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

Nos. 23-235 & 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

________________________________________

BRIEF FOR THE PHARMACEUTICAL RESEARCH

AND MANUFACTURERS OF AMERICA AS AMICUS

CURIAE IN SUPPORT OF PETITIONERS

________________________________________

James C. Stansel

Melissa B. Kimmel

Kelly Falconer Goldberg

PHARMACEUTICAL RESEARCH

AND MANUFACTURERS OF

AMERICA

950 F Street, NW, Suite 300

Washington, DC 20004

(202) 835-3400

Annie X. Wang

COVINGTON & BURLING LLP

One International Place

Suite 1020

Boston, MA 02110

(617) 603-8800

Peter Safir

David M. Zionts

Counsel of Record

Julie Dohm

Brianne Bharkhda

Mingham Ji

Daniel G. Randolph

Jessica Perez

Kendall T. Burchard

Daniel J. Nathan

COVINGTON & BURLING LLP

One CityCenter

850 Tenth Street, NW

Washington, DC 20001

DZionts@cov.com

(202) 662-6000

Counsel for Amicus Curiae

i

TABLE OF CONTENTS

Page

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

INTEREST OF AMICUS CURIAE ............................1

INTRODUCTION AND SUMMARY OF

ARGUMENT ..........................................................3

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

I. THE FIFTH CIRCUIT’S OVERBROAD

STANDING THEORY THREATENS TO

STIFLE BIOPHARMACEUTICAL

INNOVATION .......................................................5

A.

The Biopharmaceutical Industry Invests

Heavily in Research and Development in

Reliance on the FDA-Administered

Regulatory Scheme that Congress Created .........6

B.

The Fifth Circuit’s Standing Theory Could

Enable Speculative Challenges to Initial or

Supplemental Approvals, Including REMS

Modifications, Jeopardizing Incentives to

Innovate and Invest ............................................10

1. Plaintiff-Physicians’ Amorphous

Injuries Could Easily Be Alleged by

Virtually Any Healthcare Provider................11

2. Plaintiff-Physicians’ Sweeping Theory of

Traceability Would Confer Standing on

Those Harmed by Independent, ThirdParty Choices ..................................................13

ii

II. BY OVERRIDING FDA’S CONSIDERED

SCIENTIFIC JUDGMENTS, THE FIFTH

CIRCUIT’S RULING UNDERMINES

CONGRESS’S SCHEME FOR DRUG

REGULATION .....................................................16

A.

Congress Directed FDA to Apply Its

Expertise by Making Science-Based Safety

and Effectiveness Decisions ...............................16

B.

The Fifth Circuit’s Ruling Supplants FDA’s

Science-Based Approval Decisions with Its

Own Judge-Made Requirements ........................20

1. Congress Did Not Require That All

Changes to Conditions of Use Be

Assessed in a Single Controlled Study ..........20

2. The Fifth Circuit Fundamentally

Misunderstood Adverse Event

Reporting. .......................................................23

III.THE EXTRAORDINARY REMEDY HERE

FURTHER AGGRAVATES THE

POTENTIAL FOR HARM TO THE

BIOPHARMACEUTICAL INDUSTRY

AND PATIENTS ..................................................27

CONCLUSION ..........................................................31

iii

TABLE OF AUTHORITIES

Page(s)

Cases

California v. Texas,

141 S. Ct. 2104 (2021) .......................................... 13

City of Los Angeles v. Lyons,

461 U.S. 95 (1983) ................................................ 11

Clapper v. Amnesty Int’l USA,

568 U.S. 398 (2013) .................................. 11, 12, 13

Coal. for Mercury-Free Drugs v. Sebelius,

671 F.3d 1275 (D.C. Cir. 2012) ............................ 14

EME Homer City Generation, L.P. v. EPA,

795 F.3d 118 (D.C. Cir. 2015) .............................. 29

FDA v. Brown & Williamson Tobacco Corp.,

529 U.S. 120 (2000) .............................................. 17

Guillot v. Aventis Pasteur, Inc.,

2013 WL 4508003 (E.D. La. Aug. 22,

2013) ..................................................................... 14

Int’l Acad. of Oral Med. & Toxicology v.

