Amicus Curiae Brief — Merck Sharp & Dohme Corp., Petitioner v. Doris Albrecht, et al.

Supreme Court briefSep 20, 2018

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No. 17-290

In the Supreme Court of the United States

MERCK SHARP & DOHME CORP., PETITIONER

DORIS ALBRECHT, ET AL.

ON WRIT OF CERTIORARI

TO THE UNITED STATES COURT OF APPEALS

FOR THE THIRD CIRCUIT

BRIEF FOR THE UNITED STATES

AS AMICUS CURIAE SUPPORTING PETITIONER

BRIAN R. STIMSON

Principal Deputy General

Counsel

ELIZABETH H. DICKINSON

Deputy Associate General

Counsel

ANNAMARIE KEMPIC

Deputy Chief Counsel,

Litigation

KAREN E. SCHIFTER

Senior Counsel

Department of Health and

Human Services

Washington, D.C. 20201

JEFFREY B. WALL

Acting Solicitor General

Counsel of Record

JOSEPH H. HUNT

Assistant Attorney General

EDWIN S. KNEEDLER

Deputy Solicitor General

ANTHONY A. YANG

Assistant to the Solicitor

General

SCOTT R. MCINTOSH

JOSHUA M. SALZMAN

Attorneys

Department of Justice

Washington, D.C. 20530-0001

SupremeCtBriefs@usdoj.gov

(202) 514-2217

QUESTION PRESENTED

Whether a state-law failure-to-warn claim alleging

the insufficiency of brand-name drug labeling is preempted by the Federal Food, Drug, and Cosmetic Act,

21 U.S.C. 301 et seq., when the Food and Drug Administration, after the drug manufacturer provided it with

the relevant scientific data, rejected the manufacturer’s

application to modify its labeling to warn about the risk

underlying the tort claim.

(I)

TABLE OF CONTENTS

Page

Interest of the United States....................................................... 1

Statement ...................................................................................... 1

Summary of argument ............................................................... 14

Argument:

The court of appeals erred in rejecting petitioner’s

preemption defense .............................................................. 16

A. Petitioner’s preemption defense turns on the

meaning and effect of FDA’s 2009 Complete

Response Letter, which are legal questions that

a court must resolve ..................................................... 17

1. Courts, not juries, determine the meaning

of federal agency decisions ................................... 18

2. Factual findings necessary to interpret a

federal agency decision are also matters for

courts to resolve..................................................... 20

B. The court of appeals erred in holding that, under

Wyeth v. Levine, a jury must resolve petitioner’s

preemption defense as a factual matter subject

to a clear-and-convincing-evidence standard ............ 21

1. Wyeth did not address whether courts or

juries should construe an actual FDA

decision ................................................................... 22

2. Any factual findings necessary to resolve

a preemption defense need only rest on a

preponderance of the evidence............................. 24

3. Resolving this case does not require factual

findings ................................................................... 27

C. FDA’s May 2009 decision rejected a change to

Fosamax’s warnings and precautions because the

data at that time was insufficient to justify a

change ........................................................................... 30

Conclusion ................................................................................... 35

(III)

TABLE OF AUTHORITIES

Cases:

Page

Addington v. Texas, 441 U.S. 418 (1979) ...................... 24, 25

Arizona v. Inter Tribal Council of Ariz., Inc.,

570 U.S. 1 (2013) ................................................................. 25

Armour & Co. v. Wantock, 323 U.S. 126 (1944) ................. 24

Block v. Community Nutrition Inst., 467 U.S. 340

(1984) .................................................................................... 26

Boyle v. United Techs. Corp., 487 U.S. 500 (1988) ....... 28, 29

Buckman Co. v. Plaintiffs’ Legal Comm.,

531 U.S. 341 (2001).............................................................. 28

Cohens v. Virginia, 19 U.S. (6 Wheat.) 264 (1821) ............. 24

Dolin v. GlaxoSmithKline LLC, No. 17-3030,

2018 WL 4001208 (7th Cir. Aug. 22, 2018) ....................... 33

Emich Motors Corp. v. General Motors Corp.,

340 U.S. 558 (1951).............................................................. 19

English v. General Elec. Co., 496 U.S. 72 (1990) ................ 26

Geier v. American Honda Motor Co., 529 U.S. 861

(2000) .................................................................................... 26

Grogan v. Garner, 498 U.S. 279 (1991) ................................ 24

Landgraf v. USI Film Prods., 511 U.S. 244 (1994) ........... 24

Markman v. Westview Instruments, Inc.,

517 U.S. 370 (1996)........................................................ 15, 19

Microsoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91

(2011) .............................................................................. 24, 25

Mutual Pharm. Co. v. Bartlett, 570 U.S. 472 (2013) ............ 4

PLIVA, Inc. v. Mensing, 564 U.S. 604

(2011) ...............................................................4, 17, 18, 21, 23

Perez v. Mortgage Bankers Ass’n, 135 S. Ct. 1199

(2015) .................................................................................... 20

Riegel v. Medtronic, Inc., 552 U.S. 312 (2008) ................... 29

Rivera v. Minnich, 483 U.S. 574 (1987) .............................. 25

Cases—Continued:

Page

Santosky v. Kramer, 455 U.S. 745 (1982) ........................... 24

Sprietsma v. Mercury Marine, 537 U.S. 51 (2002) ............ 20

Teva Pharm. USA, Inc. v. Sandoz, Inc.,

135 S. Ct. 831 (2015) ........................................................... 21

Wyeth v. Levine, 555 U.S. 555 (2009) ......................... passim

Statutes, regulations, and rules:

Administrative Procedure Act, 5 U.S.C. 551 et seq.,

701 et seq. ............................................................................. 18

5 U.S.C. 551(6) ................................................................. 18

5 U.S.C. 551(7) ................................................................. 18

5 U.S.C. 706 ................................................................ 15, 18

Federal Food, Drug, and Cosmetic Act,

21 U.S.C. 301 et seq.:

21 U.S.C. 321(m )................................................................ 2

21 U.S.C. 352(f ).................................................................. 2

21 U.S.C. 355(b)(1) ............................................................ 4

21 U.S.C. 355(d) ............................................................. 2, 4

21 U.S.C. 355(o)(2)(A)(ii) ................................................ 10

21 U.S.C. 355(o)(4)......................................... 10, 11, 33, 34

21 U.S.C. 355(o)(4)(A) ............................................... 10, 33

21 U.S.C. 355(o)(4)(B) ..................................................... 10

21 U.S.C. 355(o)(4)(B)-(D) .............................................. 33

21 U.S.C. 355(o)(4)(C) ..................................................... 11

21 U.S.C. 355(o)(4)(D) ..................................................... 11

21 U.S.C. 355(o)(4)(E) ..................................................... 11

21 U.S.C. 355(o)(4)(I) ........................................................ 4

21 C.F.R.:

Pt. 201:

Section 201.56 ............................................................... 2

Section 201.56(a)(2) ..................................................... 4

Regulations and rules—Continued:

Page

Section 201.56(b)(1) ..................................................... 2

Section 201.56(e) .......................................................... 2

Section 201.57 ............................................................... 2

Section 201.57(c) .......................................................... 3

Section 201.57(c)(6) .................................................. 2, 3

Section 201.57(c)(6)(i) ...................................... 4, 31, 33

Section 201.57(c)(7) ........................................ 2, 3, 4, 30

Section 201.57(c)(7)(ii)(B) ........................................... 4

Section 201.80 ........................................................... 2, 3

Section 201.100(c ) ........................................................ 2

Pt. 314:

Section 314.3(b) ................................................ 5, 27, 28

Section 314.70(b) .......................................................... 5

Section 314.70(b)(1) ..................................................... 5

Section 314.70(b)(2) ..................................................... 5

Section 314.70(b)(2)(v) ................................................. 5

Section 314.70(b)(2)(v)(A) ........................................... 5

Section 314.70(b)(3) ..................................................... 5

Section 314.70(c)(6) ...................................................... 4

Section 314.70(c)(6)(iii) ............................................ 4, 5

Section 314.70(c)(6)(iii)(A) .................................... 5, 27

Section 314.70(c)(7) ................................................ 5, 17

Section 314.71(b) .......................................................... 5

Section 314.71(c) .......................................................... 5

Section 314.102(a) ........................................................ 6

Section 314.102(b) ........................................................ 6

Section 314.105(b) ........................................................ 6

Section 314.110(a) ........................................................ 6

Section 314.110(a)(1) ................................................... 6

Section 314.110(a)(2) ..................................... 6, 31, 32

VII

Regulations and rules—Continued:

Page

Section 314.110(a)(3) .............................................. 32

Section 314.125(b)(6) ................................................... 6

Section 314.125(b)(8) ................................................... 6

Fed. R. Evid. 301 ................................................................... 25

Sup. Ct. R. 15.2 ...................................................................... 27

Miscellaneous:

Center for Drug Evaluation & Research, FDA,

CDER 21st Century Review Process: Desk

Reference Guide (2014), https://www.fda.gov/

downloads/AboutFDA/CentersOffices/CDER/

Manualof PoliciesProcedures/UCM218757.pdf.................. 6

Dorland’s Illustrated Medical Dictionary

(29th ed. 2000) ....................................................................... 8

FDA:

Approved Drug Products with Therapeutic

Equivalence Evaluations (38th ed. 2018),

https://www.fda.gov/downloads/drugs/

developmentapprovalprocess/

ucm071436.pdf .................................................... 2

Guidance for Industry: Safety Labeling

Changes—Implementation of Section

505(o)(4) of the FD&C Act (July 2013),

https://www.fda.gov/downloads/

Drugs/GuidanceComplianceRegulatory

Information/Guidances/UCM250783.pdf .................. 5

Guidance for Industry: Warnings and

Precautions, Contraindications, and Boxed

Warning Sections of Labeling for Human

Prescription Drug and Biological Products—

Content and Format (Oct. 2011),

https://www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/UCM075096.pdf .................. 3

VIII

Miscellaneous—Continued:

Page

Guidance for Review Staff and Industry:

Good Review Management Principles and

Practices for PDUFA Products (Apr. 2005),

https://www.fda.gov/downloads/drugs/

guidancecomplianceregulatoryinformation/

guidances/ucm079748.pdf ........................................... 6

Supplement Approval (Mar. 1, 2010):

https://www.accessdata.fda.gov/

drugsatfda_docs/appletter/2010/

020560s051s055s057,021575s012s016s018

ltr.pdf ...................................................................... 9

https://www.accessdata.fda.gov/

drugsatfda_docs/appletter/2010/

021762s005s009sS010ltr.pdf ................................. 9

71 Fed. Reg. 3922 (Jan. 24, 2006) ........................................... 2

73 Fed. Reg. 49,603 (Aug. 22, 2008) ....................................... 3

H.R. Rep. No. 1980, 79th Cong., 2d Sess. (1946) ................ 19

U.S. Dep’t of Justice, Attorney General’s Manual on

the Administrative Procedure Act (1947) ........................ 19

In the Supreme Court of the United States

No. 17-290

MERCK SHARP & DOHME CORP., PETITIONER

DORIS ALBRECHT, ET AL.

ON WRIT OF CERTIORARI

TO THE UNITED STATES COURT OF APPEALS

FOR THE THIRD CIRCUIT

BRIEF FOR THE UNITED STATES

AS AMICUS CURIAE SUPPORTING PETITIONER

INTEREST OF THE UNITED STATES

This case concerns the circumstances under which a

decision of the Food and Drug Administration (FDA)

rejecting proposed changes to the labeling of a brandname drug preempts state-law tort claims that allege

that the drug manufacturer failed to provide adequate

warnings on its labeling. At the Court’s invitation, the

United States filed a brief as amicus curiae at the petition stage of this case.

STATEMENT

1. This case involves a series of tort claims alleging

that petitioner’s labeling for its Fosamax drug products

insufficiently warned of the drugs’ risks. Petitioner has

argued, among other things, that many of the failure-towarn claims are preempted because, in 2009, FDA rejected its attempt to strengthen relevant warnings on

(1)

that labeling. The regulatory scheme for drug labeling

establishes the framework for that defense.

a. Congress has charged FDA with ensuring that

each “drug is safe for use under the conditions prescribed, recommended, or suggested” in its “labeling.”

21 U.S.C. 355(d); cf. 21 U.S.C. 321(m) (defining “labeling”); 21 U.S.C. 352(f ) (misbranding). FDA regulations

govern the content and format of prescription-drug

labeling. See, e.g., 21 C.F.R. 201.56, 201.57; see 21

C.F.R. 201.100(c ). Those regulations are intended to

organize labeling information to more effectively communicate to healthcare professionals the “information

necessary for the safe and effective use of prescription

drugs.” 71 Fed. Reg. 3922, 3928 (Jan. 24, 2006). Two

separate labeling sections now generally required on

prescription-drug labeling are relevant here: the Warnings and Precautions section and the Adverse Reactions

section. See 21 C.F.R. 201.57(c)(6) and (7). 1

The specific requirements for labeling content and format discussed in the text generally apply to prescription drugs subject to a

new drug application (NDA) or efficacy supplement approved on or

after June 30, 2001. 21 C.F.R. 201.56(b)(1). The specific labeling

requirements for older drug products differ in certain respects. See

21 C.F.R. 201.56(e), 201.80.

This case involves the labeling of three FDA-approved Fosamax

products: Fosamax tablets (NDA 20560, approved 1995); Fosamax

oral solution (NDA 21575, approved 2003); and Fosamax Plus D tablets (NDA 21762; approved 2005). See J.A. 510-511; see also FDA,

Approved Drug Products with Therapeutic Equivalence Evaluations 3-12, 6-14 (38th ed. 2018) (listing Fosamax products). Although the newer labeling requirements discussed in this brief did

not apply to all of those products at the time relevant here, no party

has suggested that the differences between the two sets of labeling

requirements are relevant to this case. The government agrees.

This brief therefore follows the path taken by the court of appeals,

The Warnings and Precautions section must identify

“clinically significant adverse reactions” and certain

other safety hazards where “reasonable evidence of a

causal association” between the drug and such hazards

exists. 21 C.F.R. 201.57(c)(6); see 73 Fed. Reg. 49,603,

49,604 (Aug. 22, 2008) (stating that a “ ‘preponderance’

of evidence” is not required). FDA adopted that causal

standard in part to “prevent overwarning” of potential

risks, which, if included in the Warnings and Precautions section, could dilute other “more important warnings” or “deter appropriate use” of the drug. 73 Fed.

Reg. at 49,605-49,606. FDA thus reserves this section

for only a “discrete set” of hazards serious enough

to affect prescribing decisions. FDA, Guidance for

Industry: Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products—

Content and Format 3 (Oct. 2011), https://www.fda.gov/

downloads/Drugs/GuidanceComplianceRegulatory

Information/Guidances/UCM075096.pdf. 2

The Adverse Reactions section, by contrast, describes “the overall adverse reaction profile of the

drug.” 21 C.F.R. 201.57(c)(7). The causal threshold for

including an adverse reaction in this section is lower

than that for the Warnings and Precautions section: An

adverse reaction must be listed if “some basis” exists

which based its decision on the newer labeling requirements in Section 201.57(c) without discussing Section 201.80. See Pet. App. 7a-9a

& nn.6, 9-10, 16, 51a n.130, 63a-64a nn.154, 156.

The 2011 guidance describes FDA’s interpretation of its 2006 labeling regulations. FDA has informed this Office that the 2011 guidance accurately reflects how FDA treated the Warnings and Precautions section during the period relevant here.

“to believe there is a causal relationship between the

drug and the occurrence of the adverse event.” Ibid.

b. A brand-name drug “manufacturer bears responsibility for the content of its label[ing] at all times.”

Wyeth v. Levine, 555 U.S. 555, 570-571 (2009); see

21 U.S.C. 355(o)(4)(I). When new information becomes

available about a new risk or a new aspect of a known

risk that causes existing labeling to become inadequate,

the manufacturer is responsible for pursuing a revision

to its labeling. See 21 C.F.R. 201.57(c)(6)(i) (stating that

updated warning must be added “as soon as” sufficient

causal evidence of a clinically significant hazard exists);

21 C.F.R. 201.57(c)(7)(ii)(B) (requiring list of adverse

reactions identified in postmarketing experience); cf.

