions of use, which was approved

by the Agency in March 2016, following a

comprehensive scientific review by numerous FDA

scientific and medical experts who examined 16 years

of experience with mifepristone, guidelines from

professional organizations here and abroad, and

clinical trials that had been published in the peer13

Id.

14

reviewed medical literature since the drug’s approval.

J.A. 284–291.

Relying on safety and efficacy data from more than

20 studies, FDA increased the gestational age limit

from seven to ten weeks. J.A. 283–291, 298–300, 450–

456. Relying on an additional dozen studies, FDA also

reduced the number of required in-person clinical visits

from three to one, allowing patients to self-administer

misoprostol at home. J.A. 300–302, 456–457. Based on

five studies including more than 3,000 patients, FDA

modified the REMS to allow the sponsors to distribute

the drug to a broader set of healthcare providers,

rather than only physicians, to prescribe and dispense

mifepristone. J.A. 309–310, 461–462.

Finally, FDA modified a prior requirement that

prescribers of mifepristone report certain non-fatal

adverse events such as hospitalizations and blood

transfusions to Danco. J.A. 319. After considering 15

years of adverse event reporting since mifepristone’s

approval in 2000, which demonstrated the drug’s

safety, FDA found that the reporting of serious adverse

events other than death could instead be “collected in

the periodic safety update reports and annual reports”

submitted by the drug’s sponsor to FDA as it generally

requires for other prescription drugs. Ibid. This change

did not impact reporting requirements for Danco,

which remain unchanged, supra Part I.A; instead it

eliminated some, but not all, of the reporting

requirements for prescribers, which typically are not

required for prescription drugs.

In 2021, during the COVID-19 pandemic public

health emergency, after conducting a thorough review

15

of the relevant data, FDA exercised its enforcement

discretion with respect to the in-person dispensing

requirement in mifepristone’s REMS. FDA determined

that the available data and information, including

studies regarding the use of telehealth, supported

modification of the REMS to reduce the burden on the

health care delivery system and to ensure that the

benefits of the product outweighed its risks. J.A. 377.

Then, following another thorough review by multiple

scientists, FDA amended mifepristone’s REMS on

January 3, 2023 to remove the in-person dispensing

requirement.14

IV.

Under the proper standard of review, which

requires significant deference to FDA’s

scientific experts, the challenges to FDA’s

decisions must be rejected.

In reviewing FDA’s approval of mifepristone, the

courts below did not review FDA’s interpretation of a

law. Instead, they reviewed FDA’s scientific evaluation

of the studies and other data supporting the Agency’s

modifications of mifepristone’s conditions of use in

2016 and 2021. In finding that Respondents were likely

to prevail on the merits of their APA claims, the Fifth

Circuit misapplied the well-established arbitrary and

capricious standard and failed to give FDA the

requisite deference. See, e.g., Prometheus, 592 U.S. at

423. Under this standard, the courts’ role is to

14

See U.S. Food & Drug Admin., Risk Evaluation and

Mitigation Strategy (REMS) Single Shared System for

Mifepristone

200

mg

(Jan.

2023),

https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifepristo

ne_2023_01_03_REMS_Full.pdf.

16

ascertain whether agency decisions were “reasonable

and reasonably explained.” Id. As long as “the agency

has acted within a zone of reasonableness,” the

administrative action must be upheld. Id.

The scope of judicial review in assessing an

agency’s evaluation of data is even narrower when an

agency action is based on its analysis of scientific

evidence. Where a court reviews an agency’s decision

based on “scientific data within its technical expertise,”

the arbitrary and capricious standard of review is

“extreme[ly] deferential.” Nuclear Energy Inst., Inc. v.

EPA, 373 F.3d 1251, 1289 (D.C. Cir. 2004) (citation

omitted); see also Shrimpers & Fishermen of the RGV

v. U.S. Army Corps of Eng’rs, 56 F.4th 992, 1001 (5th

Cir. 2023)

The reason for this deference is clear: Courts ensure

agencies’ compliance with the law, but they are illequipped to second-guess the technical judgments of an

agency within the scope of its subject-matter expertise.

Troy Corp. v. Browner, 120 F.3d 277, 283 (D.C. Cir.