FDA,

195 F. Supp. 3d 243 (D.D.C. 2016) ...................... 14

Lujan v. Defs. of Wildlife,

504 U.S. 555 (1992) ........................................ 11, 13

Pub. Citizen, Inc. v. NHTSA,

489 F.3d 1279 (D.C. Cir. 2007) ............................ 12

iv

Spokeo, Inc. v. Robins,

578 U.S. 330 (2016) .............................................. 11

TransUnion LLC v. Ramirez,

594 U.S. 413 (2021) ........................................ 10, 12

Weinberger v. Hynson, Westcott & Dunning,

Inc.,

412 U.S. 609 (1973) .............................................. 18

Statutes

5 U.S.C. § 705 ............................................................ 28

21 U.S.C.

§ 352(n) ........................................................... 19, 25

§ 355 ..................................................................... 21

§ 355(a) ................................................................. 17

§ 355(b)(1) ............................................................. 22

§ 355(b)(1)(A) ........................................................ 18

§ 355(b)(5) ............................................................. 22

§ 355(c)(1)(A) ........................................................ 18

§ 355(d) ........................................................... 14, 18

§ 355(e) ........................................................... 24, 28

§ 355(k) ........................................................... 19, 24

§ 355(k)(1) ....................................................... 19, 24

§ 355(k)(5) ............................................................. 19

§ 355(i)(2) .............................................................. 17

§ 355-1 ...................................................... 18, 21, 24

§ 355-1(a)(1).......................................................... 22

§ 355-1(b)(3).......................................................... 22

§ 355-1(f)(2) .......................................................... 16

v

21 U.S.C.

§ 355-1(g) .............................................................. 16

§ 355-1(g)(2)(C) ..................................................... 19

§ 355-1(g)(4) .......................................................... 19

§ 355-1(g)(4)(A) ..................................................... 22

§ 355-1(g)(4)(B)(i) ........................................... 14, 19

§ 355-1(g)(4)(B)(ii) ................................................ 19

§ 355c .................................................................... 22

§ 393(b)(1) ............................................................. 17

§ 393(b)(2)(B) ........................................................ 17

§ 393(b)(4) ............................................................. 17

Regulations

21 C.F.R.

§ 201.57(a)(11)(ii) ........................................... 25, 26

§ 312.20(a) ............................................................ 17

§ 312.20(b) ............................................................ 17

§ 312.21................................................................. 17

§ 312.23(a)(8) ........................................................ 17

§ 314.50................................................................. 18

§ 314.80........................................................... 19, 24

§ 314.80(b) ............................................................ 24

§ 314.80(c)............................................................. 25

§ 314.81................................................................. 24

§ 314.98................................................................. 24

§ 314.150............................................................... 28

Other Authorities

Congressional Budget Office, Research and

Development in the Pharmaceutical

Industry (Apr. 2021) ............................................. 7

vi

FDA, Benefit-Risk Assessment for New Drug

and Biological Products: Guidance for

Industry (Oct. 2023) ............................................. 14

FDA, FDA Adverse Event Reporting System

(FAERS) Public Dashboard (Dec. 2023) ....... 19, 20

FDA, Guidance for Industry, Risk

Evaluation and Mitigation Strategies:

Modifications and Revisions (June 2020) ........... 22

FDA, New Drug Therapy Approvals 2023

(Jan. 2024) .............................................................. 8

FDA, Questions and Answers on FDA’s

Adverse Event Reporting System

(FAERS) (June 4, 2018) ....................................... 26

FDA, Report of Summary Level Review

Under Section 3031 of 21st Century

Cures (2023) ......................................................... 22

Gerald J. Dal Pan et al., Postmarketing

Spontaneous Pharmacovigilance

Reporting Systems, in Textbook of

Pharmacoepidemiology 115 (Brian L.

Strom et al. eds., 3d ed. 2021) ............................. 25

PhRMA, Annual Membership Survey (2023) ..... 1, 7, 8

PhRMA, Cancer Post Approval Infographic

(Aug. 2022) ............................................................. 8

PhRMA, Research & Development: Clinical

Trials, https://perma.cc/EMP4-RQLY

(archived Apr. 29, 2023)..................................... 7, 8

1

INTEREST OF AMICUS CURIAE1

The Pharmaceutical Research and Manufacturers

of America (“PhRMA”) is a voluntary nonprofit association representing the country’s leading researchbased pharmaceutical and biotechnology companies.

PhRMA advocates in support of public policies that

encourage the discovery of life-saving and life-enhancing new medicines. PhRMA’s members produce

innovative medicines, treatments, and vaccines that

save and improve the lives of countless individuals

every day. Since 2000, PhRMA’s member companies

have invested more than $1.2 trillion into discovering

and developing new medicines, including $100.8 billion in 2022 alone. See PhRMA, Annual Membership

Survey at 3 tbl. 1 (2023).2 Although a return on these

substantial investments is never guaranteed because

of the risks inherent in scientific innovation and discovery, the reliability and rigor of the drug approval

process facilitated by the United States Food and

Drug Administration (“FDA”) makes that risk tolerable.

PhRMA’s members share a significant interest in

protecting against disruptions to the stable and predictable statutory framework Congress created to

govern FDA’s drug approvals. The framework Congress established in the Federal Food, Drug, and

1 Pursuant to Rule 37.6, no party’s counsel authored this brief in

whole or in part. No party, counsel for a party, or person other

than amicus curiae, its members, and its counsel made any monetary contribution intended to fund the preparation or

submission of this brief.

2 https://perma.cc/XD8B-8B8X (archived Oct. 11, 2023).

2

Cosmetic Act (“FDCA”), 21 U.S.C. § 355, et seq., is

thorough and rigorous, thereby assuring patients,

healthcare providers, drug and device developers, and

drug and device manufacturers that the drugs approved for market by FDA are safe and effective for

their intended uses. This Court should reverse the

Fifth Circuit’s judgment because it sets a precedent

that—if left undisturbed—could significantly disrupt

the biopharmaceutical industry, harm patients, and

stifle innovation in drug development.

3

INTRODUCTION AND SUMMARY OF

ARGUMENT

Congress vested FDA with the authority to evaluate the safety and efficacy of the nation’s drugs. And

for decades, biopharmaceutical companies, healthcare

providers, patients, and other stakeholders have relied on FDA’s expert scientific judgment on drug

approval, labeling, and post-approval marketing requirements. Indeed, biopharmaceutical companies

invest tens of billions of dollars every year against the

regulatory backdrop that Congress established.

The Fifth Circuit’s ruling upends this settled regulatory scheme and the investments that hinge upon

it. Although the Fifth Circuit purported to limit the

damage by reversing the district court’s order as to the

drug at issue’s initial approval, the Fifth Circuit ruling nevertheless poses a serious threat to the health

and stability of the nation’s biopharmaceutical industry.

Amicus addresses three core issues with the decision below:

First, the Fifth Circuit’s flawed standing analysis

threatens limitless litigation by inviting virtually any

healthcare provider to bring suit to challenge any

drug approval or subsequent change. Biopharmaceutical research and development is expensive, time

consuming, and risky. Nevertheless, drug developers

invest in new medicines because, if their investments

succeed, FDA’s rigorous drug approvals and subsequent regulatory actions are sturdy enough to

facilitate reliable returns. If endorsed by this Court,

the Fifth Circuit’s attenuated standing analysis

4

threatens to subject every drug approval and later action to a substantial risk of litigation, reducing

revenues that drive investment and thereby diminishing the incentives to innovate in the first place.

Second, the Fifth Circuit’s ruling undermines Congress’s scheme for drug regulation by overriding

FDA’s considered scientific judgments concerning

clinical studies and adverse event reporting practices.

Congress vested FDA with the power to make sciencebased safety and effectiveness determinations. Such

determinations are the bedrock of the nation’s drug

approval process. This process involves not only thorough scientific review of New Drug Applications, but

also of Supplemental New Drug Applications—including proposed Risk Evaluation and Mitigation

Strategies (“REMS”) modifications—that seek to facilitate patient access to safe and effective medicines.