21 C.F.R. 201.56(a)(2) (requiring updated labeling “when

new information becomes available that causes the labeling to become inaccurate, false, or misleading”).3

i. After FDA has approved a new drug application

(NDA) for a drug, 21 U.S.C. 355(b)(1) and (d), two mechanisms exist for changing a brand-name prescription

drug’s labeling, both of which require that the manufacturer file a supplemental NDA for FDA approval. First,

the sponsor may submit a Changes Being Effected

(CBE) supplement for certain labeling changes, which

allows the manufacturer immediately to implement its

proposed labeling changes upon FDA’s receipt of the

supplement. 21 C.F.R. 314.70(c)(6) and (iii); see Wyeth,

555 U.S. at 571, 573. A CBE supplement may be submitted, for instance, to add or strengthen a warning,

Because a generic drug’s labeling generally must track that of

its reference listed drug, generic-drug manufacturers cannot independently change such labeling. See, e.g., Mutual Pharm. Co. v.

Bartlett, 570 U.S. 472, 486, 488 (2013); PLIVA, Inc. v. Mensing,

564 U.S. 604, 613-615, 618 (2011).

precaution, or adverse reaction to reflect “newly acquired information” if “the evidence of a causal association satisfies the [relevant] standard for inclusion in the

labeling.” 21 C.F.R. 314.70(c)(6)(iii)(A); see 21 C.F.R.

314.3(b) (defining “[n]ewly acquired information”). If

FDA later disapproves the supplement, however, it may

order the manufacturer to cease distributing the drug

with the labeling changes. 21 C.F.R. 314.70(c)(7).

Second, the sponsor may submit a Prior Approval

Supplement (PAS) to propose labeling changes. 21 C.F.R.

314.70(b) and (2)(v). Under that procedure, FDA approval is required before the changes are made. 21 C.F.R.

314.70(b)(3). A PAS “must be submitted” for certain

types of changes that “include, but are not limited to,”

certain labeling changes other than those described in

Section 314.70(c)(6)(iii) for CBE supplements. 21 C.F.R.

314.70(b)(1), (2), and (v)(A). Historically, FDA has also

accepted PAS applications instead of CBE supplements, as occurred in this case, particularly where significant questions exist on whether to revise or how to

modify existing drug labeling. 4

ii. “All procedures and actions that apply to an application” submitted to FDA generally apply “to supplements.” 21 C.F.R. 314.71(b) and (c). FDA has accordingly confirmed to this Office that it follows many of the

general principles applicable to its review of an NDA

when undertaking the more limited task of reviewing supplements that propose safety-related labeling changes.

More specifically, FDA communicates with the applicant about “scientific, medical, and procedural issues that

Cf. FDA, Guidance for Industry: Safety Labeling Changes—

Implementation of Section 505(o)(4) of the FD&C Act 7 (July 2013),

https://www.fda.gov/downloads/Drugs/GuidanceCompliance

RegulatoryInformation/Guidances/UCM250783.pdf.

arise” in the course of its review. 21 C.F.R. 314.102(a).

The “[d]evelopment of final labeling” generally is then

“an iterative process between the applicant and FDA”

involving a series of communications.5 If FDA reviewers

identify “easily correctable deficiencies” in a supplement,

they will “make every reasonable effort to communicate

[them] promptly to applicants.” 21 C.F.R. 314.102(b).

And if only “editorial or similar minor deficiencies in the

[proposed] labeling” exist, FDA may approve the supplement on the condition that the applicant makes appropriate corrections and submits a copy of the final labeling before marketing the drug with that labeling.

21 C.F.R. 314.105(b).

FDA will reject a supplement, however, if the proposed labeling change is false or misleading or if it does

“not comply with the requirements for labels and labeling in [21 C.F.R. P]art 201.” 21 C.F.R. 314.125(b)(6) and

(8). In such circumstances, FDA will send the applicant

a “complete response letter.” 21 C.F.R. 314.110(a). A

complete response letter reflects FDA’s “complete review of the data submitted” and “will describe all of the

specific deficiencies that the agency has identified.”

21 C.F.R. 314.110(a)(1) and (2).

2. a. Petitioner is the manufacturer of Fosamax, a

brand-name drug that FDA approved in tablet form in

See Center for Drug Evaluation & Research, FDA, CDER 21st

Century Review Process: Desk Reference Guide 37 (2014), https://

www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/Manual

of PoliciesProcedures/UCM218757.pdf; see also FDA, Guidance for

Review Staff and Industry: Good Review Management Principles

and Practices for PDUFA Products 21 (Apr. 2005), https://www.fda.

gov/downloads/drugs/guidancecomplianceregulatoryinformation/

guidances/ucm079748.pdf (addressing “communication between the

FDA and applicants” during “labeling discussions”).

1995 for the treatment of osteoporosis in postmenopausal women. Pet. App. 5a, 12a; see p. 2 n.1, supra. Evidence later began to emerge suggesting a connection

between Fosamax and an increased risk of an unusual

type of thigh-bone fracture known as an “atypical femoral fracture[],” which occurs with no or minimal external trauma and results in a complete fracture of the femur. Pet. App. 6a, 13a-14a. Petitioner kept FDA informed of those studies. Id. at 13a.

In June 2008, FDA informed petitioner that it was

aware of reports regarding the occurrence of atypical

femoral fractures in patients using bisphosphonates

like Fosamax. C.A. App. A1935-A1936. FDA stated

that it was “concerned about this developing safety signal” and asked petitioner to submit any information it

had on the issue. Ibid. Petitioner promptly complied.

Pet. App. 14a.

b. In September 2008, petitioner submitted three

Prior Approval Supplements for its three Fosamax

products that proposed changing the relevant labeling

to address atypical femoral fractures in two respects.

Pet. App. 14a-15a; see p. 2 n.1, supra.6

First, in the Adverse Reactions section (J.A. 715729), petitioner proposed adding a reference to “lowenergy femoral shaft fracture.” J.A. 728; see Pet. App.

16a. Petitioner also proposed including a parenthetical

cross-reference to direct readers to a discussion of

“Low-Energy Femoral Shaft Fracture” proposed for

the Warnings and Precautions section. J.A. 728 (“(see

Relevant portions of one of the PAS applications are available at

J.A. 669-761; see C.A. App. A2697-A2928 (reproducing additional

portions). FDA has confirmed to this Office that petitioner proposed the same relevant labeling language for each of its three

Fosamax products.

PRECAUTIONS, Low-Energy Femoral Shaft Fracture)”) (emphasis omitted).

Second, in the Warnings and Precautions section

(J.A. 703-715), petitioner proposed adding a new

subsection with an identical title: “Low-Energy Femoral Shaft Fracture.” J.A. 707 (emphasis omitted); see

Pet. App. 15a. That subsection stated that “[l]owenergy fractures of the subtrochanteric and proximal

femoral shaft have been reported in a small number of

bisphosphonate-treated patients.” J.A. 707. The proposed warning added that “[s]ome” of those fractures

were “stress fractures (also known as insufficiency fractures),” and the remainder of petitioner’s proposed text

repeatedly referenced stress fractures. Ibid.7

Petitioner supported its applications with evidence

regarding femoral fractures in Fosamax users. Pet.

App. 16a; see, e.g., J.A. 745-761; C.A. App. A2748A2928. The applications stated, as relevant, that petitioner’s use of the term “stress fracture” in connection

with reports of “low-energy subtrochanteric/mid femoral shaft fractures” referred to an “insufficiency fracture” that occurs with no “identifiable external traumatic event.” J.A. 746, 748; see J.A. 748-749, 751. The

treatment data in the applications indicated that 91% of

the fractures resulted in surgical intervention and the

other 9% involved patients who sustained only “incomplete stress fractures.” J.A. 753.

An “insufficiency f [racture]”—which can be associated with

“osteoporosis”—is “a stress fracture that occurs during normal

stress on a bone of abnormally decreased density”; it is thus different from the type of “stress f [racture]” experienced by athletes (a

fatigue fracture) “caused by unusual or repeated stress on a bone.”

Dorland’s Illustrated Medical Dictionary 710-711 (29th ed. 2000).

In May 2009, FDA issued a Complete Response Letter (J.A. 510-513) informing petitioner that FDA could

not “approve the[] applications in their present form.”

J.A. 511; see Pet. App. 18a. FDA stated that it “agree[d]

that atypical and subtrochanteric fractures should be

added” to the Adverse Reactions labeling section. J.A.