1997) (citation omitted) (explaining that courts “review

scientific judgments of the agency not as the chemist,

biologist, or statistician that we are qualified neither

by training nor experience to be, but as a reviewing

court exercising our narrowly defined duty of holding

agencies to certain minimal standards of rationality”)

(internal citation and quotation marks omitted). In

other words, judges are not “scientists independently

capable of assessing the validity of the agency’s

determination.” Serono Labs., Inc. v. Shalala, 158 F.3d

1313, 1327 (D.C. Cir. 1998); see also Balt. Gas & Elec.

Co. v. NRDC, 462 U.S. 87, 103 (1983); NRDC v. U.S.

Nuclear Regul. Comm’n, 823 F.3d 641, 649 (D.C. Cir.

17

2016); Zero Zone, Inc. v. U.S. Dep’t of Energy, 832 F.3d

654, 668 (7th Cir. 2016).

Here, “judgments as to what is required to ascertain

the safety and efficacy of drugs fall squarely within the

ambit of the FDA’s expertise and merit deference” from

reviewing courts. See Schering Corp. v. FDA, 51 F.3d

390, 399 (3d Cir. 1995); see also FDA v. Am. Coll. of

Obstetricians & Gynecologists, 141 S. Ct. 578, 579

(2021) (Roberts, C.J., concurring) (“[C]ourts owe

significant deference to the politically accountable

entities with the ‘background, competence, and

expertise to assess public health.’”); Pharm. Mfg. Rsch.

Servs., Inc. v. FDA, 957 F.3d 254, 262 (D.C. Cir. 2020).

Serono is instructive. 158 F.3d at 1327. In that case,

the D.C. Circuit rejected the district court’s reversal of

FDA’s drug approval, explaining that, in evaluating a

technical decision of an agency based on scientific data,

the court’s role was limited to “holding [FDA] to the

standards of rationality required by the Administrative

Procedure Act.” Id. Indeed, insofar as can be

determined, no court has ever restricted access of an

FDA-approved

drug

by

invalidating

FDA’s

modification of a drug approval, as the Fifth Circuit did

here. See, e.g., ViroPharma, Inc. v. Hamburg, 898 F.

Supp. 2d 1, 5, 28–29 (D.D.C. 2012) (citing Serono, 158

F.3d at 1327) (“To the best of the parties’ and the

Court’s knowledge, the extraordinary relief that

[plaintiff] seeks is unprecedented in this jurisdiction.”).

Further, the only two district courts to overturn FDA

drug approvals were each reversed by the D.C. Circuit

and Fifth Circuit, respectively. See Serono, 158 F.3d at

1327; Pet. App. 1a–110a.

18

Here, in finding that Respondents would likely

prevail in their challenges to the 2016 and 2021

changes to mifepristone’s REMS, the Fifth Circuit

ignored important parts of the administrative record

and the correct standard of review. When the proper

standard of review is applied, the challenges to FDA’s

decisions must be dismissed.

V.

FDA’s 2016 changes to mifepristone’s REMS

were not arbitrary and capricious.

The Fifth Circuit erred in finding that FDA’s

modifications of the mifepristone’s REMS in 2016—

increasing the gestational age limit, reducing the

number of required clinic visits, expanding the types of

providers who could prescribe, and removing the

requirement that prescribers report non-fatal adverse

events to FDA—were likely arbitrary and capricious.

Before approving the changes to mifepristone’s

conditions of use and relabeling the drug, Agency

experts reviewed more than 20 years of data from

around the world demonstrating mifepristone’s safety

and efficacy.15 These studies, which included more

than 45,000 patients, demonstrated the efficacy and

safety of the proposed changes to mifepristone’s

labeling.16 For example, a literature review of 87

studies concluded that home use of misoprostol did not

lead to increased rates of treatment failure or serious

U.S. Gov’t Accountability Off., Food and Drug Administration:

Information on Mifeprex Labeling Changes and Ongoing

Monitoring Efforts at 16, GAO-18-292 (Mar. 2018) (“GAO-18292”).

15

16

Id. at 12–16.