Notwithstanding that congressional mandate, the

Fifth Circuit effectively supplanted the FDA’s sciencebacked determinations with its own judge-made requirements. For example, the Fifth Circuit imposed

its own judgment regarding the clinical study requirements for determining the appropriate conditions of

use for a drug. And the Fifth Circuit fundamentally

misunderstood FDA’s robust adverse event reporting

system. If left uncorrected, the Fifth Circuit’s ruling

could give license to courts to act contrary to the system Congress charged FDA with implementing.

Third, the lower courts’ approach to remedy further exacerbates the potential for harm to the

biopharmaceutical industry and patients. Congress

mandated by statute a process for the withdrawal or

5

suspension of an FDA approval decision. But the district court circumvented that process by staying the

effective date of all of FDA’s challenged actions, and

the Fifth Circuit blessed that approach in part by affirming. If every FDA drug approval decision—and

every subsequent decision approving a supplemental

application—can be invalidated by a court through

what is effectively a preliminary injunction, it could

discourage biopharmaceutical companies from making the necessary investments to advance new and

approved medicines that benefit patients. The extraordinary nature of this remedy is all the more

striking where, as here, the lower courts failed to provide FDA an opportunity to supplement its reasoning

before effectively vacating the agency’s actions.

In short, the Fifth Circuit’s deeply flawed ruling

would jeopardize the settled regulatory framework

that facilitates the development of life-saving medicines. This Court should reverse.

ARGUMENT

I.

THE FIFTH CIRCUIT’S OVERBROAD STANDING

THEORY

THREATENS

TO

STIFLE

BIOPHARMACEUTICAL INNOVATION.

The Fifth Circuit held that Plaintiff-Physicians

had individual standing to challenge the 2016 Amendments and 2021 Non-Enforcement Decision and that

Plaintiff-Associations had derivative associational

6

standing. FDA Pet. App. 41a.3 If left undisturbed,

these holdings could encourage prolific litigation

based on the routine implementation of statutory provisions, such as the assessment and potential

modification of REMS, which focus on preventing and

managing risks associated with a particular drug’s

use. This could lead to decreased biopharmaceutical

investments, to the detriment of patients.

A. The Biopharmaceutical Industry Invests

Heavily in Research and Development in

Reliance on the FDA-Administered

Regulatory

Scheme

that

Congress

Created.

Biopharmaceutical research and development is

expensive, time-consuming, and risky. Compliance

with FDA’s review process requires enormous expenditures, and the low likelihood of successfully

developing an approved product means that pharmaceutical firms make these expenditures without

knowing whether their efforts will bear fruit. Nevertheless, pharmaceutical firms continue to invest in

new medicines because Congress has established a reliable regulatory scheme that allows for the prospect

of a reasonable return, discussed further in section

II.A, infra. That stable FDA-administered scheme encourages the research and development expenditures

3 The Fifth Circuit’s opinion is reported at 78 F.4th 210 (5th Cir.

2023). For consistency, this brief cites to FDA’s Appendix to the

Petition for a Writ of Certiorari filed in No. 23-235. FDA Pet.

App. 1a–110a.

7

necessary to produce safe and effective, life-saving

and life-improving drugs.

Biopharmaceutical companies invest enormous

sums in order to develop new medicines. From drug

discovery through FDA approval, developing a new

medicine costs $2.6 billion on average. PhRMA, Research & Development: Clinical Trials.4 Since 2000,

PhRMA members have invested over $1.2 trillion to

develop novel treatments and cures, including $100.8

billion in 2022. PhRMA, Annual Membership Survey

at 3 tbl. 1. Over the last decade, PhRMA members

have spent approximately 22.8% of their domestic

sales revenue on research and development. Id. at 3

tbl. 1, 5 tbl. 4. By contrast, “average R&D intensity

across all industries typically ranges between 2 percent and 3 percent.” Congressional Budget Office,

Research and Development in the Pharmaceutical Industry at 3 (Apr. 2021) (“CBO Report”).5 Even other

investment-dependent enterprises—like software and

semiconductor companies—spend significantly less

than pharmaceutical firms as a proportion of sales.

See id. at 5. The biopharmaceutical sector is thus

among the nation’s most research and development–

intensive industries. See id.

This research and development process consumes

significant time, with PhRMA members taking an average of ten years to bring a new drug from discovery

to FDA approval. PhRMA, Research & Development:

4 https://perma.cc/EMP4-RQLY (archived Apr. 29, 2023).

5 https://perma.cc/2NTL-PHJ2 (archived Apr. 29, 2023).

8

Clinical Trials. Even after FDA approves new medicines, PhRMA members often engage in additional

research and development to improve patient care.

This can include, for example, the identification and

development of new uses, new formulations, new dose

regimens, and better manufacturing processes for

quality control of already-approved medicines. For instance, nearly 60% of oncology medicines approved

over a decade ago received additional approvals in

later years, leading to new indications and treatments

and improved patient care. PhRMA, Cancer Post Approval Infographic at 1 (Aug. 2022).6 In 2022, 11.5%

of PhRMA members’ $100.8 billion research and development expenditures supported post-approval

research and development. PhRMA, Annual Membership Survey at 4 tbl. 3.

Pharmaceutical firms make these heavy investments of money and time without a guaranteed

return: Just one out of every 5,000 to 10,000 compounds under development, and less than 12% of

candidate medicines that make it to Phase 1 clinical

trials, are approved by FDA as meeting its safety and

effectiveness standards. PhRMA, Research & Development: Clinical Trials. Although thousands of

compounds are investigated as potential drugs, and

hundreds proceed to clinical trials each year, FDA approved an average of only 46 novel drugs (i.e., those

containing active ingredients not previously approved) annually over the last decade. FDA, New

6 https://perma.cc/3QXZ-7U44 (archived Oct. 3, 2023).

9

Drug Therapy Approvals 2023 at 6 (Jan. 2024).7 The

graphic below illustrates this winnowing process:

PhRMA, Research & Development: Clinical Trials.

This thorough, rigorous, and reliable system—established by Congress and administered by FDA—

assures patients, healthcare providers, and drug developers that FDA-approved drugs are safe and

effective for their intended purposes. Without this

predictable regime, pharmaceutical firms could not

expect returns on investment adequate to justify the

significant research and development expenses that

make life-saving medicines available in the United

States.

7 https://perma.cc/U4NJ-HG5C (archived Jan. 29, 2024).