511. FDA therefore recommended that petitioner modify its proposed text (J.A. 728) for that section to read

“low energy femoral shaft and subtrochanteric fractures.” J.A. 512. With respect to petitioner’s Warnings

and Precautions proposal, however, FDA determined

that the “justification for the proposed [Warnings and

Precautions] section language is inadequate.” J.A. 511.

The letter also stated that “[i]dentification of ‘stress

fractures’ may not be clearly related to the atypical subtrochanteric fractures that have been reported in the

literature” and that “[d]iscussion of the risk factors

for stress fractures is not warranted and is not adequately supported by the available literature and postmarketing adverse event reporting.” J.A. 511-512.

In June 2009, petitioner updated the Adverse Reactions section of its Fosamax labeling (J.A. 253, 267-274)

using FDA’s recommended text. J.A. 274; see J.A. 279.

Petitioner then withdrew its three pending PASs, J.A.

654-655, and submitted new CBE supplements for that

labeling change as the “quickest route to update” its labeling, J.A. 657-658. FDA later approved these CBE

supplements.8

See FDA, Supplement Approval 1-2 (Mar. 1, 2010), https://www.

accessdata.fda.gov/drugsatfda_docs/appletter/2010/020560s051s05

5s057,021575s012s016s018ltr.pdf (NDA 20560/S-057 and 21575/

S-018); FDA, Supplement Approval 1-2 (Mar. 1, 2010), https://www.

accessdata.fda.gov/drugsatfda_docs/appletter/2010/021762s005s00

9sS010ltr.pdf (NDA 21762/S-010).

c. Nearly a year after its Complete Response Letter, and after reviewing additional data submitted by

petitioner and other manufacturers, FDA issued a

Safety Announcement in March 2010 (J.A. 519-522)

stating that “FDA’s review of these data did not show

an increase in [a] risk [of atypical subtrochanteric femur fractures] in women using [bisphosphonates],” but

that FDA was working with an outside expert task force

to “gather additional information.” J.A. 519-520 (stating that the data “ha[d] not shown a clear connection

between bisphosphonate use and [that] risk”); see Pet.

App. 19a.

On September 14, 2010, the task force completed its

report, which identified an apparent association between long-term bisphosphonate use and certain atypical femoral fractures. Pet. App. 20a; see J.A. 523.

d. On October 13, 2010, after studying the report,

FDA exercised its authority under 21 U.S.C. 355(o)(4)

to initiate safety-based changes to Fosamax’s labeling.

See J.A. 526-527, 546 (FDA letter dated Oct. 13, 2010).

Under Section 355(o)(4), the Secretary of Health and

Human Services, acting through FDA, “shall promptly

notify” a brand-name drug manufacturer as the “responsible person” for a drug “[i]f the Secretary becomes

aware of new safety information that the Secretary believes should be included in the labeling of the drug.”

21 U.S.C. 355(o)(4)(A); see 21 U.S.C. 355(o)(2)(A)(ii)

(defining “responsible person”). Within 30 days, the

manufacturer then must either submit a supplemental

application to change the labeling or notify the Secretary that (and explain why) it believes that no change is

warranted. 21 U.S.C. 355(o)(4)(B). The Secretary must

“promptly review and act upon such supplement” and,

if the Secretary disagrees with the manufacturer’s labeling proposal or disagrees with the manufacturer’s

view that no changes are warranted, the Secretary “shall

initiate discussions” to reach agreement within 30 days

regarding a labeling change. 21 U.S.C. 355(o)(4)(C) and

(D). The Secretary may thereafter “issue an order directing” the manufacturer “to make such a labeling

change as the Secretary deems appropriate to address

the new safety information.” 21 U.S.C. 355(o)(4)(E).

FDA announced its decision to the public by explaining that it was requiring bisphosphonate manufacturers

to modify their labeling to include information regarding the risk of such fractures in, among other places, the

Warnings and Precautions section. J.A. 246, 249. In a

briefing to reporters, FDA’s Deputy Director for the

Office of New Drugs explained that the data that FDA

had previously reviewed was insufficient to allow the

agency to “tease out the association between [bisphosphonates] and these rare atypical fractures,” but that

the task force’s September 2010 report had helped FDA

“understand the[] fractures” better, “provide[d] more

information that more closely associate[d] the[] atypical

fractures with long-term bisphosphonate use,” and persuaded FDA that such fractures were “more closely related to these drugs * * * than [FDA] previously had evidence for.” J.A. 488-489, 493-494; see J.A. 486.

FDA’s October 2010 letter invoking Section 355(o)(4)

likewise notified petitioner that FDA “ha[d] become

aware of a possible increased risk of atypical subtrochanteric and diaphyseal femoral fractures in patients

taking bisphosphonates, including Fosamax,” and that

FDA now believed that new safety information about

that risk should be included in Fosamax’s labeling, in-

cluding changes to the Warnings and Precautions section. J.A. 527, 528-529. In response, petitioner proposed a labeling change that utilized the term “stress

fractures.” Pet. App. 22a. FDA thereafter struck those

references from petitioner’s proposal in the course

of approving the labeling change because, an FDA

employee explained, the term would suggest to most

practitioners “a minor fracture” that “would contradict

the seriousness of the atypical femoral fractures” at issue. J.A. 566, 606-607; see Pet. App. 22a-23a; cf. J.A.

547, 549-628 (redline showing FDA edits to petitioner’s

proposed labeling).

3. Over 1000 plaintiffs subsequently filed separate

state-law tort actions against petitioner, alleging that

they had sustained atypical femoral fractures caused by

taking Fosamax. Pet. App. 4a, 23a. Although plaintiffs

asserted an array of tort theories, they generally alleged that petitioner had failed to provide adequate

warnings on its Fosamax labeling. Id. at 4a, 24a. The

cases were consolidated for pretrial proceedings as a

multidistrict litigation (MDL). Id. at 23a.

One bellwether case within the MDL was selected

for trial on its failure-to-warn claim. Pet. App. 24a-25a

& n.64. Petitioner moved for summary judgment on

preemption grounds, but the district court did not immediately rule on the motion. Id. at 163a. After a jury

rendered a verdict for petitioner on case-specific grounds,

the court rendered a post-trial decision holding that the

bellwether plaintiffs’ failure-to-warn claim was preempted. Id. at 25a-26a, 153a-174a.

The district court subsequently extended that preemption holding to the other MDL cases in which the

plaintiff was injured before September 14, 2010—the

date of the expert task force report—and granted judgment to petitioner in those cases. Pet. App. 152a; see

id. at 113a-152a.

4. The court of appeals vacated and remanded. Pet.

App. 1a-74a.

The court of appeals concluded that its impossibilitypreemption analysis was controlled by this Court’s decision in Wyeth v. Levine, supra, which the court viewed

as teaching that a drug-focused failure-to-warn claim is

preempted “where there is ‘clear evidence that the FDA

would not have approved a change’ to the label,” Pet.

App. 32a-33a (quoting Wyeth, 555 U.S. at 571). See id.

at 28a-55a. The court concluded that Wyeth’s “clear evidence” discussion “announce[d] a standard of proof ”

that is “synonymous with ‘clear and convincing evidence’ ” and required proof showing it “is highly probable that the FDA would not have approved a change to

the drug’s label.” Id. at 35a, 37a; see id. at 33a-37a. The

court further concluded that the relevant preemption

determination—which involves “predict[ing] how the

FDA would have reacted in a hypothetical scenario” involving a new proposal to strengthen labeling warnings,

id. at 51a-52a—is a factual determination for a jury, not

a legal one for a court. Id. at 38a-55a.

Applying those principles, the court of appeals held

that summary judgment should not have been granted

to petitioner. Pet. App. 55a-74a. As relevant here, the

court determined that a “reasonable jury” could conclude that petitioner could have revised the Warnings

and Precautions section of its labeling before September 2010. Id. at 56a-57a, 67a. A jury, the court reasoned, could find that FDA’s 2009 decision to reject petitioner’s proposed revision to that section was not

based on FDA’s determination that the evidence at the

time was insufficient to indicate that Fosamax caused

atypical femoral fractures, but rather was based on

FDA’s dissatisfaction with the proposal’s use of the

term “stress fractures,” which medical practitioners

might misunderstand to refer to fractures less serious

than the femoral fractures in question, id. at 64a-66a.