19

complications.17 Additional studies confirmed that the

risk associated with taking mifepristone was very

low.18 FDA also reviewed 15 years of adverse event

reporting from the drug’s approval in 2000 through

November 17, 2015. During that time period, there

were 17 reported deaths associated with mifepristone,

eight of which were associated with sepsis.19 Further,

this data showed that “the rates of hospitalizations,

severe infections, blood loss requiring transfusion, and

complications related to ectopic pregnancy remained

stable and acceptably low.”20

Although the Fifth Circuit correctly recognized that

FDA was not required to rely on studies with matching

conditions of use to those set forth in the 2016 REMS,

supra Part I.A, the court effectively imposed such a

requirement when it found that the 2016 changes

likely violated the Administrative Procedure Act

because FDA failed to consider the effect of all the

changes “as a whole.” Pet. App. 53a. The Fifth Circuit’s

analysis misapprehends the applicable legal standard

and ignores the administrative record. First, the Fifth

Circuit adopted the erroneous reasoning of the district

court opinion, which cited Michigan v. EPA, a case

Id. at 14 (citing Elizabeth G. Raymond and David A. Grimes,

The Comparative Safety of Legal Induced Abortion and Childbirth

in the United States, 119 Obstetrics & Gynecology 215 (2012)).

17

18

See id. (citing Daniel Grossman et al., Effectiveness and

Acceptability of Medical Abortion Provided through Telemedicine,

118 Obstetrics & Gynecology 296 (2011)).

GAO-18-292 at 17 (explaining that “[s]even of the 8 sepsis

cases were associated with vaginal use of misoprostol, which was,

but no longer is, a common practice, according to FDA”).

19

20

Id.

20

reviewing an agency’s interpretation of its enabling

statute—not the agency’s evaluation of scientific

evidence before it. 576 U.S. 743 (2015). The scope of

judicial review that this Court articulated in Michigan

v. EPA is distinct from the extremely deferential

standard that applies to an agency’s evaluation of

scientific data. See, e.g., Am. Coll. of Obstetricians &

Gynecologists, 141 S. Ct. at 579 (2021) (Roberts, C.J.,

concurring) (“[C]ourts owe significant deference to the

politically accountable entities with the ‘background,

competence, and expertise to assess public health.’”).

Further, the Fifth Circuit ignored the portions of

the record which showed that FDA did consider the

cumulative effect of the changes through at least three

studies that implemented multiple changes at once.21

This demonstrates that FDA did consider the

cumulative safety of the amendments to mifepristone’s

REMS.

The Fifth Circuit likewise erred in finding that

FDA’s 2016 removal of the non-fatal adverse event

reporting requirement for prescribers was likely

arbitrary and capricious. A review of the

administrative record confirms that this change was

also supported by ample evidence. As GAO recognized

in a review of mifepristone’s labeling changes and

FDA’s continuous safety monitoring in 2018, the

See, e.g., J.A. 299 n.1, 3, 4 (citing studies applying at least

three of the challenged 2016 changes). One cited study

implemented all changes except the removal of the FAERS

reporting requirement. See J.A. 299 n.4 (citing Claudia Diaz

Olavarrieta et al., Nurse versus physician-provision of early

medical abortion in Mexico: a randomized controlled noninferiority trial, 93 Bull World Health Organ 249 (2015)).

21

21

Agency relied on 15 years of periodic adverse event

reports as well as studies demonstrating that the

proposed changes did not significantly change

mifepristone’s risk profile.22

VI.

FDA’s decision not to enforce the in-person

dispensing requirement in 2021 was not

arbitrary and capricious.

FDA also acted reasonably in 2021 when it relied on

available data to remove mifepristone’s in-person

dispensing requirement. Just as it had before re-labeling

mifepristone in 2016, the Agency undertook a rigorous

analysis of the evidence before changing the drug’s

REMS. FDA required data from mifepristone’s sponsors

to support its decision and also relied on “an extensive

review of the published literature,” which was

summarized in the administrative record. See J.A. 399–

408. Further, FDA concluded from its review of the

available data that there was no evidence of “a difference

in adverse events when in-person dispensing was and

was not enforced.” J.A. 399; see J.A. 398–408.

The Fifth Circuit compounds its error by deeming

FDA’s analysis of adverse event data insufficient to

support the 2021 change due to the “uncontested

limitations” of the FDA Adverse Event Reporting

System (FAERS) database. See Pet App. 59a. The court

incorrectly suggested that there was no mandatory

adverse event reporting system for mifepristone after

2016. Pet. App. 59a–63a. To the contrary, the 2016

changes implemented for mifepristone the same

reporting system required for all other approved drugs.