10

B. The Fifth Circuit’s Standing Theory Could

Enable Speculative Challenges to Initial

or Supplemental Approvals, Including

REMS

Modifications,

Jeopardizing

Incentives to Innovate and Invest.

The Fifth Circuit’s ruling deals a major blow to this

regulatory scheme and the investments it supports.

By endorsing a sweeping theory of standing, the decision could permit plaintiffs with speculative asserted

injuries to challenge FDA’s drug approvals and postapproval decisions. The threat of such litigation undermines the reliability and stability of the regime

that Congress established, thus jeopardizing pharmaceutical investments and diminishing incentives to

pursue further research and development.

To establish Article III standing, “a plaintiff must

show (i) that he suffered an injury in fact that is concrete, particularized, and actual or imminent; (ii) that

the injury was likely caused by the defendant; and

(iii) that the injury would likely be redressed by judicial relief.” TransUnion LLC v. Ramirez, 594 U.S.

413, 423 (2021). Plaintiff-Physicians fail to satisfy

these basic requirements as they are normally applied: They rely on a generalized, multistep theory

that heaps speculation upon speculation. In holding

that this theory complies with Article III, the Fifth

Circuit impermissibly expanded the class of claims for

which this Court has recognized standing.

If affirmed, the decision below could invite virtually any healthcare provider to challenge any FDA

approval or post-approval action for any drug. The

upshot will be a proliferation of court challenges to

11

medicines that FDA has, in its expert scientific opinion, approved as safe and effective through the

comprehensive and rigorous process that Congress

prescribed.

1. Plaintiff-Physicians’ Amorphous

Injuries Could Easily Be Alleged by

Virtually Any Healthcare Provider.

Injury in fact must be both “imminent” and “concrete.” Spokeo, Inc. v. Robins, 578 U.S. 330, 339

(2016) (citation omitted). Plaintiff-Physicians’ alleged

injuries are neither.

To satisfy Article III, alleged future injuries must

be “certainly impending,” Clapper v. Amnesty Int’l

USA, 568 U.S. 398, 401 (2013), such that there is “a

real and immediate threat” of future harm, City of Los

Angeles v. Lyons, 461 U.S. 95, 105 (1983). But here,

Plaintiff-Physicians impermissibly rely on an “attenuated chain of possibilities,” Clapper, 568 U.S. at 401,

all of which “depend[] on the unfettered choices made

by independent actors not before the courts,” Lujan v.

Defs. of Wildlife, 504 U.S. 555, 562 (1992).

Their theory is as follows: First, some unspecified,

non-plaintiff healthcare provider might write a prescription for a patient.

Second, the patient

experiences a rare side effect after taking the drug as

prescribed. Third, the patient would have to seek the

assistance of a different healthcare provider—perhaps one of the Plaintiff-Physicians—rather than

contacting the prescribing provider. Fourth, PlaintiffPhysician’s provision of that medical care—or even

just a related issue, such as an increased workload—

12

would become a cognizable harm to Plaintiff-Physician.

Such harm cannot qualify as “certainly

impending” without engaging in the “attenuated

chain of possibilities” this Court has rejected. Clapper, 568 U.S. at 401.

The final step in that chain illustrates another defect in Plaintiff-Physicians’ standing theory: The

alleged harms are not sufficiently “concrete” and “particularized.” TransUnion, 594 U.S. at 423. The Fifth

Circuit held that Plaintiff-Physicians would “sustain

a concrete injury” if they were “forced to divert time

and resources away from their regular patients” by

rendering emergent care, or if rendering such care

“expose[d] them to greater liability and increased insurance costs.” FDA Pet. App. 31a. But these alleged

harms describe the work that all physicians routinely

perform during their daily treatment of patients.

By endorsing a standing theory that fails to satisfy

Article III’s injury-in-fact requirements, the Fifth Circuit’s ruling risks enabling suits from virtually any

medical practitioner opposed to any drug. Cf. Pub.

Citizen, Inc. v. NHTSA, 489 F.3d 1279, 1295 (D.C. Cir.

2007) (Kavanaugh, J.) (“Under [Plaintiff’s] theory of

probabilistic injury, after an agency takes virtually

any action, virtually any citizen—because of a fractional chance of benefit from alternative action—

would have standing to obtain judicial review of the

agency’s choice.”). That threatens limitless litigation

that would undermine the regulatory scheme and,

consequently, the reliability of biopharmaceutical investments.

13

2. Plaintiff-Physicians’ Sweeping Theory

of Traceability Would Confer Standing

on Those Harmed by Independent,

Third-Party Choices.

Plaintiff-Physicians’ standing theory also fails for

lack of causation. In assessing whether a defendant

likely caused an injury in a way that is “fairly traceable” to the defendant’s conduct, this Court has

emphasized its “reluctance to endorse standing theories that rest on speculation about the decisions of

independent actors.” Clapper, 568 U.S. at 414. In

such situations, “it is ordinarily substantially more

difficult” for a plaintiff to establish traceability.

Lujan, 504 U.S. at 562 (cleaned up). Such is the case

here.

The Fifth Circuit concluded that Plaintiff-Physicians had shown causation by speculating that the

2016 Amendments and 2021 Non-Enforcement Decision would increase the number of patients who suffer

complications from the drug at issue. FDA Pet. App.

36a. But such a hypothetical harm is far removed

from Plaintiff-Physicians. It turns on the unpredictable “decisions of . . . independent third parties”—such

as patients, prescribers, and other medical practitioners—and cannot satisfy the “substantially more

difficult” traceability standard that applies under

such circumstances. California v. Texas, 141 S. Ct.

2104, 2117 (2021) (cleaned up).

Plaintiffs-Appellees are not the first to try to challenge FDA’s ability to approve medical products for

use by other people. Faced with similar challenges,

courts routinely refuse to find standing, correctly rejecting the tenuous theories of imminent injury and

14

traceability underlying such suits. See, e.g., Coal. for

Mercury-Free Drugs v. Sebelius, 671 F.3d 1275, 1277

(D.C. Cir. 2012) (Kavanaugh, J.) (“[Plaintiffs] do not

have standing to challenge FDA’s decision to allow

other people to receive . . . vaccines.”).8

The Fifth Circuit accepted the unsubstantiated assertion that increasing access to a drug will

necessarily result in an increased risk of adverse

events. In doing so, it ignored that FDA must conduct

a benefit-risk assessment whenever it evaluates a proposed change—including a REMS modification—to an

approved New Drug Application. See 21 U.S.C.