See id. at 59a-68a.9

SUMMARY OF ARGUMENT

Petitioner provided FDA with the relevant scientific

data about Fosamax’s risks and, in May 2009, FDA rejected petitioner’s proposal to add a warning about

atypical femoral fractures in the Warnings and Precautions section of Fosamax’s labeling. The court of appeals erroneously rejected petitioner’s impossibilitypreemption defense to respondents’ state-law failureto-warn claims, based on its determination that preemption required petitioner to establish by “clear and convincing” evidence that FDA would have denied a CBE

supplement, which the court deemed to be a factual

question for a jury to decide. The proper focus here is

on whether FDA’s May 2009 decision embodied a determination by FDA that insufficient causal evidence existed

to warrant strengthening the Warnings and Precautions section of the Fosamax labeling to address atypical femoral fractures. That is a question of law for a

court to resolve, not a question of fact for a jury. Moreover, FDA’s 2009 decision, construed in light of the

governing regulatory regime, and FDA’s subsequent

The court of appeals also concluded that the district court erred

in granting summary judgment on claims based on the Adverse

Reactions section of Fosamax’s labeling before its 2009 revision,

Pet. App. 69a-73a, and on non-failure-to-warn claims, id. at 74a.

actions show that petitioner could not have altered

Fosamax’s labeling until late 2010.

A. FDA’s May 2009 Complete Response Letter is a

legal document reflecting the agency’s exercise of legal

authority to adjudicate petitioner’s regulatory labeling

application. The meaning and effect of such agency

action is a legal question within the exclusive province

of a court. Indeed, courts have long been vested with

authority to interpret agency action as a question of law.

See, e.g., 5 U.S.C. 706. Judges, rather than lay juries,

are best suited to evaluate the scope of an agency’s determination because judges are trained and experienced in construing legal documents and are far better

equipped to understand agency decisions in light of the

governing statutory and regulatory context. Vesting

that legal construction in judges familiar with administrative law also fosters the type of interpretive uniformity appropriate when determining the scope and effect of federal agency action. That holds true even when

subsidiary factual questions are relevant to the court’s

legal determination of the meaning and effect of agency

action. Cf. Markman v. Westview Instruments, Inc.,

517 U.S. 370, 388-389 (1996).

B. The court of appeals concluded that Wyeth v.

Levine, 555 U.S. 555 (2009), required a clear-andconvincing-evidence standard, Pet. App. 35a-37a, that a

jury must apply in this case, id. at 38a-55a. But Wyeth

addressed distinct circumstances and did not address

how to determine the meaning and effect of an actual

FDA labeling decision. The longstanding rule is that

judges, not courts, interpret such agency action as a

question of law. Nor does Wyeth’s passing reference to

“clear evidence” alter the preponderance-of-the-evidence

standard that applies in civil actions involving monetary

disputes between private litigants.

C. FDA’s May 2009 Complete Response Letter, the

relevant regulatory context, and the agency’s subsequent actions concerning Fosamax demonstrate that

FDA determined that existing information about atypical

femoral fractures was insufficient to warrant a change

to Fosamax’s Warnings and Precautions section. The

record amply demonstrates that petitioner could not

have updated its labeling until late 2010. Accordingly,

respondents’ corresponding state-law failure-to-warn

claims are preempted.

ARGUMENT

THE COURT OF APPEALS ERRED IN REJECTING

PETITIONER’S PREEMPTION DEFENSE

The court of appeals erred in holding that a jury

must determine whether FDA’s May 2009 decision—

which declined to approve petitioner’s proposal to revise Fosamax’s Warnings and Precautions section to

warn against “[l]ow-energy fractures of the subtrochanteric and proximal femoral shaft,” J.A. 707—preempted

respondents’ state-law failure-to-warn claims arising

from that same type of injury. Where, as here, FDA

renders a decision declining to approve a drug-labeling

change, the interpretation of that administrative decision and its significance for a failure-to-warn claim are legal questions for a court to resolve, not factual questions for a jury. Moreover, because FDA’s action prevented petitioner from modifying the relevant labeling

before late 2010, the court of appeals erred in rejecting

petitioner’s impossibility-preemption defense.

A. Petitioner’s Preemption Defense Turns On The Meaning

And Effect Of FDA’s 2009 Complete Response Letter,

Which Are Legal Questions That A Court Must Resolve

“The question for ‘impossibility’ [preemption] is

whether the private party could independently do under

federal law what state law requires of it.” PLIVA, Inc.

v. Mensing, 564 U.S. 604, 620 (2011). A state-law failureto-warn claim that rests on the contention that a drug

manufacturer failed to provide adequate warnings on

drug labeling is therefore preempted if, under federal

law, the manufacturer could not have “independently”

altered the labeling at the relevant time without FDA’s

“special permission and assistance.” Id. at 618-619, 623624 & n.8. As a general matter, a name-brand drug

“manufacturer may only change a drug label after the

FDA approves a supplemental application.” Wyeth v.

Levine, 555 U.S. 555, 568 (2009). When that is so, potential failure-to-warn claims are preempted.

Some failure-to-warn claims, however, are not preempted under the Court’s formulation in Mensing. A

manufacturer may in certain circumstances submit a

CBE supplement, which, upon its receipt by FDA, “permits [the] manufacturer to make certain [safety-based]

changes to its label[ing] before receiving the agency’s

approval.” Wyeth, 555 U.S. at 568 (emphasis added);

see pp. 4-5, supra (discussing CBE process). FDA may

thereafter disapprove the supplemental application and

order the manufacturer to cease distributing the drug

with such labeling changes. 21 C.F.R. 314.70(c)(7).

This Court has accordingly concluded that a brandname drug manufacturer will establish an impossibilitypreemption defense by sufficiently establishing that

FDA “would not have approved [the relevant] change to

[the drug’s] label[ing]” under its CBE regulation. Wyeth,

555 U.S. at 571; see Mensing, 564 U.S. at 624 n.8.

In this case, the court of appeals held that the relevant judicial task in resolving petitioner’s preemption

defense “is to predict how the FDA would have reacted”

under the requirements of its “CBE regulation” “in a

hypothetical scenario” involving “a different label

amendment than the one it actually rejected in [its] May

2009 [Complete Response] letter.” Pet. App. 51a-52a.

That is incorrect. The threshold inquiry here is whether

FDA’s May 2009 decision embodied a determination by

FDA that insufficient causal evidence existed to warrant

strengthening Fosamax’s Warnings and Precautions

section to address atypical femoral fractures. If FDA’s

May 2009 decision did reflect such a determination, then

petitioner has established an impossibility-preemption

defense. And the meaning of FDA’s Complete Response

Letter is a question of law for a court to resolve, not a

question of fact for a jury.

1. Courts, not juries, determine the meaning of federal

agency decisions

A federal agency’s written decision on a regulatory

application is a legal document: an agency action that

embodies the agency’s exercise of legal authority to adjudicate the application. Cf. 5 U.S.C. 551(6) and (7) (defining agency adjudication). The meaning and effect of

such agency action present legal questions within the

exclusive province of a court.

When Congress enacted the Administrative Procedure Act (APA), 5 U.S.C. 551 et seq., 701 et seq., it specified that a “reviewing court shall * * * determine the

meaning or applicability of the terms of an agency action.” 5 U.S.C. 706. That provision reflects the longstanding view that “questions respecting the * * *

terms of any agency action” and the “application”

thereof are “questions of law” and therefore matters for

“courts * * * to decide.” H.R. Rep. No. 1980, 79th Cong.,

2d Sess. 44 (1946); see U.S. Dep’t of Justice, Attorney

General’s Manual on the Administrative Procedure

Act 108 (1947) (APA’s review provision “restates the

present law”).

The legal nature of that inquiry is consistent with

this Court’s precedent addressing the meaning and

effect of a prior judicial adjudication. When issues

adjudicated in prior litigation are relevant to factfinding

in a subsequent civil action, this Court has held that the

question of “[w]hat issues were decided [in that prior]

litigation is * * * a question of law” that the trial court

must itself decide by examining relevant materials from

the prior case. Emich Motors Corp. v. General Motors

Corp., 340 U.S. 558, 571-572 (1951). That holds true

even where a jury must consider “the scope and effect

of the former judgment on the case at trial.” Id. at 572;

see id. at 568. In such circumstances, the trial court

must first determine the prior adjudication’s scope and

effect before “instruct[ing] the jury” on its legal determination. Id. at 571. Just as the scope of a prior judicial

adjudication is a question of law for a court to decide, so

too is the scope of a federal agency adjudication like the

one at issue here.