22

See GAO-18-292 at 17.

22

Accordingly, since 2016, FDA has continually received

and monitored data about serious adverse events

through the FAERS database for mifepristone. This is

confirmed by the fact that, as the Fifth Circuit pointed

out, “Danco’s data was exactly the same as the data FDA

obtained from FAERS.” Pet. App. 61a. Further, as

previously explained, supra Part III, the 2016 REMS

only removed prescribers’ requirement to report nonfatal adverse events to FDA. The Fifth Circuit’s

questions about the reliability of FAERS data are far

beyond the scope of judicial review of an agency’s

evaluation of scientific data and amount to an

inappropriate attempt to “substitute its own policy

judgment for that of the agency.” See Prometheus, 592

U.S. at 423.

VII.

Allowing the Fifth Circuit’s decision to stand

would upend FDA’s drug approval system

and harm patients.

The Fifth Circuit’s opinion flips Congress’s chosen

scheme on its head—subjecting scientific decisions by

FDA’s expert doctors, pharmacologists, chemists,

biologists, and statisticians to unscientific secondguessing by courts. Every time FDA modifies the

postmarketing restrictions for an approved drug, it is

the product of hundreds of scientific judgments,

including analysis of clinical trial data, examination of

experimental controls, and interpretation of adverse

event reports. Opening each of these judgments up to

fresh review by courts would supplant this rational,

evidence-based drug regulatory scheme with a chaotic

patchwork susceptible to endless legal challenges and

inconsistent outcomes.

23

Further, adopting the Fifth Circuit’s approach—

which expands the scope of judicial review to allow

courts to upend the scientific judgments of Agency

experts—would open the door to the re-litigation of

drug approvals by many interested parties. Drug

companies seeking to protect their investments and

potential future profits could challenge the approval of

a competitor’s drug by challenging one of the many

scientific judgments that go into each drug approval.

After the denial of an NDA, companies could also use

the courts to obtain reversal of FDA’s scientific

judgments. Interest groups that question the use of

drugs for certain conditions could sue to have their

approval revoked or to require application of

unnecessary restrictions. Organizations representing

patients who experience rare adverse events could

challenge FDA’s risk-benefit analyses and attempt to

bar access to safe and effective remedies for others who

need them.

This new paradigm would take a significant toll on

public health. Successful litigation challenging drug

approvals could threaten patient access to necessary

drugs and vaccines. It would also adversely impact the

effectiveness of healthcare providers who rely on FDA

approval when making critical treatment decisions. At

the same time, drug companies unhappy with FDA’s

denial of their new drug applications could seek court

rulings that would risk allowing the introduction of

unsafe drugs into the market.

Further, this new patchwork system for evaluating

drug safety and efficacy would chill crucial investment

in pharmaceutical research and the development of

new medications. As it is, drug development is a risky,

24

cost-intensive proposition: Research and development

costs for each new drug can reach upwards of $2 billion,

and only about 12% of drugs that undergo clinical trials

are ultimately approved.23 As a result of the Fifth

Circuit’s approach, even the relatively few drugs that

attain FDA approval would be perpetually susceptible

to legal challenges to applicable conditions of use—

discouraging companies from investing in new lifesaving remedies. The Fifth Circuit’s approach upends

the regulatory framework designed by Congress that

has produced essential drugs for more than 60 years.

Patients in need will ultimately bear the catastrophic

consequences of the resulting instability.

CONCLUSION

The Court should reverse the Fifth Circuit’s

judgment.

See Cong. Budget Off., Research and Development in the

Pharmaceutical

Industry

at

2

(Apr.

2021),

https://www.cbo.gov/publication/57126.

23

25

Respectfully submitted,

WILLIAM B. SCHULTZ

Counsel of Record

MARGARET M. DOTZEL

ALYSSA M. HOWARD

ZUCKERMAN SPAEDER LLP

1800 M St. NW, Ste. 1000

Washington, DC 20036

(202) 778-1800

wschultz@zuckerman.com

mdotzel@zuckerman.com

ahoward@zuckerman.com

Counsel for Amici Curiae

February 1, 2024