§ 355(d) (requiring FDA to “implement a structured

risk-benefit assessment framework in the new drug

approval process to facilitate the balanced consideration of benefits and risks”); id. § 355-1(g)(4)(B)(i)

(discussing benefit-risk assessment in the context of

REMS modifications); FDA, Benefit-Risk Assessment

for New Drug and Biological Products: Guidance for

Industry at 3 (Oct. 2023) (“Because all drugs can have

adverse effects, the demonstration of safety requires a

showing that the benefits of the drug outweigh its

risks.”).9

8 See also Int’l Acad. of Oral Med. & Toxicology v. FDA, 195 F.

Supp. 3d 243, 264‒66 (D.D.C. 2016) (concluding that dental association lacked standing to compel harsher FDA mercury-filling

regulations because it could not identify any members who would

be exposed to mercury); Guillot v. Aventis Pasteur, Inc., 2013 WL

4508003, at *8 (E.D. La. Aug. 22, 2013) (holding that parents who

oppose vaccinations lacked standing to enjoin distribution of thimerosal-containing vaccine because their child would likely not

receive such a vaccine).

9 https://perma.cc/EV8A-86YV (archived Jan. 25, 2024).

15

By artificially inflating the “risks” of greater access

and failing to account adequately for the benefits,

Plaintiff-Physicians’ theory seeks to skew a drug’s

benefit-risk profile against REMS modifications that

are otherwise warranted, such as to improve patient

access to a drug or reduce burdens on the healthcare

delivery system. Such an outcome would be contrary

to FDA’s statutory requirement to weigh these factors, among others, for the type of REMS at issue in

this case. See 21 U.S.C. § 355-1(f)(2). This fear is not

hypothetical. The FDCA requires manufacturers of

drugs that are subject to REMS to conduct and submit

periodic REMS assessments; it also empowers FDA to

determine whether the findings in such assessments

warrant REMS modifications or, more generally,

whether the statutory standard for modifications has

been met. Id. § 355-1(g). Manufacturers also may propose a REMS modification “at any time.” Id. PlaintiffPhysicians’ theory of traceability would threaten to

transform this routine implementation of the statute

into sources of litigation.

In sum, the Fifth Circuit’s ruling depends on a

flawed standing analysis that threatens to invite attenuated challenges to countless drug approvals and

post-approval changes, such as new uses and REMS

modifications. Under such a regime, drug approvals

and REMS modifications could become litigation triggers.

16

II. BY OVERRIDING FDA’S CONSIDERED SCIENTIFIC

JUDGMENTS, THE FIFTH CIRCUIT’S RULING

UNDERMINES CONGRESS’S SCHEME FOR DRUG

REGULATION.

Congress charged FDA with the responsibility of

serving as the nation’s expert for evaluating the safety

and effectiveness of drugs in this country. These evaluations occur both before FDA approves a drug for the

first time and after the drug has entered the market,

including when FDA reviews proposed changes to an

approved New Drug Application (such as new uses).

Congress specified a complex and thorough framework within which the agency must operate. That

statutory framework requires FDA to exercise expertise in evaluating and regulating drugs by, among

other things: analyzing the significant amounts of information received from various sources such as the

manufacturer or third parties about a drug’s safety or

effectiveness (which applies equally to original and

supplemental applications); consulting with scientific

experts outside the government, as well as within

other parts of the government when needed; and considering submissions from the public. The Fifth

Circuit’s decision upends this framework by overriding FDA’s expert judgments, imposing new judicially

created requirements, and fundamentally misconstruing the operative statute.

A. Congress Directed FDA to Apply Its

Expertise by Making Science-Based

Safety and Effectiveness Decisions.

FDA’s congressionally mandated “[m]ission” is to

“protect the public health by ensuring that . . . drugs

17

are safe and effective.” 21 U.S.C. § 393(b)(2)(B). This

Court has emphasized that FDA’s “objective” is to “ensure that any product regulated” is “‘safe’ and

‘effective’ for its intended use.” FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120, 133 (2000).

That “essential purpose pervades the FDCA.” Id.

As part of FDA’s congressionally mandated mission, Congress designated the agency as the scientific

expert when it comes to evaluating the safety and effectiveness of drugs approved in this country.

Congress required that FDA approve a drug before it

can be “introduce[d] or deliver[ed] for introduction

into interstate commerce.” 21 U.S.C. § 355(a). When

considering drug applications, FDA must “promptly

and efficiently review[] clinical research and tak[e] appropriate action on the marketing of regulated

products.” Id. § 393(b)(1). It must also grow and develop its expertise by “consult[ing] with experts in

science, medicine, and public health.” Id. § 393(b)(4).

To start the approval process for a new drug, a

pharmaceutical company must generally conduct a series of laboratory studies to test how a proposed

medicine works and assess its safety. See 21 C.F.R.

§ 312.23(a)(8). If such studies produce promising results, the company submits an Investigational New

Drug Application to FDA outlining those results and

offers a plan for clinical trials. See 21 U.S.C.

§ 355(i)(2); 21 C.F.R. § 312.20(a)–(b). After completing multiple rounds of clinical trials, the company can

submit a New Drug Application to seek FDA drug approval. See 21 C.F.R. § 312.21. A New Drug

Application often exceeds 100,000 pages in length and

18

must include (among other things) “full reports of investigations which have been made to show whether

such drug is safe for use and whether such drug is effective in use.” 21 U.S.C. § 355(b)(1)(A).

Once a company files a New Drug Application, an

FDA review team of multidisciplinary experts diligently evaluates whether the studies submitted show

that the drug is safe and effective for its proposed use.

“Safe” in this context means that the benefits of the

drug outweigh the known risks. A safety assessment

is based on information in the New Drug Application,

which includes the reports of investigations by the applicant and information about the drug pertinent to

the application’s evaluation from any source. See 21

C.F.R. § 314.50. Effectiveness must be based on “substantial evidence”—i.e., “evidence consisting of

adequate and well-controlled investigations.” Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S.