No sound reason exists for treating the meaning and

effect of an FDA administrative determination any differently. Judges, rather than lay juries, are best suited

to evaluate the scope of an agency’s determination, both

because judges are trained and experienced in “[t]he

construction of written instruments,” Markman v.

Westview Instruments, Inc., 517 U.S. 370, 388 (1996), and

because judges are far better equipped to understand and

interpret agency decisions in light of the governing statutory and regulatory context. Moreover, framing the

decision as a question of law to be decided by judges familiar with principles of administrative law will foster

the type of uniformity appropriate when determining

the scope and effect of federal agency action. See id. at

390-391; id. at 391 (concluding that uniformity would “be

ill served by submitting issues of document construction

to juries”). Whether the agency action is a notice-andcomment regulation or something less formal like the

adjudicatory decision at issue here, the meaning of

agency action is a legal question that a court should decide. See, e.g., Sprietsma v. Mercury Marine, 537 U.S.

51, 64-68 (2002); cf. Perez v. Mortgage Bankers Ass’n,

135 S. Ct. 1199, 1208 n.4 (2015) (“[I]t is the court that

ultimately decides wh[at] a given regulation means.”).

2. Factual findings necessary to interpret a federal

agency decision are also matters for courts to resolve

In some contexts, disputed factual questions can be

relevant to a court’s legal determination of the meaning and effect of an agency decision. For example, if

FDA rejected a labeling supplement on the ground that

the information supporting it was insufficient to warrant a labeling change, the meaning and scope of that

decision can depend on what information FDA had before it. Yet in tort litigation between private parties

(which typically will lack compilation of an official administrative record for an FDA decision), litigants may

dispute whether a drug manufacturer submitted all material data to FDA. In addition, to the extent that an

agency decision read in the proper regulatory context is

insufficiently clear, a private litigant might seek to submit extrinsic material to provide further context for interpreting the decision. Where consideration of such

material requires resolution of factual matters for a

court to determine the meaning and scope of the agency

decision, the court itself should resolve them.

This Court in Markman confronted analogous circumstances when it held that “the construction of a patent”

is a “purely legal” issue “exclusively within the province

of the court.” 517 U.S. at 372, 391. The Court reasoned

that “judges, not juries, are the better suited” for discerning the meaning of patent terms, even though factual questions involving “credibility determinations”

are sometimes “subsumed” within the relevant analysis.

Id. at 388-389. In other words, the “ultimate issue of

the proper construction of a [patent] claim [is] treated

as a question of law” for a court to decide, even though

“subsidiary factfinding is sometimes necessary.” Teva

Pharm. USA, Inc. v. Sandoz, Inc., 135 S. Ct. 831, 838

(2015). The same rationale applies here. To the extent

extrinsic evidence may sometimes be relevant in litigation between private parties to determine the meaning

and effect of FDA’s agency action, the court’s evaluation of such subsidiary facts does not alter the ultimate

legal character of the inquiry or the court’s exclusive

authority to resolve it.

B. The Court Of Appeals Erred In Holding That, Under

Wyeth v. Levine, A Jury Must Resolve Petitioner’s

Preemption Defense As A Factual Matter Subject To A

Clear-And-Convincing-Evidence Standard

The court of appeals should have treated the interpretation of FDA’s 2009 labeling decision as a legal

question for the courts to decide. As explained further

below, the basis for FDA’s 2009 Fosamax labeling decision is properly determined as a matter of law from

FDA’s Complete Response Letter, read in the context

of petitioner’s underlying labeling supplement and the

governing regulatory framework and related FDA actions. See pp. 30-34, infra.

The court of appeals, however, concluded that petitioner’s preemption defense presented a question of

fact for a jury and this Court’s decision in Wyeth v. Levine, supra, required petitioner to provide “clear evidence” from which a jury could find that FDA “would

[have] reject[ed] [the] plaintiff ’s proposed warning” for

Fosamax if petitioner had proposed that warning to

FDA. Pet. App. 33a, 54a. In addressing that “hypothetical scenario,” the court of appeals determined that a

jury could reasonably conclude that “FDA rejected [petitioner’s] proposed warning about femoral fractures in

2009 not because” FDA deemed the “causal link between Fosamax and fractures” to be insufficient, but because FDA was dissatisfied with petitioner’s proposed

text. Id. at 51a, 64a-65a. There was nothing “hypothetical” about FDA’s actual 2009 decision in this case,

and nothing in Wyeth addresses how courts should determine the meaning and effect of such actual agency

action.

1. Wyeth did not address whether courts or juries

should construe an actual FDA decision

In Wyeth, this Court determined that a state-law

failure-to-warn claim involving a brand-name drug was

not foreclosed by the doctrine of impossibility preemption, because the drug manufacturer had a duty to ensure the adequacy of its own labeling and could have invoked FDA’s CBE regulation to update its labeling

promptly to provide additional warnings. 555 U.S. at

570-573. The Court recognized that “FDA retains authority to reject [a manufacturer’s unilateral] labeling

changes made pursuant to the CBE regulation,” id. at

571, but it explained that Wyeth did “not argue” that

any actual FDA decision had “prohibited” it from

strengthening its labeling, id. at 572.

The Court instead viewed Wyeth as arguing that

FDA had “intended to prohibit it” from changing the labeling when FDA approved prior applications for the

relevant drug, a contention that the state trial and supreme courts had rejected. 555 U.S. at 572 & n.5. Thus,

without any relevant agency decision at hand, this

Court stated that it would not conclude that it was

impossible for Wyeth to comply with both federal and

state requirements “absent clear evidence that the

FDA would not have approved a change to [the] label[ing]” in question. Id. at 571 (emphasis added). In

other words, the Court reasoned that Wyeth needed to

make a clear showing that “FDA would have rescinded

any change in the label” that Wyeth made through the

CBE process in order to establish the impossibility of

such a change. Mensing, 564 U.S. at 624 n.8. The Court

concluded that Wyeth, which did “not argue” that it had

provided FDA with an analysis of the “specific dangers”

in question, had failed to show that “FDA would have

prevented it from adding a stronger warning.” Wyeth,

555 U.S. at 572-573.

Because Wyeth discussed the question whether FDA

would have rejected a CBE labeling change if the manufacturer in that case had unilaterally made such a

change to strengthen its labeling, Wyeth did not resolve

how to determine the meaning and effect of an actual

FDA decision rejecting a proposed labeling change.

For that reason, the court of appeals erred in transplanting Wyeth’s discussion about the need for “clear

evidence” of what FDA “would have [done]” to this context, which concerns the meaning and effect of what

FDA actually did. This Court has long cautioned that

it is “often misleading” to transplant “[g]eneral expressions” from one opinion “to other facts” because every

opinion must be “read in the light of the facts of the case

under discussion.” Armour & Co. v. Wantock, 323 U.S.

126, 133 (1944); see Landgraf v. USI Film Prods.,

511 U.S. 244, 265 (1994) (citing Cohens v. Virginia,

19 U.S. (6 Wheat.) 264, 399 (1821) (Marshall, C.J.)). Wyeth simply does not speak to the circumstances presented here.

2. Any factual findings necessary to resolve a preemption

defense need only rest on a preponderance of the

evidence

The court of appeals erroneously determined (Pet.

App. 35a-37a) that Wyeth requires “a factual showing”

of impossibility by “clear and convincing evidence” in

order to establish a preemption defense. To the extent

any factual disputes must be resolved to establish

preemption, the proper standard of proof is a preponderance of the evidence.

a. The preponderance-of-the-evidence standard applies in “civil actions between private litigants unless

‘particularly important individual interests or rights are

at stake’ ” or a statute prescribes a different standard.

Grogan v. Garner, 498 U.S. 279, 286 (1991); see Microsoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 100-103

(2011) (interpreting patent statute to require clear-andconvincing evidence in certain contexts). 10 Accordingly,

The clear-and-convincing evidence standard applies when, for

instance, the government seeks to terminate an individual’s parental rights, Santosky v. Kramer, 455 U.S. 745, 769-770 (1982), or

seeks to deprive an individual of liberty in involuntary commitment

proceedings, Addington v. Texas, 441 U.S. 418, 433 (1979).

in a “typical civil case involving a monetary dispute between private parties,” the preponderance standard applies because private litigants should “share the risk of

error in roughly equal fashion.” Addington v. Texas,

441 U.S. 418, 423 (1979); see, e.g., Rivera v. Minnich,

483 U.S. 574, 576, 579 (1987) (action by mother to obtain

child-support payments by establishing paternity).

This is a typical private civil action for money damages, and nothing warrants a higher standard of proof

to resolve the preemption question here. The Court’s

preemption decisions do not suggest that a higher

evidentiary showing would generally be required where

resolution of factual issues is necessary to establish that

a state-law duty conflicts with federal law. Although the

Court has applied a presumption against implied conflict preemption, that presumption is a “rule of construction [that] rests on an assumption about congressional intent,” Arizona v. Inter Tribal Council of Ariz.,

Inc., 570 U.S. 1, 13 (2013) (emphasis added), not an evidentiary principle governing the standard of proof. Cf.

Microsoft Corp., 564 U.S. at 103 (noting that the existence of a presumption alone does not “establish[] the

governing standard of proof ”); Fed. R. Evid. 301 (evidentiary presumptions shift the burden of production

unless a statute or rule provides otherwise).

b. The court of appeals based its “clear and convincing evidence” requirement on a single sentence in Wyeth, Pet. App. 35a & n.94, 37a, in which the Court stated

that it “w[ould] not conclude that it was impossible” for

Wyeth to strengthen a drug’s labeling under the CBE

process “absent clear evidence that the FDA would not

have approved a change to [the] label,” 555 U.S. at 571

(emphasis added). But Wyeth did not squarely address

or definitively resolve the relevant standard of proof

with the phrase “clear evidence.” Cf. Pet. App. 28a, 33a35a (characterizing Wyeth’s discussion as “cryptic”).

Wyeth provides no analysis or any citation to suggest

the Court believed it was imposing a higher burden of

proof with respect to factual issues, and Wyeth’s passing reference to “clear” evidence is not properly read to

require one.

This Court has used the term “clear evidence” in contexts in which the Court analyzes preemption issues as

a question of law, reflecting an interpretive presumption against preemption. See, e.g., Geier v. American

Honda Motor Co., 529 U.S. 861, 885 (2000) (noting that

“a court should not find pre-emption too readily in the

absence of clear evidence of a conflict”); English v. General Elec. Co., 496 U.S. 72, 86 (1990) (“[W]e find no evidence of a ‘clear and manifest’ intent on the part of Congress to pre-empt tort claims like petitioner’s.”). The

Court has also held that its use of the even more specific

phrase “clear and convincing evidence” in another context involving a question of law should not be understood in its “strict evidentiary sense,” but merely as a

“useful reminder” that a general presumption concerning a legal interpretation should control if substantial

doubt exists about “congressional intent.” Block v.

Community Nutrition Inst., 467 U.S. 340, 350-351

(1984). The Court in Wyeth appears to have similarly

used the phrase not as a shorthand for a formal clearand-convincing evidentiary standard, but merely to indicate that a manufacturer asserting preemption must

show that a labeling change was not warranted under

the relevant statutory and regulatory framework. If

the Court had intended to depart from the preponderance standard that applies to factual issues in almost all

civil actions between private litigants, it presumably

would have explained such an unusual departure.

3. Resolving this case does not require factual findings

a. As the case comes to this Court, the preemption

question is limited to a situation in which FDA considered the “relevant scientific data” in a prior labeling decision, Pet. i. See Gov’t Cert. Amicus Br. 19 n.10; see

also Pet. Br. 35 (discussing Sup. Ct. R. 15.2). This case

is therefore properly resolved solely on the basis of a

legal interpretation of FDA’s 2009 labeling decision in

light of the governing regulatory regime and subsequent FDA action. Respondents argue (Br. in Opp. 26)

that, because petitioner relied below on an internal company document describing a telephone conversation with

an FDA employee about petitioner’s proposed labeling

change, see Pet. App. 17a; J.A. 764-767, a factfinder

should assess the reliability and weight of that evidence.

But assuming that it would be appropriate to rely on

such material in interpreting an agency decision, as explained above (pp. 20-21, supra), such a subsidiary factual question would be for courts to resolve in construing the meaning of FDA’s 2009 decision; and as explained below (pp. 30-34, infra), there is in any event no

need here for resort to such evidence because the meaning of FDA’s 2009 decision is clear.

To be sure, an actual FDA labeling decision might

not in itself resolve preemption if, for instance, FDA did

not consider certain safety information in approving

name-brand drug labeling or in denying a labeling

change because the information was not provided to

FDA or because it arose after FDA’s decision. In such

a situation, a plaintiff could argue that information that

FDA did not consider constitutes “newly acquired information,” 21 C.F.R. 314.3(b), 314.70(c)(6)(iii)(A), showing

that the drug caused a sufficiently serious hazard to

have allowed the manufacturer to update its labeling

under the CBE process. Cf. pp. 3-5, supra.11 The

proper adjudication of such a contention would need to

account for the meaning and scope of any prior FDA labeling decision and the information that FDA previously evaluated in light of the governing statutory and

regulatory scheme (matters that the court must resolve,

see pp. 18-21, supra) in order to determine whether any

arguably new information is materially different from

the information that FDA previously determined to be

insufficient. This case, however, does not present that

question.

b. Respondents incorrectly analogize (Br. in Opp.

26; Supp. Cert. Br. 11) this case to Boyle v. United Technologies Corp., 487 U.S. 500 (1988). In Boyle, this Court

discussed the jury’s role in evaluating whether a military contractor could raise a federal-common-law defense to a state-law design-defect claim. Id. at 504, 507508, 514; see Buckman Co. v. Plaintiffs’ Legal Comm.,

531 U.S. 341, 347 (2001) (describing Boyle). That defense required the contractor to make three factbound

showings: (1) the United States approved reasonably

Information—including “new analyses of previously submitted

data”—will qualify as “[n]ewly acquired information” only if it “reveal[s] risks of a different type or greater severity or frequency than

previously included in submissions to FDA.” 21 C.F.R. 314.3(b).

Accordingly, nominally “new” information concerning risks of a materially similar type, severity, and frequency as those revealed in

information previously evaluated by FDA is cumulative and not

“newly acquired information” that could justify a CBE supplement.

If for instance, FDA previously determined that that evidence of X

was insufficient to warrant a warning about risk Y, the existence of

additional but similar information about X would be insufficient to

justify a warning.

precise specifications; (2) the allegedly defective military equipment conformed to those specifications; and

(3) the contractor warned the United States about the

dangers in the use of the equipment that were known to

the contractor but not to the United States. Boyle,

487 U.S. at 512. In that context, the Court concluded

that “whether the facts establish the conditions for the

defense is a question for the jury,” and it “would be error” for a reviewing court to itself determine that “the

defense had [not] been established” unless “no reasonable jury” could have found that “that the Government

contractor defense was inapplicable.” Id. at 514.

Boyle, like Wyeth, did not involve the interpretation

of an actual federal agency decision. Boyle thus does

not address the key question here: whether the interpretation of FDA’s 2009 decision is a legal inquiry for a

court. Nor did Boyle address whether a jury should resolve the ultimate matter of preemption when preemption turns on the application of a complex regulatory regime implemented by an expert federal agency like

FDA. Cf. Riegel v. Medtronic, Inc., 552 U.S. 312, 325

(2008) (observing that a jury that “sees only the cost” of

an FDA-approved product in a lawsuit about a plaintiff ’s injuries is unlikely to “apply cost-benefit analysis

similar to that applied by the experts at the FDA”).

Certainly, Boyle did not hold that the ultimate matter

of preemption must always rest with a jury when the

parties dispute what might be characterized as underlying factual issues. That question, which is not presented here, warrants further development in the lower

courts once this Court has clarified that the preemptive

effect of federal agency decisions involves legal questions for courts rather than juries.