609, 613, 617 (1973) (noting that FDA must “refuse

approval” of a New Drug Application “if ‘substantial

evidence’ that the drug is effective for its intended use

is lacking”) (cleaned up). If FDA concludes that a drug

is safe and effective for its proposed use and finds that

“none” of seven specified “grounds for denying approval” apply, then FDA will approve the drug for use.

21 U.S.C. § 355(c)(1)(A), (d).

Congress also gave FDA statutory authority over

REMS, which may be required as part of an initial application approval or added after that initial approval,

and which FDA may modify later when approving a

Supplemental New Drug Application. See id. § 355-1.

REMS focus on preventing and managing risks associated with a particular drug’s use—for example, by

19

reinforcing specific practices among providers and patients.

FDA’s authority over REMS includes

requiring modifications to “ensure the benefits of the

drug outweigh the risks of the drug,” or to “minimize

the burden on the health care delivery system of complying with the [REMS].” Id. § 355-1(g)(4)(B)(i), (ii).

Drug application holders must periodically submit assessments of REMS to assist FDA in “evaluat[ing]

whether the approved [REMS] should be modified.”

Id. § 355-1(g)(2)(C). And application holders may also

propose REMS modifications through Supplemental

New Drug Applications based on “adequate rationale[s]” that support the changes. Id. § 355-1(g)(4).

After approving a New Drug Application or Supplemental New Drug Application, FDA manages a

robust monitoring regime to track the approved drug’s

safety profile, as mandated by statute. See id.

§ 355(k)(1), (5). This regime is facilitated by the FDA

Adverse Event Reporting System (“FAERS”), through

which FDA collects, reports, and publicizes adverse

event data received from a variety of sources, including manufacturers, healthcare providers, and

patients. See id. §§ 352(n), 355(k)(1), (5). Manufacturers are required to submit adverse event reports

that they receive in accordance with timelines and

procedures established by FDA regulation. See 21

U.S.C. § 355(k), 21 C.F.R. § 314.80.

FAERS has long provided a source of information

for FDA to monitor an approved drug’s safety after it

enters the market. See FDA, FDA Adverse Event Reporting System (FAERS) Public Dashboard (Dec.

20

2023).10 FDA’s management of FAERS, like the rest

of FDA’s statutory mandate, reflects Congress’s determination that the expert agency is best positioned to

monitor safety information and assess if certain action may be warranted.

B. The Fifth Circuit’s Ruling Supplants

FDA’s Science-Based Approval Decisions

with Its Own Judge-Made Requirements.

The Fifth Circuit usurped FDA’s congressional

mandate by imposing unworkable, extra-statutory requirements and misapprehending critical features of

the FDCA’s governing statutory framework. Although the Fifth Circuit’s analysis purported to limit

itself to the 2016 Amendments and 2021 Non-Enforcement Decision, its reasoning could have far-reaching

implications for initial and supplemental drug approvals alike.

1. Congress Did Not Require That All

Changes to Conditions of Use Be

Assessed in a Single Controlled Study.

In 2016, FDA approved a Supplemental New Drug

Application to change various conditions of use for the

drug at issue (e.g., allowing prescriptions by licensed

non-physician providers, adjusting the dosage, increasing the time under which to prescribe, and

modifying the method of administration). At the time,

FDA concluded that the scientific evidence gathered

over decades of use supported the 2016 Amendments—and in making this determination, FDA

10 https://perma.cc/7YB9-2PNG (archived Jan. 29, 2024).

21

considered at least three studies that tested the same

or similar changes that it then implemented in the

2016 Amendments. See, e.g., J.A. 299 nn.1, 3 & 4

(FDA Summary Review, Mifeprex REMS Changes

(Mar. 29, 2016)).

Nevertheless, the Fifth Circuit determined that

FDA’s approval decision “was likely arbitrary and capricious,” and thus invalid, because FDA allegedly

“did not consider the cumulative effect of the 2016

Amendments” given that “[n]one of the studies [FDA]

relied on examined the effect of implementing all of

those changes together.” FDA Pet. App. 53a; see also

id. 235a (stay ruling)11 (faulting FDA for citing “zero

studies that evaluated the safety-and-effectiveness

consequences of the 2016 [Amendments] as a whole”).

In other words, the Fifth Circuit effectively imposed a

requirement that all proposed changes to a medication’s conditions of use in the context of a

Supplemental New Drug Application be assessed together in a single controlled study.

Contrary to the Fifth Circuit’s ruling, the FDCA

does not require FDA to evaluate a single controlled

study testing the cumulative impact of changes proposed in a Supplemental New Drug Application before

approving such changes. See generally 21 U.S.C.

§§ 355, 355-1. In outlining the procedures for approving New Drug Applications and Supplemental New

11 The Fifth Circuit’s order granting a stay in part is not pub-

lished in the Federal Reporter but is available at 2023 WL

2913725. For consistency, this brief cites to FDA’s Appendix to

the Petition for a Writ of Certiorari filed in No. 23-235. FDA Pet.

App. 196a–244a.

22

Drug Applications, Congress required that applicants

submit an extensive set of information, including “full

reports of investigations which have been made to

show whether such drug is safe [and effective] in use,”

research into pediatric uses (if required by 21 U.S.C.

§ 355c), and plans for future clinical trials. Id.

§ 355(b)(1), (5). FDA approves an average of 200 supplemental applications annually, permitting new

uses, expanding treatment to different patient populations, and modifying conditions of use. See FDA,

Report of Summary Level Review Under Section 3031

of 21st Century Cures (2023).12

The same is true of the initial imposition of a

REMS or a REMS modification. When considering

whether to impose a REMS, FDA must look at factors

such as population, the seriousness of the targeted

disease or condition, and the expected benefits and

risks of the drug. If a drug has been approved without

a REMS, FDA can nevertheless later decide to impose

one based on “new safety information . . . derived from

a clinical trial, an adverse event report, a postapproval study . . . , or peer-reviewed biomedical

literature.” 21 U.S.C. § 355-1(a)(1), (b)(3). If a manufacturer later seeks to modify a REMS, the FDCA

mandates that such modification be supported by “an

adequate rationale,” id. § 355-1(g)(4)(A), which “may

include . . . evidence or data to support the proposed

change.” FDA, Guidance for Industry, Risk Evaluation and Mitigation Strategies: Modifications and

Revisions at 12 (June 2020 Rev. 2) (emphasis added).13

12 https://perma.cc/E7QB-G6HA (archived Sept. 29, 2023).