C. FDA’s May 2009 Decision Rejected A Change To

Fosamax’s Warnings And Precautions Because The Data

At That Time Was Insufficient To Justify A Change

FDA’s May 2009 decision rejecting petitioner’s proposal to modify Fosamax’s Warnings and Precautions

section to address atypical femoral fractures was based

on the agency’s determination that the information

about that risk was then insufficient to justify such a

warning. That conclusion flows directly from the terms

of the agency’s May 2009 Complete Response Letter,

the relevant regulatory context, and the agency’s subsequent actions. Given FDA’s determination, respondents’ claim that petitioner should have updated its

Warnings and Precautions labeling before late 2010 is

preempted.

FDA’s Complete Response Letter (J.A. 510-513)

shows that FDA determined that the existing data for

atypical femoral fractures was sufficient to update

Fosamax’s Adverse Reactions section, but not its Warnings and Precautions section. FDA determined that

“atypical and subtrochanteric fractures should be

added” as adverse reactions, J.A. 511, reflecting that

FDA found “some basis to believe there [wa]s a causal

relationship between the drug and the occurrence of

th[at] adverse event.” 21 C.F.R. 201.57(c)(7).

Petitioner’s proposed addition to the Warnings and

Precautions section was based on the exact same risk.

Petitioner proposed a title (“Low-Energy Femoral

Shaft Fracture”) for its proposed subsection in Warnings and Precautions, J.A. 707, that was identical (with

only differing capitalization) to its proposed text for the

Adverse Reactions section, J.A. 728. The proposed

warning for “[l]ow-energy fractures of the subtrochanteric and proximal femoral shaft,” J.A. 707, likewise

addressed the same type of adverse reaction that FDA

concluded should be added to Fosamax’s labeling. See

J.A. 512 (FDA’s recommendation to add “low energy

femoral shaft and subtrochanteric fractures” to Adverse Reaction section). And because both proposed labeling additions addressed the same risk, petitioner

proposed adding an explicit cross-reference in the labeling’s Adverse Reactions section (“[S]ee PRECAUTIONS,

Low-Energy Femoral Shaft Fracture,” J.A. 728) that

would have directed readers to the more fulsome description of the same hazard proposed for the Warnings

and Precaution section.

Under the governing regulations, however, such an

adverse reaction is to be elevated to the Warnings and

Precautions section only if “reasonable evidence of a

causal association with [the] drug” exists. 21 C.F.R.

201.57(c)(6)(i). Here, FDA rejected petitioner’s addition because the “justification for the proposed [Warnings and Precautions] section language [wa]s inadequate.” J.A. 511 (emphasis added). Petitioner had also

proposed stating that “[s]ome” of the reported fractures were “insufficiency” “stress fractures,” J.A. 707.

See p. 8 & n.7, supra. But FDA determined that such

fractures “may not be clearly related to the atypical

subtrochanteric fractures * * * reported in the literature,” and the associated discussion of stress-fracture

risk factors was likewise “not adequately supported by

the available literature and post-marketing adverse

event reporting.” J.A. 511-512 (emphases added).

FDA’s decision thus was based on the lack of adequate

data to support a warning.

The court of appeals focused instead on the possibility that “FDA [might have] rejected [petitioner’s] proposed warning” because of the warning’s use of the term

“stress fractures.” Pet. App. 64a-65a. But a Complete

Response Letter reflects “FDA’s complete review of

the data submitted”; and FDA’s regulations make clear

that the letter need not address any “proposed product

labeling” if FDA determines that the “data submitted

are inadequate.” 21 C.F.R. 314.110(a)(2) and (3) (emphasis added). By contrast, if FDA determines that a

safety-based labeling change is warranted based on the

data, FDA will attempt promptly to identify easily correctable deficiencies in the proposed text and will develop

final labeling text with the manufacturer in an iterative

process. See pp. 5-6, supra. As a result, the May 2009

letter embodies FDA’s “recommend[ation]” that petitioner modify its proposed Adverse Reactions text with

language (shown here in italics) that FDA itself proposed: “low energy femoral shaft and subtrochanteric

fractures.” J.A. 512 (emphasis added); cf. J.A. 728 (petitioner’s proposal). FDA made no similar suggestions

for revisions to petitioner’s proposed addition in the

Warnings and Precautions section because no warning

was justified based on the information at the time.

That understanding is reinforced by FDA’s subsequent actions in late 2010, when it concluded that the

Warnings and Precautions section should be revised.

FDA personnel directly edited petitioner’s proposed

language to remove stress-fracture references deemed

insufficiently clear. Pet. App. 22a-23a; see J.A. 547, 549628 (email with redline showing FDA edits to petitioner’s proposed labeling); J.A. 606-607 (FDA edits to

proposed warning about atypical subtrochanteric and

diasphyseal femoral fractions). No sound basis thus exists for concluding that FDA determined in May 2009

that the data was sufficient to warrant a warning but

that it rejected petitioner’s proposal because of petitioner’s proposed text. Cf. Dolin v. GlaxoSmithKline

LLC, No. 17-3030, 2018 WL 4001208, at *9 (7th Cir. Aug.

22, 2018) (concluding that it would be “unreasonable” to

conclude that FDA rejected a proposed warning because the manufacturer had proposed adding it to the

wrong place in the labeling, rather than because FDA

had concluded that the warning was not warranted).

Significantly, FDA’s own regulations require that

the Warnings and Precautions section “must be revised” to add such a clinically significant hazard “as

soon as” sufficient causal evidence exists. 21 C.F.R.

201.57(c)(6)(i) (emphasis added). And if FDA had

“believe[d]” in May 2009 that the “new safety information” that petitioner had submitted “should [have]

be[en] included in [Fosamax’s] labeling,” Section

355(o)(4) would have required that FDA “promptly notify” petitioner, 21 U.S.C. 355(o)(4)(A), and engage in expedited discussions to revise the labeling, 21 U.S.C.

355(o)(4)(B)-(D). Given the statutory and regulatory

framework, it would not be reasonable to interpret

FDA’s 2009 decision as reflecting a determination that

a new warning was justified but that FDA rejected petitioner’s proposed warning because petitioner’s proposed text was inadequate.

Indeed, nearly a year later, in March 2010, FDA

announced—after reviewing further information—that

it had yet to identify an “increase in [a] risk [of atypical

subtrochanteric femur fractures] in women using [bisphosphonates].” J.A. 520. It was only in October 2010—

after an external task force had completed its report on

the issue—that FDA came to “believe that the information” about atypical femoral fractures should be

added to the Warnings and Precautions section and

therefore invoked Section 355(o)(4) to revise the labeling for Fosamax and other bisphosphonates. See J.A.

527-528; see also pp. 10-12, supra.

In short, FDA’s 2009 Complete Response Letter

rejecting petitioner’s PAS proposal to update Fosamax’s Warnings and Precautions section, when read in

the proper context of the governing statutory and regulatory regime—as well as FDA’s subsequent regulatory actions regarding Fosamax—demonstrate that, in

FDA’s judgment, an update to Fosamax’s Warnings and

Precautions section to discuss atypical femoral fractures would not have been called for before late 2010.

Accordingly, it would have been impossible under federal law for petitioner to provide such a warning at an

earlier time. Any state-law failure-to-warn claim predicated on a state-law duty to provide such a warning is

therefore preempted.

CONCLUSION

The judgment of the court of appeals should be

reversed and the case remanded for further proceedings.

Respectfully submitted.

BRIAN R. STIMSON**

Principal Deputy General

Counsel

ELIZABETH H. DICKINSON

Deputy Associate General

Counsel

ANNAMARIE KEMPIC

Deputy Chief Counsel,

Litigation

KAREN E. SCHIFTER

Senior Counsel

Department of Health and

Human Services

JEFFREY B. WALL*

Acting Solicitor General

JOSEPH H. HUNT

Assistant Attorney General

EDWIN S. KNEEDLER

Deputy Solicitor General

ANTHONY A. YANG

Assistant to the Solicitor

General

SCOTT R. MCINTOSH

JOSHUA M. SALZMAN

Attorneys

SEPTEMBER 2018

Solicitor General Noel J. Francisco is recused from this matter.

General Counsel Robert P. Charrow is recused from this matter.

This is a copy of a public record, reproduced as it was published. It is not legal advice, and it may not be the version a court would rely on. Check the official source before you cite it.