13 https://perma.cc/R42Y-7WUT (archived Apr. 14, 2023).

23

But Congress did not require FDA to cite a controlled

study, let alone a controlled study that tests the proposed changes together. See 21 U.S.C. § 355-1.

The Fifth Circuit’s novel requirement that FDA examine the effect of all proposed changes through a

single controlled study could seriously harm

healthcare providers, patients, and pharmaceutical

innovation. Such a study would be at minimum impractical and at worst impossible to effectuate. The

economic and temporal costs of such a study, not to

mention its practical complexity, would likely render

it infeasible. And even if commissioned, such a study

would consume valuable years and resources. Important changes to conditions of use for medicines

could happen slowly or not at all. Such a regime could

also freeze in place various REMS restrictions that

are unwarranted by current data, thus burdening

drug manufacturers and healthcare providers and impeding patients’ access to safe and effective medicines.

2. The Fifth Circuit Fundamentally

Misunderstood

Adverse

Event

Reporting.

The Fifth Circuit held that the 2021 Non-Enforcement Decision (which halted enforcement of the inperson dispensing requirement during the COVID-19

pandemic) was arbitrary and capricious in part because, in the Fifth Circuit’s view, FDA “no longer had

access to perhaps the best source of [adverse event]

data: the prescribers.” FDA Pet. App. 59a. That reasoning stemmed from a flawed understanding of the

adverse event reporting data available to FDA.

24

Congress provided for a robust adverse event reporting system, which FDA implements primarily

through FAERS, to facilitate decisions of whether to

withdraw drug approvals. See 21 U.S.C. § 355(k).

Congress further mandated that FDA’s recordkeeping

and reporting framework have “due regard for the

professional ethics of the medical profession and the

interests of patients.” Id. Consistent with these congressional directives, FDA has instituted and

implemented a framework comprising mandatory adverse event reporting from drug application holders

and voluntary reporting from providers and patients,

all captured in FAERS.

Adverse event reporting responsibilities start with

drug application holders—often drug manufacturers.

Federal law mandates that a drug application holder

maintain records and report information relating to

clinical experience and other data the manufacturer

receives or obtains to FDA as prescribed by regulation

so that FDA can determine whether grounds exist for

withdrawing a drug approval under 21 U.S.C.

§ 355(e). 21 U.S.C. § 355(k)(1). FDA’s implementing

regulations in turn require drug application holders

to report all adverse events to FDA. See 21 C.F.R.

§§ 314.98, 314.80, 314.81. A drug application holder

must promptly review all adverse event information

obtained directly and indirectly from any source, including healthcare providers, patients, postmarketing

clinical investigations, epidemiological surveillance

studies, scientific literature, and unpublished scientific papers, and must establish procedures for the

surveillance, receipt, evaluation, and reporting of adverse events to FDA. See id. § 314.80(b). Once a drug

application holder has received and reviewed adverse

25

event information, it must submit reports to FDA. Id.

§ 314.80(c).

Federal law also encourages other stakeholders,

such as physicians and patients, to voluntarily report

adverse events. See 21 U.S.C. § 352(n) (providing that

a prescription drug shall be deemed misbranded, subject to limited exceptions not applicable here, unless

published direct-to-consumer advertisements contain

the following statement: “You are encouraged to report negative side effects of prescription drugs to the

FDA. Visit www.fda.gov/medwatch, or call 1–800FDA-1088.”); see also 21 C.F.R. § 201.57(a)(11)(ii) (requiring that prescription drug product labels contain

contact information for the manufacturer and FDA for

reporting).14

Stakeholders have a strong incentive to report adverse events to application holders to improve patient

healthcare. See, e.g., Gerald J. Dal Pan et al., Postmarketing Spontaneous Pharmacovigilance Reporting

Systems, in Textbook of Pharmacoepidemiology 115,

118 (Brian L. Strom et al. eds., 3d ed. 2021). In fact,

to facilitate adverse event reporting, federal law generally requires that prescription drug product labeling

include the following verbatim statement:

To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer)

at (insert manufacturer’s phone number) or

FDA at (insert current FDA phone number and

14 Healthcare providers and patients can easily report adverse

events on FDA’s MedWatch website. See https://perma.cc/3M5HJLZ5 (archived Jan. 29, 2024).

26

Web address for voluntary reporting of adverse

reactions).

21 C.F.R. § 201.57(a)(11)(ii).

FDA then collects all adverse event reports received from all sources—including drug application

holders, healthcare providers, and patients—into

FAERS. See, e.g., FDA, Questions and Answers on

FDA’s Adverse Event Reporting System (FAERS)

(June 4, 2018).15

The 2016 Amendments removed only one atypical

REMS-imposed reporting measure for the drug: The

requirement that healthcare providers report non-fatal events. Mandatory reporting of non-fatal adverse

events by healthcare providers is not a requirement

for most FDA-approved drugs. Contrary to the Fifth

Circuit’s assumption, see FDA Pet. App. 59a, FDA did

not lack “access” to adverse event reports from prescribers.

Even after the 2016 Amendments,

healthcare providers were still required to report any

fatal adverse events (in the exceedingly rare instance

that such an event were to occur). And the manufacturers were also still subject to mandatory reporting

requirements for all adverse events (fatal or non-fatal) under the regulations described above. Moreover,

it remained the case that healthcare providers and

others could voluntarily submit reports about any adverse events to FDA. Thus, even after the 2016

Amendments, FDA continued to receive adverse event

15 https://perma.cc/Y25N-VZ67 (archived Jan. 29, 2024); see also

supra note 10.

27

reports from multiple sources, just as it does for every

FDA-approved drug.16

Indeed, even after the 2016 Amendments, the

drug at issue remains subject to adverse event reporting requirements that exceed those of most other

drugs on the market. Thus, FDA did not behave arbitrarily and capriciously by relying on a “thorough

scientific review” of the “available clinical outcomes

data and adverse event reports” when issuing its 2021

Non-Enforcement Decision. J.A. 377, 397‒408 (FDA

Denial Letter, 2019 Citizen Petition (Dec. 16, 2021)).

Importantly, if this Court deems FAERS and other

safety data evaluated by FDA “insufficient” to ground

FDA’s safety determinations here, FDA Pet. App.

59a‒60a, the ramifications could extend beyond the

drug at issue. Such a holding would drastically impinge on FDA’s fulfillment of its congressionally

directed mission to protect and promote public health

by inviting lawsuits challenging FDA’s reliance on the

safety information in FAERS to evaluate drug safety

profiles.

III. THE EXTRAORDINARY REMEDY HERE FURTHER

AGGRAVATES THE POTENTIAL FOR HARM TO THE

BIOPHARMACEUTICAL INDUSTRY AND PATIENTS.

The Fifth Circuit’s ruling was unprecedented—

and harmful to the drug industry and patients—in yet

another respect: The court awarded extraordinary

preliminary relief, contrary to Congress’s statutory

16 This is in addition to the adverse event reports compiled during

the more than fifteen years that the drug was subject to mandatory reporting from physicians and the manufacturer.

28

scheme and without affording FDA a chance to further explain its assessments.

In addition to the authority to approve drugs, evaluate subsequent changes, and administer REMS,

Congress vested FDA with the exclusive authority to

withdraw approval of a New Drug Application or a

Supplemental New Drug Application. FDA can withdraw an approval if it finds that “experience,” “tests,”

“scientific data,” or other “new evidence” show that

the drug “is unsafe for use under the conditions” for

which it was approved. 21 U.S.C. § 355(e). As part of

this process, Congress required FDA to provide the

drug application holder “due notice and opportunity

for hearing” before withdrawing or suspending approval. Id. Nevertheless, if FDA makes a series of

findings that “there is an imminent hazard to the public health,” it can suspend a drug approval

“immediately,” although it must provide the drug application holder with an opportunity for an expedited

hearing after suspension. Id.

All these procedures—which involve due notice

and opportunity for hearing to the applicant—are

mandated by statute. They serve, in part, to protect

the sizeable investments that make the approval,

marketing, and distribution of drugs possible; to prevent shocks to the U.S. biopharmaceutical market;

and to ensure that any safety concerns are promptly

and thoroughly addressed. See 21 U.S.C. § 355(e); 21

C.F.R. § 314.150.

Yet the decisions below worked an end-run around

this statutory process. The district court stayed the

two-decade-old drug approval under 5 U.S.C. § 705—

29

a provision directed at “postpon[ing]” the effective

date of an agency action pending judicial review—and

the Fifth Circuit endorsed that approach as it applied

to the 2016 and 2021 post-approval actions (even

while finding that the 2000 approval decision was

time-barred). Circumventing the FDCA’s withdrawal

requirements with a dubious use of the Administrative Procedure Act’s stay provision deprives drug

application holders of their property interests without

proper notice or hearings. That in turn diminishes

their incentives to invest in the development of drugs

in the first place.

The remedy fashioned by the lower courts was misguided in another key respect: It vacated the 2016

and 2021 actions before affording FDA an opportunity

to further explain itself. Even if the lower courts had

correctly addressed the merits, the proper remedy

would have been to remand to FDA for additional explanation, without vacatur of the agency action.

Remand without vacatur is often the proper course

when “vacatur could cause substantial disruption.”

EME Homer City Generation, L.P. v. EPA, 795 F.3d

118, 132 (D.C. Cir. 2015) (Kavanaugh, J.). That criterion applies with special force when a drug approval

is challenged. FDA’s drug approval decisions implicate enormous reliance interests on the part of

patients, healthcare providers, biopharmaceutical

companies, and other stakeholders. The stakes could

not be higher when a medication is on the market one

day and off the market the next.

30

Nor are those reliance interests limited to FDA’s

initial drug approval decisions. The Fifth Circuit dismissed concerns that its decision “would destabilize

the pharmaceutical industry, especially research-anddevelopment sections,” maintaining that those concerns “appl[ied] primarily (if not wholly) to the

challenge to the 2000 Approval.” FDA Pet. App. 69a–

70a. But that reasoning was deeply flawed for two

reasons: First, even though the Fifth Circuit limited

its holding to supplemental actions, its underlying

reasoning could apply with equal force to initial approvals, thus risking the very type of discord that the

court disregarded here. Second, Supplemental New

Drug Applications, including those for REMS modifications, play a critical role in FDA’s overall regulatory

regime. As discussed above, innovation does not stop

when FDA approves a new prescription medicine. See

supra section I.A. FDA often approves supplemental

applications seeking new indications to treat further

ailments, or the broadening of use parameters that

ease patient access. Those decisions—just like initial

drug approvals—have substantial and immediate impacts on patients, providers, and industry. And

reversing those decisions can accordingly cause deep

and immediate harm.

If endorsed by this Court, the lower courts’ remedy

could greenlight lawsuits seeking the reversal of certain longstanding FDA drug approvals and postapproval decisions at a preliminary stage, without

even affording the agency an opportunity to supplement its reasoning. That approach would bypass the

extensive drug-withdrawal procedures that Congress

mandated, jeopardize investments in life-saving medicines, and ultimately undermine patient care.

31

CONCLUSION

The judgment below should be reversed.

Respectfully submitted,

James C. Stansel

Melissa B. Kimmel

Kelly Falconer Goldberg

PHARMACEUTICAL

RESEARCH AND

MANUFACTURERS OF

AMERICA

950 F Street, NW

Suite 300

Washington, DC 20004

(202) 835-3400

Peter Safir

David M. Zionts

Counsel of Record

Julie Dohm

Brianne Bharkhda

Mingham Ji

Daniel G. Randolph

Jessica Perez

Kendall T. Burchard

Daniel J. Nathan

COVINGTON & BURLING LLP

One CityCenter

Annie X. Wang

850 Tenth Street, NW

COVINGTON & BURLING LLP Washington, DC 20001

One International Place

DZionts@cov.com

Suite 1020

(202) 662-6000

Boston, MA 02110

(617) 603-8800

January 30, 2024

Counsel for Amicus Curiae